WO2022087018A1 - Improved fluorouracil-based multi-agent chemotherapy for treatment of metastatic colorectal cancer - Google Patents

Improved fluorouracil-based multi-agent chemotherapy for treatment of metastatic colorectal cancer Download PDF

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Publication number: WO2022087018A1
Authority: WO; WIPO (PCT)
Prior art keywords: administered; day; human; inhibitor; cdk4
Prior art date: 2020-10-19

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PCT/US2021/055681

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English (en)

French (fr)

Inventor

Jessica A. SORRENTINO

Rajesh Kumar MALIK

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G1 Therapeutics, Inc.

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2020-10-19

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2021-10-19

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2022-04-28

2021-10-19 Application filed by G1 Therapeutics, Inc. filed Critical G1 Therapeutics, Inc.

2022-04-28 Publication of WO2022087018A1 publication Critical patent/WO2022087018A1/en

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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/22—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against growth factors ; against growth regulators
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum

Definitions

This invention is in the area of improved colorectal cancer treatment protocols that provide reduced toxicity compared to currently used regimens, including reduced chemotherapy -induced myelosuppression (CIM), diarrhea, mucositis, and/or stomatitis, while in some embodiments also improving anti-cancer efficacy.
the improved protocols incorporate a highly selective, transient cyclin dependent kinase (CDK) 4/6 inhibitor into the colorectal cancer treatment protocol, allowing for the expanded use of these effective fluorouracil-based multi-agent chemotherapies, for example but not limited to FOLFOXIRI and FOLFIRINOX, into patient populations previously excluded from these protocols.
CDK transient cyclin dependent kinase
Fluorouracil-based multi-agent chemotherapy remains the cornerstone of treatment for metastatic disease and almost all patients will receive some combination of fluorouracil (5-FU), folinic acid (e.g., leucovorin or levoleucovorin), oxaliplatin, and/or irinotecan, and either a monoclonal antibody (mAb) targeting the VEGF pathway, for example bevacizumab or, for those with KRAS wild type and BRAF wild type disease, or a mAb targeting the EGFR pathway, for example cetuximab or panitumumab.
mAb monoclonal antibody
FOLFOX fluorescence-activated FOLFOX
folinic acid e.g., leucovorin or levoleucovorin
FOLFIRI FOLFIRI
folinic acid e.g., leucovorin or levoleucovorin
irinotecan FOLFIRI
the patient Upon progression on this therapy, the patient then received the alternative therapy. For example, if a patient started on FOLFOX/mAb, they would be switched to FOLFIRI/m Ab upon progression on FOLFOX/mAb, and vice-versa.
FOLFOXIRI folinic acid (e.g., leucovorin or, alternatively levoleucovorin), oxaliplatin, and irinotecan; and a further modified protocol termed FOLFIRINOX) — now, indicate that four drugs are better than three with respect to anti-tumor efficacy in metastatic colorectal cancer (mCRC).
mCRC metastatic colorectal cancer
FOLFOXIREbevacizumab was statistically significantly better than FOLFOX/bevacizumab at prolonging median PFS (12.4 months vs 9.3 months) (Sastre et al., Randomized phase III study comparing FOLFOX + bevacizumab versus FOLFOXIRI + bevacizumab (BEV) as 1st line treatment in patients with metastatic colorectal cancer (mCRC) with >3 baseline circulating tumor cells (bCTCs). J Clin Oncol. 2019;37: suppl abstract 3507).
FOLFOXIRI protocol has shown significantly better progression free survival (PFS) and overall survival (OS) compared to either FOLFOX or FOLFIRI, such improvements, however, have come at the expense of increased chemotherapy -induced toxicity (see Montagnani et al., A systematic review of FOLFOXIRI chemotherapy for the first-line treatment of metastatic colorectal cancer: improved efficacy at the cost of increased toxicity. Colorectal Dis. 2011; 13: 846-52). Although the toxicities associated with FOLFOX and FOLFIRI treatment protocols are significant, the toxicities associated with FOLFOXIRI are significantly more severe.
CIM chemotherapy-induced myelosuppression
CIM commonly leads to dose reductions and delays, which limit therapeutic dose intensity and can compromise the anti-tumor efficacy benefits of fluorouracil -based multi-agent chemotherapy.
CID chemotherapy-induced diarrhea
Findings in such patients include volume depletion, renal failure, and electrolyte disorders such as metabolic acidosis and depending upon water intake, hyponatremia (increased water intake that cannot be excreted because of the hypovolemic stimulus to the release of antidiuretic hormone) or hypernatremia (insufficient water intake to replace losses)
hyponatremia increased water intake that cannot be excreted because of the hypovolemic stimulus to the release of antidiuretic hormone
hypernatremia insufficient water intake to replace losses
CID can interfere with and detract from cancer treatment by causing dosing delays or reductions which may have an impact on survival.
Stomatitis/mucositis is a result of the toxic effect of chemotherapeutics on the rapidly dividing epithelial cells lining the gastro-intestinal tract (which goes from the mouth to the anus), leaving the mucosal tissue open to ulceration and infection.
Stomatitis/mucositis generally begins 5-10 days following the initiation of chemotherapy and lasts anywhere from one week to six weeks or more.
Many patients with stomatitis/mucositis develop significant nutritional issues due to the inability to eat because of the associated pain, leading to hypovolemia, electrolyte abnormalities, malnutrition, and even death. Severe stomatitis/mucositis often results in dose reductions of or interruptions to the therapeutic protocol.
FOLFOXIRI and FOLFIRINOX fluorouracil -based multi-agent chemotherapy administration
CIM chemotherapy-induced myelosuppression
diarrhea stomatitis
mucositis can influence the risk/benefit ratio of fluorouracil -based multi-agent chemotherapy administration
FOLFOXIRI and FOLFIRINOX their use is frequently limited to younger patients with fewer comorbidities and in need of aggressive cytoreduction surgery.
Most clinical trials evaluating FOLFOXIRI specifically exclude patients over 70 years of age with an Eastern Cooperative Oncology Group (ECOG) performance status other than 0 (fully active, able to carry on all pre-disease performance without restriction).
ECOG Eastern Cooperative Oncology Group
the median age for colon cancer detection is 68 in men and 72 in women suggesting that a substantially large portion of those diagnosed will not be considered for more aggressive fluorouracil-based multi-agent chemotherapy regimens such as FOLFOXIRI.
FOLFOXIRI fluorouracil-based multi-agent chemotherapy regimens
prolonged exposure to the cytotoxic chemotherapeutic agents comprising fluorouracil-based multi-agent chemotherapy regimens such as FOLFOXIRI can lead to cumulative bone marrow toxicity and myelosuppression that can limit the ability to deliver subsequent lines of therapy at the standard of care doses and schedule.
the present invention provides improved fluorouracil-based multi-agent chemotherapy protocols for treating colorectal cancer in a human subject by incorporating into the protocol the selective, short-acting, and transient CDK4/6 inhibitor trilaciclib, or a pharmaceutically acceptable salt thereof, which provides for the reduction of chemotherapy associated side-effects, including chemotherapy-induced myelosuppression (CIM) and gastrointestinal toxicities.
the present invention provides improved anti-cancer efficacy, progression free survival, and/or overall survival.
the protocol can be more safely administered at the standard of care dose and schedule.
current treatments for CIM such as the administration of an erythropoiesis-stimulating agent (ESA) and/or granulocyte-colony stimulating factor (G-CSF) are hematological lineage specific and used after the damage to hematopoietic stem and progenitor cells (HSPCs) has already occurred — placing patients at risk for the development of additional toxicities associated with the administration of these CIM treatments — incorporation of trilaciclib into the fluorouracil-based multi-agent chemotherapy protocols prevents or limits damage to hematopoietic stem and progenitor cells (HSPCs) and therefore associated CIM, thus resulting in an overall improved safety profile and reduced use of standard hematological lineage specific treatments.
ESA erythropoiesis-stimulating agent
G-CSF granulocyte-colony stimulating factor
FOLFOXIRI e.g., those individuals over 70 years of age with an ECOG performance status other than 0 — can receive these protocols safely. This is especially significant in protocols such as FOLFOXIRI and FOLFIRINOX, as FOLFOXIRI and FOLFIRINOX are more efficacious than either FOLFOX or FOLFIRI, but may be less tolerated by older, sicker patients.
trilaciclib is also capable of enhancing the anti-cancer effect of these protocols in certain patient subgroups having colorectal tumors that may be immunologically susceptible to immune suppression.
metastatic colorectal cancer can have variable tumor-immune microenvironment across the patient population, allowing the tumor to be immunologically classified as immunologically hot, altered, and cold based on immune effector cell populations and the presence or absence of certain immunogenic biomarkers and signals, which correlate with prognosis and relapse (see Camus et al., Coordination of intratumoral immune reaction and human colorectal cancer recurrence, Cancer Research 69, 2685-2693 (2009), incorporated herein by reference).
a fluorouracil-based multi-agent chemotherapy protocol employs an agent associated with the induction of immunogenic cell death (ICD), including 5-FU (or a 5-FU derivative, analog, or pro-drug), irinotecan and/or oxaliplatin (see Ruan et al., Immunogenic cell death in colon cancer prevention and therapy. Molecular Carcinogenesis 2020; 59:783-793).
ICD immunogenic cell death
ICD is a form of regulated cell death apoptosis that induces the release of tumor associated antigens and is capable of triggering an anti-tumor immune response, and involves the release of damage-associated molecular pathways (DAMPS) that alert the host’s immune system that the cell is damaged (see Locy et al., immunomodulation of the tumor microenvironment: turn foe into friend: Frontiers in Immunology, 2018; 9:2020; Wang et al., Immunogenic effects of chemotherapy induced tumor cell death. Genes & Diseases (2016) 5, 194- 203).
DAMPS damage-associated molecular pathways
trilaciclib to fluorouracil-based multi-agent chemotherapy, which includes one or more ICD-inducing chemotherapeutic agents, in addition to reducing CIM and other toxi cities, may enhance quality of life and/or anti -turn or efficacy and increase the progression free survival and/or overall survival in patients having immunologically hot or altered tumors due to trilaciclib’ s preservation of immune effector cells during chemotherapy and differential G1 arrest of cytotoxic T-cells (CTLs) and regulatory T-cells (Tregs), which allows a faster recovery of cytotoxic T-cells from G1 arrest compared with regulatory T-cells in the tumor microenvironment.
CTLs cytotoxic T-cells
Regs regulatory T-cells
trilaciclib may play an important role in expanding anti-tumor T-cell subsets during treatment, and inducing an immune mediated response.
this improved immune mediated response occurs without the addition of an immune checkpoint inhibitor, for example an anti-PD-1, anti-PD-Ll, or anti-CTLA4 agent such as an antibody.
an immune checkpoint inhibitor for example an anti-PD-1, anti-PD-Ll, or anti-CTLA4 agent such as an antibody.
the present invention provides a method of treating a human subject having colorectal cancer, including metastatic colorectal cancer, comprising administering to the subject an effective amount of trilaciclib and fluorouracil-based multi-agent chemotherapy, wherein the trilaciclib is administered prior to receiving a chemotherapeutic agent administered during the protocol.
trilaciclib is added to a FOLFOX-based regimen.
the FOLFOX regimen generally includes the administration of 5-FU, folinic acid (e.g., leucovorin or levoleucovorin, or similar acting folinate salt), and oxaliplatin.
5-FU is administered either as a continuous infusion, or as both a bolus administration and a continuous infusion, wherein the continuous infusion is administered over, for example 22 hours a day for 2 days, or over between about 44 and 48 hours over 2-days.
FOLFOX regimens used in the treatment of colorectal cancer and suitable for inclusion of trilaciclib include FOLFOX4, FOLFOX6, modified FOLFOX6 (mFOLFOX6), FOLFOX7, and modified FOLFOX7 (mFOLFOX7).
the various FOLFOX protocols provide variations in dosing and/or administration timing.
An anti-VEGF or anti-EGFR monoclonal antibody or compound may also be administered in the various FOLFOX protocols.
trilaciclib is administered a first time about 4 hours or less prior to the initiation of the FOLFOX protocol, and a second time between 18 and 26 hours after the first administration.
a 5-FU prodrug is administered instead of 5-FU.
trilaciclib is added to a FOLFIRI-based regimen.
the FOLFIRI regimen generally includes the administration of 5-FU, folinic acid (e.g., leucovorin or levoleucovorin, or similar acting folinate salt), and irinotecan, wherein 5-FU is administered as either a continuous infusion, or both a bolus administration and a continuous infusion, wherein the continuous infusion is administered over, for example 22 hours a day for 2 days, or over between about 44 and 48 hours over 2-days.
a modification of the FOLFIRI protocol has been administered to colorectal patients providing variations in dosing and/or administration timing.
an anti-VEGF or anti-EGFR monoclonal antibodies may also be administered in the various FOLFIRI protocols.
trilaciclib is administered a first time about 4 hours or less prior to the initiation of the FOLFIRI protocol, and a second time between 18 and 26 hours after the first administration.
a 5-FU prodrug is administered instead of 5-FU.
trilaciclib is added to a FOLFOXIRI-based regimen.
the FOLFOXIRI regimen comprises 5-FU, folinic acid (e.g., leucovorin or levoleucovorin, or similar acting folinate salt), oxaliplatin, and irinotecan, wherein 5-FU is administered as a continuous infusion over between about 44 and 48 hours over 2-days.
folinic acid e.g., leucovorin or levoleucovorin, or similar acting folinate salt
oxaliplatin e.g., oxaliplatin
irinotecan e.g., 5-FU is administered as a continuous infusion over between about 44 and 48 hours over 2-days.
Modification of the FOLFOXIRI protocol have been administered to colorectal patients involving variations to dosing and/or administration timing.
An anti-VEGF or anti-EGFR monoclonal antibody or compound may also be administered in the various FOLFOXIRI protocols.
the trilaciclib- FOLFOXIRI-based regimen is administered to a patient previously ineligible for FOLFOXIRI administration, including, but not limited to, a patient over 70 years of age with an ECOG > 1.
trilaciclib is administered a first time about 4 hours or less prior to the initiation of the FOLFOXIRI protocol, and a second time between 18 and 26 hours after the first administration.
a 5-FU prodrug is administered instead of 5-FU.
trilaciclib is added to a FOLFIRINOX-based regimen.
the FOLFIRINOX regimen comprises 5-FU, folinic acid (e.g., leucovorin or levoleucovorin, or similar acting folinate salt), oxaliplatin, and irinotecan, wherein 5-FU is administered as both a bolus administration and a continuous infusion, wherein the continuous infusion is administered over between about 44 and 48 hours over 2-days.
Modification of the FOLFIRINOX protocol have been administered to colorectal patients involving variations to dosing and/or administration timing.
An anti-VEGF or anti-EGFR monoclonal antibody or compound may also be administered in the various FOLFIRI protocols.
the trilaciclib-FOLFOXIRI-based regimen is administered to a patient previously ineligible for FOLFIRINOX administration, including, but not limited to, a patient over 70 years of age with an ECOG > 1.
trilaciclib is administered a first time about 4 hours or less prior to the initiation of the FOLFIRINOX protocol, and a second time between 18 and 26 hours after the first administration.
a 5-FU prodrug is administered instead of 5-FU.
the colorectal cancer treated is metastatic colorectal cancer (mCRC).
the metastatic colorectal cancer is proficient mismatch repair (pMMR) mCRC.
the metastatic colorectal cancer is microsatellite stable (MSS) mCRC.
the metastatic colorectal cancer is proficient mismatch repair (pMMR)/microsatellite stable (MSS) mCRC (pMMR/MSS mCRC).
the pMMR/MSS mCRC has not been responsive to a previous treatment with a single agent checkpoint inhibitor.
the mCRC has a BRAF or KRAS mutation.
the BRAF mutation is a V600E substitution mutation.
the colorectal cancer is CDK4/6 replication dependent. In some embodiments, the colorectal cancer is CDK4/6 replication independent. In some embodiments, the colorectal cancer is CDK4/6 replication indeterminate.
the subject being treated has a tumor that exhibits specific characteristics as described herein according to the Ayer’s interferon-y signature, the Ayer’s expanded immune signature or the Thorsson et al Six Class Immune Signature.
the tumor has is interferon-y (IFN-y) dominant according to Thorsson’ s Six Class Immune Signature, or a high IFN-y signature or expanded immune signature according to the Ayer’s IFN-y Signature Score or Expanded Immune Signature Score.
the cancer is PD-L1 positive.
the inclusion of trilaciclib in the protocol results in a reduction and/or prevention in one or more fluorouracil-based multi-agent chemotherapy-associated toxicities, for example, but not limited to, chemotherapy-induced myelosuppression (CIM), chemotherapy-induced diarrhea (CID), stomatitis, and/or mucositis.
the inclusion of trilaciclib results in an improvement in progression free survival (PFS) in comparison to the predicted PFS based on administration of fluorouracil-based multi-agent chemotherapy without the inclusion of trilaciclib.
PFS progression free survival
the inclusion of trilaciclib results in an improvement in overall survival (OS) in comparison to the predicted OS based on administration of fluorouracil-based multi-agent chemotherapy alone.
the subject has not received a prior chemotherapeutic regimen for the treatment of the colorectal cancer. In some embodiments, the subject has failed prior chemotherapeutic regimen for the treatment of colorectal cancer.
the trilaciclib/fluorouracil-based multi-agent chemotherapy is administered in a cycle every 14 days. In some embodiments, the trilaciclib/fluorouracil-based multi-agent chemotherapy is administered in 3 or more induction cycles, 4 or more induction cycles, 5 or more induction cycles, 6 or more induction cycles, 7 or more induction cycles, 8 or more induction cycles, 9 or more induction cycles, 10 or more induction cycles, or 11 or more induction cycles.
the trilaciclib/fluorouracil-based multi-agent chemotherapy is administered up to 12 times.
the subject is further administered a maintenance regimen of trilaciclib, 5-FU, and a folinic acid (e.g., leucovorin or levoleucovorin, or similar acting folinate salt) following cessation of the trilaciclib/fluorouracil-based multi-agent chemotherapy induction protocol.
the subj ect maintains an absolute neutrophil count (ANC) of greater than 1.0 x 10 9 /L when measured prior to the beginning of each trilaciclib/fluorouracil-based multi-agent chemotherapy treatment cycle.
the subject maintains a platelet count of greater than 75 x 10 9 /L when measured prior to the beginning of each trilaciclib/fluorouracil-based multi-agent chemotherapy treatment cycle.
a method of treating a human subject with colorectal cancer comprising: i) administering to the subject an effective amount of trilaciclib; ii) administering to the subject an effective amount of 5-FU; iii) administering to the subject an effective amount of folinic acid (e.g., leucovorin or levoleucovorin, or similar acting folinate salt); iv) administering to the subject an effective amount of oxaliplatin and/or irinotecan; and, v) optionally administering to the subject an anti-VEGF or anti-EGFR monoclonal antibody or compound; wherein the trilaciclib is administered prior to the initiation of administration of the 5-FU, folinic acid, and oxaliplatin and/or irinotecan.
trilaciclib is administered prior to the initiation of administration of the 5-FU, folinic acid, and oxaliplatin and/or irinotecan.
the trilaciclib is administered about 4 hours or less prior to the administration of the 5-FU, folinic acid, and oxaliplatin and/or irinotecan. In some embodiments, the trilaciclib is administered a first time about 4 hours or less prior to the administration of the 5-FU, folinic acid, and oxaliplatin and/or irinotecan, and a second time between 18 and 26 hours after the first administration. In some embodiments, the trilaciclib is administered a first time about 4 hours or less prior to the administration of the 5-FU, and a second time between 18 and 26 hours after the first administration. In some embodiments, the subject is further administered an anti-VEGF or an anti-EGFR antibody or compound.
the subject is administered an anti-VEGF antibody selected from bevacizumab, bevacizumab-awwb, ramucirumab, or ziv-aflibercept.
the subject is administered an anti-EGFR antibody selected from cetuximab or panitumumab.
the subject is administered oxaliplatin.
the subject is administered irinotecan.
the subject is administered both irinotecan and oxaliplatin.
the folinic acid is leucovorin. In some embodiments, the folinic acid is levoleucovorin.
a folinate salt with a similar mechanism of action as leucovorin or levoleucovorin is administered instead of leucovorin or levoleucovorin.
a 5-FU prodrug is administered instead of 5-FU.
a method of treating a human subject with colorectal cancer comprising: i) administering to the subject on day 1 and day 2 of each 14-day cycle an effective amount of trilaciclib; ii) administering to the subject on day 1 and day 2 of each 14-day cycle an effective amount of 5-FU, wherein the 5-FU is administered as a continuous infusion (CI) over a period of between about 20 and 24 hours, or iii) administering to the subject on day 1 and day 2 of each 14-day cycle an effective amount of folinic acid (e.g., leucovorin or levoleucovorin, or similar acting folinate salt); and, iv) administering to the subject on day 1 of each 14-day cycle an effective amount of oxaliplatin; and, v) optionally administering to the subject on day 1 of each 14-day cycle an anti-VEGF or anti-EGFR monoclonal antibody or compound; wherein
the subject is further administered an anti-VEGF or an anti-EGFR antibody or compound on day 1 of each 14-day cycle.
anti-VEGF antibody is selected from bevacizumab, bevacizumab-awwb, ramucirumab, or ziv-aflibercept
the anti- EGFR antibody is cetuximab or panitumumab.
the subject is administered up to 12 cycles of the protocol above.
the subject is further administered one or more maintenance cycles of trilaciclib, 5-FU, and folinic acid on the same schedule above, following cessation of the protocol above.
the folinic acid is leucovorin.
the folinic acid is levoleucovorin.
a folinate salt with a similar mechanism of action as leucovorin or levoleucovorin is administered instead of leucovorin or levoleucovorin.
a 5-FU prodrug is administered instead of 5-FU.
a method of treating a human subject with colorectal cancer comprising one or more 14-day cycles comprising: i) administering to the subject on day 1 and day 2 of each 14-day cycle an effective amount of trilaciclib; ii) administering to the subject on day 1 of each 14-day cycle an effective amount of 5-FU, wherein the 5-FU is administered as a bolus intravenous injection; iii) administering to the subject starting on day 1 of each 14-day cycle an effective amount of 5-FU, wherein the 5-FU is administered as a continuous infusion (CI) over a period of between about 44 and 48 hours; iv) administering to the subject on day 1 of each 14-day cycle an effective amount of folinic acid (e.g., leucovorin or levoleucovorin, or similar acting folinate salt); and, v) administering to the subject on day 1 of each 14-day cycle an effective amount of oxaliplatin; and, vi) optionally administering to the
the trilaciclib is administered a first time about 4 hours or less prior to the administration of the 5-FU, and a second time between 18 and 26 hours after the first administration.
trilaciclib is administered on day 2 between about 20 and 24 hours after its administration on day 1.
the trilaciclib is administered on day 2 of each cycle between about 20 and 22 hours after its administration on day 1 of each cycle. The day 2 infusion of trilaciclib is being administered to ensure that synchronization and release of the HSPC G1 arrest (-24-32 hours after a single dose of trilaciclib) does not occur while 5FU is at sufficient concentrations such that 5FU-related myelosuppression is exacerbated rather than mitigated.
the subject is further administered an anti-VEGF or an anti- EGFR antibody or compound on day 1 of each 14-day cycle.
anti-VEGF antibody is selected from bevacizumab, bevacizumab-awwb, ramucirumab, or ziv-aflibercept, and the anti-EGFR antibody is cetuximab or panitumumab.
the subject is administered up to 12 cycles of the protocol above.
the subject is further administered one or more maintenance cycles of trilaciclib, 5-FU, and folinic acid on the same schedule above following cessation of the protocol above.
the folinic acid is leucovorin.
the folinic acid is levoleucovorin.
a folinate salt with a similar mechanism of action as leucovorin or levoleucovorin is administered instead of leucovorin or levoleucovorin.
a 5- FU prodrug is administered instead of 5-FU.
a method of treating a human subject with colorectal cancer comprising: i) administering to the subject on day 1 and day 2 of each 14-day cycle an effective amount of trilaciclib; ii) administering to the subject starting on day 1 of each 14-day cycle an effective amount of 5-FU, wherein the 5-FU is administered as a continuous infusion (CI) over a period of between about 44 and 48 hours; iii) administering to the subject on day 1 of each 14-day cycle an effective amount of folinic acid (e.g., leucovorin or levoleucovorin, or similar acting folinate salt); and, iv) administering to the subject on day 1 of each 14-day cycle an effective amount of oxaliplatin; and, v) optionally administering to the subject on day 1 of each 14-day cycle an anti-VEGF or anti-EGFR monoclonal antibody or compound; wherein the trilaciclib is administered about
the trilaciclib is administered a first time about 4 hours or less prior to the administration of the 5-FU, and a second time between 18 and 26 hours after the first administration.
trilaciclib is administered on day 2 between about 20 and 24 hours after its administration on day 1.
the trilaciclib is administered on day 2 of each cycle between about 20 and 22 hours after its administration on day 1 of each cycle. The day 2 infusion of trilaciclib is being administered to ensure that synchronization and release of the HSPC G1 arrest (-24-32 hours after a single dose of trilaciclib) does not occur while 5FU is at sufficient concentrations such that 5-FU-related myelosuppression is exacerbated rather than mitigated.
the subject is further administered an anti-VEGF or an anti- EGFR antibody or compound on day 1 of each 14-day cycle.
anti-VEGF antibody is selected from bevacizumab, bevacizumab-awwb, ramucirumab, or ziv-aflibercept, and the anti-EGFR antibody is cetuximab or panitumumab.
the subject is administered up to 12 cycles of the protocol above.
the subject is further administered one or more maintenance cycles of trilaciclib, 5-FU, and folinic acid (e.g., leucovorin or levoleucovorin), on the same schedule as the protocol above following cessation of the protocol above.
the folinic acid is leucovorin. In some embodiments, the folinic acid is levoleucovorin. In alternative embodiments, a folinate salt with a similar mechanism of action as leucovorin or levoleucovorin is administered instead of leucovorin or levoleucovorin. In some alternative embodiments, a 5-FU prodrug is administered instead of 5-FU.
a method of treating a human subject with colorectal cancer comprising: i) administering to the subject on day 1 and day 2 of each 14-day cycle an effective amount of trilaciclib; ii) administering to the subject on day 1 of each 14-day cycle an effective amount of 5-FU, wherein the 5-FU is administered as a bolus intravenous injection; iii) administering to the subject starting on day 1 of each 14-day cycle an effective amount of 5-FU, wherein the 5-FU is administered as a continuous infusion (CI) over a period of between about 44 and 48 hours; iv) administering to the subject on day 1 of each 14-day cycle an effective amount of folinic acid (e.g., leucovorin or levoleucovorin, or similar acting folinate salt); and, v) administering to the subject on day 1 of each 14-day cycle an effective amount of irinotecan; and, vi) optionally administer
the trilaciclib is administered a first time about 4 hours or less prior to the administration of the 5-FU, and a second time between 18 and 26 hours after the first administration.
the trilaciclib is administered on day 2 of each cycle between about 20 and 24 hours after its administration on day 1 of each cycle.
the trilaciclib is administered on day 2 of each cycle between about 20 and 22 hours after its administration on day 1 of each cycle. The day 2 infusion of trilaciclib is being administered to ensure that synchronization and release of the HSPC G1 arrest (-24-32 hours after a single dose of trilaciclib) does not occur while 5-FU is at sufficient concentrations such that 5-FU-related myelosuppression is exacerbated rather than mitigated.
the subject is further administered an anti-VEGF or an anti-EGFR antibody or compound on day 1 of each 14-day cycle.
anti-VEGF antibody is selected from bevacizumab, bevacizumab-awwb, ramucirumab, or ziv-aflibercept, and the anti-EGFR antibody is cetuximab or panitumumab.
the subject is administered up to 12 cycles of the protocol above.
the subject is further administered one or more maintenance cycles of trilaciclib, 5-FU, and folinic acid on the same schedule as the above protocol following cessation of the protocol above.
the folinic acid is leucovorin.
the folinic acid is levoleucovorin.
a folinate salt with a similar mechanism of action as leucovorin or levoleucovorin is administered instead of leucovorin or levoleucovorin.
a 5-FU prodrug is administered instead of 5- FU.
a method of treating a human subject with colorectal cancer comprising: i) administering to the subject on day 1 and day 2 of each 14-day cycle an effective amount of trilaciclib; ii) administering to the subject starting on day 1 of each 14-day cycle an effective amount of 5-FU, wherein the 5-FU is administered as a continuous infusion (CI) over a period of between about 44 and 48 hours; iii) administering to the subject on day 1 of each 14-day cycle an effective amount of folinic acid (e.g., leucovorin or levoleucovorin, or similar acting folinate salt); and, iv) administering to the subject on day 1 of each 14-day cycle an effective amount of irinotecan; and v) optionally administering to the subject on day 1 of each 14-day cycle an anti-VEGF or anti-EGFR monoclonal antibody or compound; wherein the trilaciclib is administered about 4
the trilaciclib is administered a first time about 4 hours or less prior to the administration of the 5-FU, and a second time between 18 and 26 hours after the first administration.
the trilaciclib is administered on day 2 of each cycle between about 20 and 24 hours after its administration on day 1 of each cycle.
the trilaciclib is administered on day 2 of each cycle between about 20 and 22 hours after its administration on day 1 of each cycle. The day 2 infusion of trilaciclib is being administered to ensure that synchronization and release of the HSPC G1 arrest (-24-32 hours after a single dose of trilaciclib) does not occur while 5FU is at sufficient concentrations such that 5FU-related myelosuppression is exacerbated rather than mitigated.
the subject is further administered an anti-VEGF or an anti-EGFR antibody or compound on day 1 of each 14-day cycle.
anti-VEGF antibody is selected from bevacizumab, bevacizumab-awwb, ramucirumab, or ziv-aflibercept, and the anti-EGFR antibody is cetuximab or panitumumab.
the subject is administered up to 12 cycles of the protocol above.
the subject is further administered one or more maintenance cycles of trilaciclib, 5-FU, and folinic acid, on the same schedule above following cessation of the protocol above.
the folinic acid is leucovorin.
the folinic acid is levoleucovorin.
a folinate salt with a similar mechanism of action as leucovorin or levoleucovorin is administered instead of leucovorin or levoleucovorin.
a 5-FU prodrug is administered instead of 5-FU.
a method of treating a human subject with colorectal cancer comprising i) administering to the subject on day 1 and day 2 of each 14-day cycle an effective amount of trilaciclib; ii) administering to the subject starting on day 1 of each 14-day cycle an effective amount of 5-FU, wherein the 5-FU is administered as a continuous infusion (CI) over a period of between about 44 and 48 hours; iii) administering to the subject on day 1 of each 14-day cycle an effective amount of folinic acid (e.g., leucovorin or levoleucovorin, or similar acting folinate salt); iv) administering to the subject on day 1 of each 14-day cycle an effective amount of oxaliplatin; and, v) administering to the subject on day 1 of each 14-day cycle an effective amount of irinotecan; and, vi) optionally administering to the subject on day 1 of each 14-day cycle an
folinic acid e.g., leucovorin or
the trilaciclib is administered a first time about 4 hours or less prior to the administration of the 5-FU, and a second time between 18 and 26 hours after the first administration.
the trilaciclib is administered on day 2 of each cycle between about 20 and 24 hours after its administration on day 1 of each cycle.
the trilaciclib is administered on day 2 of each cycle between about 20 and 22 hours after its administration on day 1 of each cycle. The day 2 infusion of trilaciclib is being administered to ensure that synchronization and release of the HSPC G1 arrest (-24-32 hours after a single dose of trilaciclib) does not occur while 5FU is at sufficient concentrations such that 5FU-related myelosuppression is exacerbated rather than mitigated.
the subject is further administered an anti-VEGF or an anti-EGFR antibody or compound on day 1 of each 14-day cycle.
anti-VEGF antibody is selected from bevacizumab, bevacizumab-awwb, ramucirumab, or ziv-aflibercept, and the anti-EGFR antibody is cetuximab or panitumumab.
the subject is administered up to 12 cycles of the protocol above.
the subject is further administered one or more maintenance cycles of trilaciclib, 5-FU, and folinic acid on the same schedule above following cessation of the protocol above.
the folinic acid is leucovorin.
the folinic acid is levoleucovorin.
a folinate salt with a similar mechanism of action as leucovorin or levoleucovorin is administered instead of leucovorin or levoleucovorin.
a 5-FU prodrug is administered instead of 5-FU.
a method of treating a human subject with colorectal cancer comprising i) administering to the subject on day 1 and day 2 of each 14-day cycle an effective amount of trilaciclib; ii) administering to the subject on day 1 of each 14-day cycle an effective amount of 5-FU, wherein the 5-FU is administered as a bolus injection; iii) administering to the subject starting on day 1 of each 14-day cycle an effective amount of 5-FU, wherein the 5-FU is administered as a continuous infusion (CI) over a period of between about 44 and 48 hours beginning on day 1; iv) administering to the subject on day 1 of each 14-day cycle an effective amount of folinic acid (e.g., leucovorin levoleucovorin, or similar acting folinate salt); v) administering to the subject on day 1 of each 14-day cycle an effective amount of oxaliplatin; and, vi) administering to the subject
the trilaciclib is administered a first time about 4 hours or less prior to the administration of the 5-FU, and a second time between 18 and 26 hours after the first administration.
the trilaciclib is administered on day 2 of each cycle between about 20 and 24 hours after its administration on day 1 of each cycle.
the trilaciclib is administered on day 2 of each cycle between about 20 and 22 hours after its administration on day 1 of each cycle. The day 2 infusion of trilaciclib is being administered to ensure that synchronization and release of the HSPC G1 arrest (-24-32 hours after a single dose of trilaciclib) does not occur while 5FU is at sufficient concentrations such that 5-FU-related myelosuppression is exacerbated rather than mitigated.
the subject is further administered an anti-VEGF or an anti-EGFR antibody or compound on day 1 of each 14-day cycle.
anti-VEGF antibody is selected from bevacizumab, bevacizumab-awwb, ramucirumab, or ziv-aflibercept, and the anti-EGFR antibody is cetuximab or panitumumab.
the subject is administered up to 12 cycles of the protocol above.
the subject is further administered one or more maintenance cycles of trilaciclib, 5-FU, and folinic acid on the same schedule as the protocol above following cessation of the protocol above.
the folinic acid is leucovorin.
the folinic acid is levoleucovorin.
a folinate salt with a similar mechanism of action as leucovorin or levoleucovorin is administered instead of leucovorin or levoleucovorin.
a 5-FU prodrug is administered instead of 5- FU.
a method of treating a human subject with colorectal cancer comprising i) administering to the subject on day 1, day 8, day 15, day 22, day 29, and day 36 of each 56-day cycle an effective amount of trilaciclib; ii) administering to the subject on day 1, day 8, day 15, day 22, day 29, and day 36 of each 56-day cycle an effective amount of 5-FU, wherein the 5-FU is administered as a bolus injection; iii) administering to the subject on day 1, day 8, day 15, day 22, day 29, and day 36 of each 56-day cycle an effective amount of folinic acid (e.g., leucovorin or levoleucovorin, or similar acting folinate salt); iv) administering to the subject on day 1, day 15, and day 29 of each 56-day cycle an effective amount of oxaliplatin; and, v) optionally administering to the subject on day 1, day 15, and day 29 of each 56-day cycle an anti-VE
the treatment comprises one or more 56-day cycles comprising i) administer
the trilaciclib is administered about 4 hours or less prior to the administration of the 5-FU.
the subject is further administered an anti-VEGF or an anti-EGFR antibody or compound on day 1, day 15, and day 29 of each 56-day cycle.
the anti-VEGF antibody is selected from bevacizumab, bevacizumab-awwb, ramucirumab, or ziv-afhbercept
the anti- EGFR antibody is selected from cetuximab or panitumumab.
the subject is administered up to 3 cycles of the protocol above.
the subject is further administered one or more maintenance cycles of trilaciclib, 5-FU, and folinic acid on the same schedule as the protocol above following cessation of the protocol above.
the folinic acid is leucovorin.
the folinic acid is levoleucovorin.
a folinate salt with a similar mechanism of action as leucovorin or levoleucovorin is administered instead of leucovorin or levoleucovorin.
a 5-FU prodrug is administered instead of 5-FU.
the colorectal cancer treated in one of the 5 fluorouracil-based multi-agent protocols provided herein is metastatic colorectal cancer.
the cancer is selected from pancreatic cancer, gastric cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, neuroendocrine carcinoma, peritoneal carcinosis, or liver cancer.
the treatment results in a reduction and/or prevention in one or more fluorouracil -based multi-agent chemotherapy-associated toxicities, for example, chemotherapy- induced myelosuppression (CIM), chemotherapy-induced diarrhea (CID), stomatitis, and/or mucositis.
CIM chemotherapy- induced myelosuppression
CID chemotherapy-induced diarrhea
stomatitis stomatitis
mucositis a treatment-associated toxicities
the treatment results in an improvement in progression free survival (PFS) in comparison to the predicted PFS based on administration of the fluorouracilbased multi -agent chemotherapy regimen without trilaciclib.
the treatment results in an improvement in overall survival (OS) in comparison to the predicted OS based on administration of the fluorouracil -based multi-agent chemotherapy regimen without trilaciclib.
OS overall survival
the administration of a protocol described herein provides improved my el opreservation of hematopoietic stem and progenitor cells (HSPCs) and immune effector cells such as lymphocytes including T-lymphocytes.
HSPCs hematopoietic stem and progenitor cells
the administration of a protocol described herein provides enhanced anti -turn or efficacy in subjects compared to those receiving the fluorouracil-based multi-agent chemotherapy without trilaciclib.
the administration of a protocol described herein provides myelopreservation of the neutrophil lineage in subjects compared to those receiving fluorouracil-based multi -agent chemotherapy without trilaciclib.
the administration of a protocol described herein provides a reduction in the duration of severe (Grade 4) neutropenia in subjects compared to those receiving fluorouracil-based multi-agent chemotherapy without trilaciclib. In some embodiments, the administration of a protocol described herein provides a reduction of chemotherapy-induced fatigue (CIF) in subjects compared to those receiving fluorouracil-based multi-agent chemotherapy without trilaciclib. In some embodiments, the reduction of CIF is a reduction in the time to first confirmed deterioration of fatigue (TTCD-fatigue), as measured by the Functional Assessment of Cancer Therapy -Fatigue (FACIT-F).
TTCD-fatigue time to first confirmed deterioration of fatigue
the administration of a protocol described herein provides improved progression free survival (PFS) and/or overall survival (OS) in subjects compared to those receiving fluorouracil-based multiagent chemotherapy without trilaciclib.
PFS progression free survival
OS overall survival
an improvement in PFS is based on per Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1).
the administration of a protocol described herein provides a reduction in severe neutropenia events, a reduction in granulocyte-colony stimulating factor (G-CSF) treatment, or a reduction in febrile neutropenia (FN) adverse events (AEs).
G-CSF granulocyte-colony stimulating factor
FN febrile neutropenia
the administration of a protocol described herein provides a reduction in Grade 3 or 4 decreased hemoglobin laboratory values, red blood cell (RBC) transfusions, or erythropoiesis-stimulating agent (ESA) administration.
the administration of a protocol described herein provides a reduction in Grade 3 or 4 decreased platelet count laboratory values and/or the number of platelet transfusions.
the administration of a protocol described herein provides a reduction in Grade 3 or 4 hematologic laboratory values.
the administration of a protocol described herein provides a reduction in all -cause dose reductions or cycle delays and relative dose intensity for fluorouracil -based multi-agent chemotherapy.
the administration of a protocol described herein provides a reduction in i) hospitalizations, including but not limited to those due to all causes, febrile neutropenia/neutropenia, anemia/RBC transfusion, thrombocytopenia/bleeding and infections) or ii) antibiotic use, including but not limited to intravenous (IV), oral, and oral and IV administered antibiotics.
the administration of a protocol described herein provides an improvement to one or more of: Functional Assessment of Cancer Therapy-General (FACT-G) domain scores (physical, social/family, emotional, and functional well-being); Functional Assessment of Cancer Therapy- Anemia (FACT-An): Anemia; Functional Assessment of Cancer Therapy-colorectal cancer (FACT-C) : Colorectal Cancer Subscale; 5-level EQ-5D (EQ-5D-5L); Patient Global Impression of Change (PGIC) fatigue item; or Patient Global Impression of Severity (PGIS) fatigue item.
FACT-G Functional Assessment of Cancer Therapy-General
FACT-An Functional Assessment of Cancer Therapy- Anemia
FACT-C Functional Assessment of Cancer Therapy-colorectal cancer
PGIC Patient Global Impression of Change
PGIS Patient Global Impression of Severity
Fig. 1 A is a schematic of an exemplary FOLFOX4 protocol incorporating trilaciclib.
Trila trilaciclib
OX oxaliplatin
mAb anti-VEGF or anti-EGFR monoclonal antibody or compound
5-FU fluorouracil
LV leucovorin.
levoleucovorin can be substituted for leucovorin as the folinic acid, wherein levoleucovorin is administered at one-half the dose of leucovorin.
a folinate salt with a similar mechanism of action as leucovorin or levoleucovorin is administered instead of leucovorin or levoleucovorin.
Fig. IB is a schematic of an exemplary FOLFOX6 protocol incorporating trilaciclib.
Trila trilaciclib
OX oxaliplatin
mAb anti-VEGF or anti-EGFR monoclonal antibody or compound
5-FU fluorouracil
LV leucovorin.
levoleucovorin can be substituted for leucovorin as the folinic acid, wherein levoleucovorin is administered at one-half the dose of leucovorin.
a folinate salt with a similar mechanism of action as leucovorin or levoleucovorin is administered instead of leucovorin or levoleucovorin.
Fig. 1C is a schematic of an exemplary mFOLFOX6 protocol incorporating trilaciclib.
Trila trilaciclib
OX oxaliplatin
mAb anti-VEGF or anti-EGFR monoclonal antibody or compound
5-FU fluorouracil
LV leucovorin.
levoleucovorin can be substituted for leucovorin as the folinic acid, wherein levoleucovorin is administered at one-half the dose of leucovorin.
a folinate salt with a similar mechanism of action as leucovorin or levoleucovorin is administered instead of leucovorin or levoleucovorin.
Fig. ID is a schematic of an exemplary FOLFOX7 protocol incorporating trilaciclib.
Trila trilaciclib
OX oxaliplatin
mAb anti-VEGF or anti-EGFR monoclonal antibody or compound
5-FU fluorouracil
LV leucovorin.
levoleucovorin can be substituted for leucovorin as the folinic acid, wherein levoleucovorin is administered at one-half the dose of leucovorin.
a folinate salt with a similar mechanism of action as leucovorin or levoleucovorin is administered instead of leucovorin or levoleucovorin.
Fig. IE is a schematic of an exemplary mFOLFOX7 protocol incorporating trilaciclib.
Trila trilaciclib
OX oxaliplatin
mAb anti-VEGF or anti-EGFR monoclonal antibody or compound
5-FU fluorouracil
LV leucovorin.
levoleucovorin can be substituted for leucovorin as the folinic acid, wherein levoleucovorin is administered at one-half the dose of leucovorin.
a folinate salt with a similar mechanism of action as leucovorin or levoleucovorin is administered instead of leucovorin or levoleucovorin.
Fig. 2A is a schematic of an exemplary FOLFIRI protocol incorporating trilaciclib.
Trila trilaciclib
IR irinotecan
mAb anti-VEGF or anti-EGFR monoclonal antibody or compound
5-FU fluorouracil
LV leucovorin.
levoleucovorin can be substituted for leucovorin as the folinic acid, wherein levoleucovorin is administered at one-half the dose of leucovorin.
a folinate salt with a similar mechanism of action as leucovorin or levoleucovorin is administered instead of leucovorin or levoleucovorin.
Fig. 2B is a schematic of an exemplary mFOLFIRI protocol incorporating trilaciclib.
Trila trilaciclib
IR irinotecan
mAb anti-VEGF or anti-EGFR monoclonal antibody or compound
5-FU fluorouracil
LV leucovorin.
levoleucovorin can be substituted for leucovorin as the folinic acid, wherein levoleucovorin is administered at one-half the dose of leucovorin.
a folinate salt with a similar mechanism of action as leucovorin or levoleucovorin is administered instead of leucovorin or levoleucovorin.
Fig. 3A is a schematic of an exemplary FOLFOXIRI protocol incorporating trilaciclib.
Trila trilaciclib
IR irinotecan
OX oxaliplatin
mAb anti-VEGF or anti-EGFR monoclonal antibody or compound
5-FU fluorouracil
LV leucovorin.
Fig. 3B is a schematic of an alternative exemplary FOLFOXIRI protocol incorporating trilaciclib.
Trila trilaciclib
IR irinotecan
OX oxaliplatin
mAb anti-VEGF or anti-EGFR monoclonal antibody or compound
5-FU fluorouracil
LLV levoleucovorin.
Fig. 4A is a schematic of an exemplary FOLFIRINOX protocol incorporating trilaciclib.
Trila trilaciclib
IR irinotecan
OX oxaliplatin
mAb anti-VEGF or anti-EGFR monoclonal antibody or compound
5-FU fluorouracil
LV leucovorin.
Fig. 4B is a schematic of an exemplary FOLFIRINOX protocol incorporating trilaciclib.
Trila trilaciclib
IR irinotecan
OX oxaliplatin
mAb anti-VEGF or anti-EGFR monoclonal antibody or compound
5-FU fluorouracil
LLV levoleucovorin.
Fig. 5 is a schematic of an exemplary FLOX protocol incorporating trilaciclib.
Trila trilaciclib
OX oxaliplatin
mAb anti-VEGF or anti-EGFR monoclonal antibody or compound
5-FU fluorouracil
LV leucovorin.
levoleucovorin can be substituted for leucovorin as the folinic acid, wherein levoleucovorin is administered at one-half the dose of leucovorin.
a folinate salt with a similar mechanism of action as leucovorin or levoleucovorin is administered instead of leucovorin or levoleucovorin.
Fig. 6 is a reproduction of figure 3 found in Galon, J., and Bruni, D., Approaches to treat immune hot, altered and cold tumours with combination immunotherapies, Nature Reviews Drug Discovery (18), March 2019, 197-218, incorporated herein in its entirety, describing an immunogram for use as a tool to direct anticancer therapy. Cancers can be classified into four main subtypes (hot, altered- excluded, altered- immunosuppressed and cold) according to their associated T cell (CD3+ and CD8+) presence and distribution.
Hot cancers are defined by the simultaneous presence of immune contexture parameters: the cell type (CD3+, CD8+, follicular helper T (TFH), T helper 1 (TH1), memory and exhausted T cells); the location (invasive margin, tumor core and tertiary lymphoid structures); the density (immune density and quantity); and the functional immune orientation (chemokines, cytokines, cytotoxic factors, adhesion, attraction and TH1).
TSH follicular helper T
TH1 T helper 1
memory and exhausted T cells the location (invasive margin, tumor core and tertiary lymphoid structures); the density (immune density and quantity); and the functional immune orientation (chemokines, cytokines, cytotoxic factors, adhesion, attraction and TH1).
DORA2A A2A adenosine receptor
P m P2- microglobulin
BET bromodomain and extra-terminal motif proteins
BTLA B and T lymphocyte attenuator
CAR T-cell chimeric antigen receptor T-cell
CCR CC-chemokine receptor
CIN chromosomal instability, CSF1R, colony-stimulating factor 1 receptor
CTL A4 cytotoxic T lymphocyte-associated antigen
CXCL CXC-chemokine ligand
DDR DNA damage response
ECM extracellular matrix
EMT epithelial-mesenchymal transition
FDA US Food and Drug Administration
GITR glucocorticoid-induced TNFR-related protein
GM-CSF granulocyte-macrophage colonystimulating factor
HD AC histone de
Fig. 7A is a reproduction of Fig. 1 A found in Galon, J., and Bruni, D., Approaches to treat immune hot, altered and cold tumors with combination immunotherapies, Nature Reviews Drug Discovery (18), March 2019, 197-218, incorporated herein in its entirety, which illustrates examples of hot, altered and cold immune cancers.
Dark (3,3'-diaminobenzidine (DAB)) staining represents CD3+ T cells and lighter (alkaline phosphatase) counterstaining provides homogeneous tissue background staining.
CD3+ and CD8+ T cell infiltration differentiates four distinct solid tumor phenotypes: hot (or inflamed); altered, which can be excluded or immunosuppressed; and cold (or non- inflamed). These tumor phenotypes are characterized by high, intermediate, and low immunoscore, respectively.
Fig. 7B is a reproduction of Fig. IB found in Galon, J., and Bruni, D., Approaches to treat immune hot, altered and cold tumors with combination immunotherapies, Nature Reviews Drug Discovery (18), March 2019, 197-218, incorporated herein in its entirety, which is a schematic representation of the four subtypes of immune tumor.
CD3+ and CD8+ T cell infiltrates are low at the tumor center and high at the invasive margin, resulting overall in an intermediate immunoscore.
Altered- immunosuppressed tumors display instead a more uniform pattern of (low) CD3+ and CD8+ T cell infiltration.
CT center of tumor
Hi high
IM invasive margin
Lo low.
Fig. 8 is a schematic of a randomized, double-blind, placebo-controlled, global, multicenter, Phase 3 trial evaluating the impact of trilaciclib on myelopreservation and anti-tumor efficacy when administered prior to FOLFOXIRI/bevacizumab in patients with pMMR/MSS mCRC who have not received systemic therapy for metastatic disease.
improved methods and compositions for use in treating colorectal cancer including metastatic or advanced colorectal cancer.
improved fluorouracil-based multi-agent chemotherapy regimens such as FOLFOX, FOLFIRI, FOLFOXIRI, FOLFIRINOX, and FLOX that include the CDK4/6 inhibitor trilaciclib.
Trilaciclib is a highly potent and selective, reversible, CDK4/6 inhibitor that is typically administered intravenously (IV) prior to fluorouracil-based multi-agent chemotherapy administration, including but not limited to FOLFOXIRI or FOLFIRINOX, and is designed to preserve HSPCs during chemotherapy (myelo-preservation) and enhance anti-tumor immunity (anti-tumor efficacy). Both HSPC and lymphocyte populations are dependent on CDK4/6 activity for proliferation (see, e.g., Kozar et al., Mouse development and cell proliferation in the absence of D-cyclins. Cell. 2004;!
This transient, drug-induced, cell cycle arrest by trilaciclib provides protection from chemotherapy- induced cell damage during treatment by preventing HSPCs and immune effector cells from proliferating in the presence of cytotoxic chemotherapy and to favorably alter the tumor immune microenvironment through transient T cell inhibition when combined with ICD-chemotherapy.
immune effector cells Upon release of the transient G1 arrest, immune effector cells are positioned to respond to the increased antigenicity induced through the ICD-chemotherapeutic agents contained in these chemotherapeutic protocols.
trilaciclib may protect other CDK4/6-dependent replicating cells such as the epithelial lining of the gastro-intestinal tract from the harmful and toxic effects associated with these protocols, and reduce side effects such as mucositis/stomatitis.
a safer, less toxic fluorouracil-based multi-agent chemotherapy protocol for example FOLFOXIRI or FOLFIRINOX, allows for administration to patients previously excluded from these otherwise efficacious treatments, for example patients 70 years older with ECOG scores of 1 or greater.
the compound may be in the form of a racemate, enantiomer, mixture of enantiomers, diastereomer, mixture of diastereomers, tautomer, N-oxide, or isomer, such as a rotamer, as if each is specifically described unless specifically excluded by context.
the compound may be in the form of a tautomer, N-oxide, or isomer, such as a rotamer, as if each is specifically described unless specifically excluded by context.
an “effective amount” as used herein means an amount which provides a therapeutic or prophylactic benefit.
a disease as the term is used herein, means to reduce the frequency or severity of at least one sign or symptom of a disease, disorder, or side-effect experienced by a subject (i.e. palliative treatment) or to decrease a cause or effect of the disease, disorder (i.e. disease-modifying treatment), or side effect experienced by a subject as a result of the administration of a therapeutic agent.
compositions are compositions comprising at least one active agent, and at least one other substance, such as a carrier.
“Pharmaceutical combinations” are combinations of at least two active agents which may be combined in a single dosage form or provided together in separate dosage forms with instructions that the active agents are to be used together to treat any disorder described herein.
“pharmaceutically acceptable salt” is a derivative of the disclosed compound in which the parent compound is modified by making inorganic and organic, non-toxic, acid or base addition salts thereof.
the salts of the present compounds can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two.
salts of the present compounds further include solvates of the compounds and of the compound salts.
Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
the pharmaceutically acceptable salts include the conventional non-toxic salts and the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC-(CH2)n- COOH where n is 0-4, and the like, or using a different acid that produces the same counterion.
inorganic acids such as hydrochloric, hydrobromic, sulfuric
the term "prodrug” means a compound which when administered to a host in vivo is converted into the parent drug.
parent drug means any of the presently described chemical compounds that are useful to treat any of the disorders described herein, or to control or improve the underlying cause or symptoms associated with any physiological or pathological disorder described herein in a host, typically a human.
Prodrugs can be used to achieve any desired effect, including to enhance properties of the parent drug or to improve the pharmaceutic or pharmacokinetic properties of the parent.
Prodrug strategies exist which provide choices in modulating the conditions for in vivo generation of the parent drug, all of which are deemed included herein.
Nonlimiting examples of prodrug strategies include covalent attachment of removable groups, or removable portions of groups, for example, but not limited to acylation, phosphorylation, phosphonylation, phosphoramidate derivatives, amidation, reduction, oxidation, esterification, alkylation, other carboxy derivatives, sulfoxy or sulfone derivatives, carbonylation or anhydride, among others.
carrier applied to pharmaceutical compositions/combinations of the invention refers to a diluent, excipient, or vehicle with which an active compound is provided.
a “pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition/combination that is generally safe, and neither biologically nor otherwise inappropriate for administration to a host, typically a human.
an excipient is used that is acceptable for veterinary use.
trilaciclib can be used in a form that has at least one desired isotopic substitution of an atom, at an amount above the natural abundance of the isotope, i.e., enriched.
Isotopes are atoms having the same atomic number but different mass numbers, i.e., the same number of protons but a different number of neutrons.
isotopes that can be incorporated into trilaccilib for use in the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine and iodine such as 2H, 3H, 11C, 13C, 14C, 15N, 18F 31P, 32P, 35S, 36CI, and 1251 respectively.
isotopically labelled compounds can be used in metabolic studies (with 14C), reaction kinetic studies (with, for example 2H or 3H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
PET positron emission tomography
SPECT single-photon emission computed tomography
an 18F labeled compound may be particularly desirable for PET or SPECT studies.
Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
isotopes of hydrogen for example, deuterium (2H) and tritium (3H) may be used anywhere in described structures that achieves the desired result.
isotopes of carbon e.g., 13C and 14C, may be used.
Isotopic substitutions for example deuterium substitutions, can be partial or complete. Partial deuterium substitution means that at least one hydrogen is substituted with deuterium.
the isotope is 90, 95 or 99% or more enriched in an isotope at any location of interest. In one non-limiting embodiment, deuterium is 90, 95 or 99% enriched at a desired location.
Trilaciclib for use in the present invention may form a solvate with solvents (including water). Therefore, in one non-limiting embodiment, the invention includes a solvated form of trilaciclib.
solvate refers to a molecular complex of trilaciclib (including a salt thereof) with one or more solvent molecules.
solvents are water, ethanol, dimethyl sulfoxide, acetone and other common organic solvents.
hydrate refers to a molecular complex comprising a compound of the invention and water.
Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent may be isotopically substituted, e.g. D2O, d6-acetone, d6-DMSO.
a solvate can be in a liquid or solid form.
patient or “subject” treated is typically a human patient, although it is to be understood the methods described herein are effective with respect to other animals, such as mammals. More particularly, the term patient can include animals used in assays such as those used in preclinical testing including but not limited to mice, rats, monkeys, dogs, pigs and rabbits; as well as domesticated swine (pigs and hogs), ruminants, equine, poultry, felines, bovines, murines, canines, and the like.
animals used in assays such as those used in preclinical testing including but not limited to mice, rats, monkeys, dogs, pigs and rabbits; as well as domesticated swine (pigs and hogs), ruminants, equine, poultry, felines, bovines, murines, canines, and the like.
hematopoietic stem and progenitor cells includes, but are not limited to, long term hematopoietic stem cells (LT-HSCs), short term hematopoietic stem cells (ST-HSCs), hematopoietic progenitor cells (HPCs), multipotent progenitors (MPPs), oligodendrocyte pre-progenitors (OPPs), monocyte progenitors, granulocyte progenitors, common myeloid progenitors (CMPs), common lymphoid progenitors (CLPs), granulocyte-monocyte progenitors (GMPs), granulocyte progenitors, monocyte progenitors, and megakaryocyte-erythroid progenitors (MEPs), megakaryocyte progenitors, erythroid progenitors, HSC/MPPs (CD45dim/CD34+/CD38-), OPPs
LT-HSCs long term hematopo
Immune effector cell generally refers to an immune cell that performs one or more specific functions.
Immune effector cells are known in the art and include for example, but are not limited to, T-cells, including Naive T-cells, Memory T-cells, Activated T-cells (Thelper (CD4+) and Cytotoxic T cells (CD8+)), TH1 activated T-cells, TH2 activated T-cells, TH17 activated T-cells, Naive B cells, Memory B cells, plasmablasts, dendritic cells, monocytes, and natural killer (NK) cells.
T-cells including Naive T-cells, Memory T-cells, Activated T-cells (Thelper (CD4+) and Cytotoxic T cells (CD8+)
TH1 activated T-cells TH2 activated T-cells
TH17 activated T-cells
Naive B cells Memory B cells
Memory B cells plasmablasts
dendritic cells
ICI immune checkpoint inhibitor
ICIs include those targeting immune checkpoint proteins such as programmed cell death- 1 protein (PD-1), PD-1 Ligand- 1 (PD-L1), PD-1 Ligand-2 (PD-L2), CTLA-4, LAG-3, TIM-3, and V-domain Ig suppressor of T-cell activation (VISTA), B7- H3/CD276, indoleamine 2,3 -dioxygenase (IDO), killer immunoglobulin-like receptors (KIRs), carcinoembryonic antigen cell adhesion molecules (CEACAM) such as CEACAM-1, CEACAM- 3, and CEACAM-5, sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15), T cell immunoreceptor with Ig and ITIM domains (TIGIT), and B and T lymphocyte attenuator (BTLA) protein.
Immune checkpoint inhibitors are known in the art.
CRC Colorectal cancer
Colorectal cancer starts in the colon or the rectum. These cancers can also be called colon cancer or rectal cancer, depending on where they start. Adenocarcinomas of the colon and rectum make up 95 percent of all colorectal cancer cases. Other types include carcinoid tumors which involve the hormone-producing cells in the intestines, gastrointestinal stromal tumors which are soft tissue sarcomas which start in the blood vessels or connective tissue of the colon, and colorectal lymphoma.
CRC like numerous other solid tumors, is a heterogeneous disease in which different subtypes may be distinguished by their specific clinical and/or molecular features. Mutations in specific genes can lead to the onset of colorectal cancer, as happens in other types of cancer. Those mutations can appear in oncogenes, tumor suppressor genes and genes related to DNA repair mechanisms. Depending on the origin of the mutation, colorectal carcinomas can be classified as sporadic, inherited and familial. Point mutations, which appear during life, are not associated with inherited syndromes and only affect individual cells and their descendants. Cancers derived from point mutations are called sporadic cancers, and account for 70% of all colorectal cancers.
the molecular pathogenesis of sporadic cancer is heterogeneous as mutations can target different genes (see Marmol et al., Colorectal Carcinoma: A General Overview and Future Perspectives in Colorectal Cancer. Int. J. Mol. Sci. 2017 Jan; 18(1): 197).
approximately 70% of CRC cases follow a specific succession of mutations that is then translated into a specific morphological sequence, starting with the formation of an adenoma and ending in the carcinoma state.
the first mutation occurs in adenomatous polyposis coli (APC), a tumor suppressor gene, triggering the formation of non- malignant adenomas, also called polyps.
APC adenomatous polyposis coli
Genomic instability is an important feature underlying colorectal cancer.
the pathogenic mechanisms leading to this situation can be included in three different pathways, namely chromosomal instability (CIN), microsatellite instability (MSI) and CpG island methylator phenotype (CIMP) (see Marmol 2017).
CIN chromosomal instability
MSI microsatellite instability
CIMP CpG island methylator phenotype
the CIN pathway which is also considered to be the classical pathway since it represents the cause of up to 80%-85% of all CRC cases, is characterized by imbalances in the number of chromosomes, thus leading to aneuploydic tumors and loss of heterozygosity (LOH).
the mechanisms underlying CIN include alterations in chromosome segregation, telomere dysfunction and DNA damage response, which affect critical genes involved in the maintenance of correct cell function, such as APC, KRAS, PI3K, and TP53 amongst others.
APC mutations cause the translocation of P-catenin to the nucleus and drive the transcription of genes implicated in tumourigenesis and invasion, whereas mutations in KRAS and PI3K lead to a constant activation of MAP kinase, thus increasing cell proliferation.
loss-of-function mutations in TP53 which encodes for p53, the main cell-cycle checkpoint, cause an uncontrolled entry in the cell cycle (Pino et al., The chromosomal instability pathway in colon cancer. Gastroenterology. 2010 Jun; 138(6):2059-72).
the Microsatellite instability pathway is caused by a hypermutable phenotype due to loss of DNA repair mechanisms.
the ability to repair short DNA chains or tandem repeats (two to five base-pair repeats) is decreased in tumors with microsatellite instability; therefore, mutations tend to accumulate in those regions.
These mutations can affect non-coding regions as well as codifying microsatellites, and tumors develop when reading frames of oncogenes or tumor suppressor genes codified in microsatellites are altered (see Marmol 2017).
Loss of expression of mismatch repair genes (MMR) can be caused by spontaneous events (promoter hypermethylation) or germinal mutations such as those found in Lynch syndrome. These tumors are mainly diploid and harbor less LOH.
MSI tumors have a better prognosis than sporadic tumors (Umar et al., Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst. 2004 Feb 18; 96(4):261-8).
microsatellite markers including two mononucleotide (BAT26 and BAT25) and three dinucleotide (D2S123, D5S346, and D17S250) repeats, has been recommended according to the Bethesda Guidelines. Tumors are then classified based on the number of microsatellites exhibiting instability. Particularly, tumors are classified as MSI high (MSI-H) when >30% of the markers exhibit instability; those with ⁇ 30% markers exhibiting instability are defined as MSI low, and those with no apparent instability are microsatellite stable (MSS).
MSI-H MSI high
MSI low microsatellite stable
MSI is associated with post-replicative DNA MMR deficiency, primarily involving mutL homolog 1 (MLH1) and mutS homolog 2 (MSH2)
MMR1 mutL homolog 1
MSH2 mutS homolog 2
Impairment of MMR genes can occur by either mutational inactivation or by epigenetic inactivation through CpG island methylation of the promoter of the genes. Loss or insufficiency of MMR activity leads to replication errors with an increased mutation rate and a higher potential for malignancy.
CRC Epigenetic instability
oncogene promoters which leads to genetic silencing and a loss of protein expression.
Genetics and epigenetics are not exclusive in colorectal cancer, and both cooperate in its development, with more methylation events than point mutations often being found (Lao et al., Nat Rev Gastroenterol Hepatol. 2011 Oct 18; 8(12):686-700).
Colorectal cancers are generally CDK4/6 replication independent, although heterogeneity does exist.
CDK4/6-replication independent colorectal cancer refers to a CRC that does not significantly require the activity of CDK4/6 for replication.
CDK4/6 replication independent cancers generally have a retinoblastoma gene (Rbl) aberration.
Rbl retinoblastoma gene
the gene product of Rbl — Rb- protein — is a downstream target of CDK4/6.
RBI is commonly dysregulated in cancer cells through deletion, mutation or epigenetic modification resulting in loss of RB expression, as well as by aberrant CDK kinase activity leading to excessive phosphorylation and inactivation of RB function (Chen et al.
CCNE1/2 (cyclin E) is part of a parallel pathway that provides functional redundancy with CDK4/6 and helps to transition cells from the G1 to S phase. Overexpression will decrease the reliance on the CDK4/6 pathway leading to CDK4/6 independence (Turner et al., Cyclin El Expression and Palbociclib Efficacy in Previously Treated Hormone Receptor-Positive Metastatic Breast Cancer. J Clin Oncol. 2019;37(14): 1169-78.). Therefore, a tumor with either CCNE1/2 amplification or RB loss will generally be considered “CDK4/6 independent”.
CDK4/6 replication dependent CRCs generally have an intact and functional Rb pathway and/ increased expression of CDK4/6 activators (cyclin D), and/or a d-type cyclin activating features (DCAF) — including CCND1 translocation, CCND1-3 3’UTR loss, and amplification of CCND2 or CCND3 (see Gong et al. Genomic aberrations that activate D-type cyclins are associated with enhanced sensitivity to the CDK4 and CDK5 inhibitor abemaciclib. Cancer Cell. 2017;32(6):761-76). Tumors that are wildtype for RB and CCNE1/2 as well as have one of the DCAF described above are generally classified as “CDK4/6 dependent”.
CDK4/6-replication dependent or CDK4/6- replication independent Tumors that cannot be classified as either CDK4/6-replication dependent or CDK4/6- replication independent is generally classified as “CDK4/6 indeterminate” since they cannot be confirmed as CDK4/6 dependent or independent.
CDK4/6 genetic signature analysis involves the utilization of tumor tissue collected from a patients’ biopsy (colorectal primary or metastatic site) and are described in Shapiro GI. Genomic biomarkers predicting response to selective CDK4/6 inhibition: Progress in an elusive search. Cancer Cell. 2017;32(6):721-3 and Gong et al. Genomic aberrations that activate D-type cyclins are associated with enhanced sensitivity to the CDK4 and CDK5 inhibitor abemaciclib. Cancer Cell. 2017;32(6):761-76.
anti-VEGF or anti-EGFR targeting agents in colorectal cancer is dependent on the mutational status of KRAS (Kirsten rat sarcoma 2 viral oncogene homolog) and BRAF (v-Raf murine sarcoma viral oncogene homolog B) in the tumor.
KRAS Kerat rat sarcoma 2 viral oncogene homolog
BRAF v-Raf murine sarcoma viral oncogene homolog B
the use of anti-EGFR targeting agents is generally limited to those having wild-type KRAS and BRAF status. Comparatively, the use of anti-VEGF agents is not dependent on KRAS and BRAF status. Methods for the assessment of BRAF and KRAS mutations are generally known in the art.
the methods described herein are directed to the treatment of a subject with colorectal cancer.
the colorectal cancer is colorectal adenocarcinoma.
the colorectal cancer is metastatic colorectal cancer (mCRC).
the colorectal cancer is proficient mismatch repair (pMMR) mCRC.
the CRC is not pMMR.
the colorectal cancer is microsatellite stable (MSS) CRC.
MSI-Hi CRC In some embodiment, the colorectal cancer is MSI-Lo CRC.
the colorectal cancer is pMMR/MSS mCRC. In some embodiments, the colorectal cancer is pMMR/MSS mCRC and has not been responsive to previous treatment with single agent checkpoint inhibitors. In some embodiments, the colorectal cancer has a mutation, chromosomal change, or translocation which affects one or more of the WNT, MAPK/PI3K, TGF-P, or TP53 pathways. In some embodiments, the colorectal cancer has a mutation in a gene selected from c-MYC, KRAS, NRAS, HRAS, BRAF, PIK3CA, PTEN, SMAD2, or SMAD4.
the mCRC has a BRAF or KRAS mutation.
the BRAF mutation is V600E substitution mutation.
the KRAS mutation is a V9, G12, G13, V14, L19, Q22, D33, A59, G60, Q61 R68, KI 17, A146, R164, K176, or K180 substitution.
the KRAS mutation is a G12D, G12V, G12C, G12A, or other G12 variant.
the NRAS mutation is selected from G12, G13, G60, Q61, E123, or Pl 85.
the HRAS mutation is G12, G13, Q61, KI 17, R164, or P167.
the colorectal cancer is KRAS wild-type. In some embodiments, the colorectal cancer is BRAF wild-type.
the cancer to be treated according to the protocols described herein is pancreatic cancer.
the pancreatic cancer is metastatic or advanced pancreatic cancer.
the cancer to be treated according to the protocols described herein is gastric cancer.
the gastric cancer is metastatic or advanced gastric cancer.
the cancer to be treated according to the protocols described herein is gastroesophageal junction adenocarcinoma.
the gastroesophageal junction adenocarcinoma is metastatic or advanced gastroesophageal junction adenocarcinoma.
the cancer to be treated according to the protocols described herein is biliary tract cancer (cholangiocarcinoma), including intrahepatic cholangiocarcinoma, hilar cholangiocarcinoma, and distal cholangiocarcinoma.
the biliary tract cancer is metastatic or advanced biliary tract cancer.
the cancer to be treated according to the protocols described herein is neuroendocrine carcinoma.
the neuroendocrine carcinoma is metastatic or advanced neuroendocrine carcinoma.
the cancer to be treated according to the protocols described herein is peritoneal carcinosis.
the peritoneal carcinosis is metastatic or advanced peritoneal carcinosis.
the cancer to be treated according to the protocols described herein is liver cancer, including but not limited to hepatocellular carcinoma (HCC).
HCC hepatocellular carcinoma
the liver cancer, including but not limited to hepatocellular carcinoma is metastatic or advanced.
the colorectal cancer to be treated is an immunologically susceptible cancer.
the colorectal cancer to be treated has a high-immunoscore.
the subject being treated has a colorectal cancer that exhibits specific characteristics as described herein according to the Ayer’s interferon-y signature, the Ayer’s expanded immune signature or the Thorsson et al Six Class Immune Signature.
the cancer is interferon-y (IFN-y) dominant according to Thorsson’ s Six Class Immune Signature, or has a high IFN-y signature or expanded immune signature according to the Ayer’s IFN-y Signature Score or Expanded Immune Signature Score.
the cancer is PD-L1 positive.
progression free survival and/or overall survival can be improved when a cancer that is highly immunogenic, for example, a hot tumor (as defined in Galon, J., and Bruni, D., Approaches to treat immune hot, altered and cold tumours with combination immunotherapies”, Nature Reviews Drug Discovery (18), March 2019, 197-218 incorporated herein by reference and discussed further below), high IFN-y expression, or other acceptable indicator of immunogenic susceptibility is treated with a chemotherapy that causes an immune- mediated response including, but not limited to, immunogenic cell death and/or regulatory T-cell (Treg cell) suppression, in combination with a short acting CDK4/6 inhibitor administered at least prior to the administration of the chemotherapy or alternatively, administered both prior to and concurrently with the chemotherapy.
a cancer that is highly immunogenic for example, a hot tumor (as defined in Galon, J., and Bruni, D., Approaches to treat immune hot, altered and cold tumours with combination immunotherapies”, Nature Reviews Drug Discovery (18), March 2019, 197-218 incorporated herein by reference
a cancer therapy When a cancer therapy includes these three components in the appropriate dosage regimen, there is an immuno-oncology effect that promotes progression free survival and/or overall survival by alteration of the milieu of T-cells away from an immunosuppressive environment (i.e., Treg cells) and toward an enhancement of T-cell activity and an increase in cytotoxic T cells (CD8+ cells).
an immunosuppressive environment i.e., Treg cells
CD8+ cells cytotoxic T cells
hot immune tumors are those that have (i) a high degree of T-cell and cytotoxic T cell infiltration, i.e., a high immunoscore; and (ii) ability for checkpoint activation (programmed cell death protein 1 (PD-1), cytotoxic T lymphocyte- associated antigen 4 (CTLA4), T-cell immunoglobulin mucin receptor 3 (TIM3) and lymphocyte activation gene 3 (LAG3)) or otherwise impaired T-cell functions (for example, extracellular potassium- driven T-cell suppression).
PD-1 programmed cell death protein 1
CTLA4 cytotoxic T lymphocyte- associated antigen 4
TIM3 T-cell immunoglobulin mucin receptor 3
LAG3 lymphocyte activation gene 3
hot tumors characteristically display possible genomic instability and the presence of a pre-existing antitumor immune response.
TILs tumor-infiltrating lymphocytes
P-L1 anti-programmed death-ligand 1
Altered-immunosuppressed tumors are categorized by (i) poor, albeit not absent, T-cell and cytotoxic T-cell infiltration (intermediate immunoscore), (ii) presence of soluble inhibitory mediators (transforming growth factor- P (TGFP), interleukin 10 (IL- 10) and vascular endothelial growth factor (VEGF)), (iii) the presence of immune suppressive cells (myeloid- derived suppressor cells and regulatory T-cells), and (iv) presence of T-cell checkpoints (PD-1, CTLA4, TIM3 and LAG3). Altered-immunosuppressed tumor sites display a low degree of immune infiltration (FIG.
Fig. 7A An exemplified resected tumor having the characteristics of an altered-immunosuppressed immune tumor is illustrated in Fig. 7A.
the determination of the immunogenic classification of a tumor can be carried out on resected tumors (primary or metastatic) (see e.g., Fig. 7A).
PET immuno-positron-emission tomography
CIBERSORT which infers the relative fractions of immune subsets in the total leukocyte population
xCell which predicts the abundance of immune cells in the overall TME
TIMER which generates enrichment scores on the basis of proportions among 64 immune and stromal cell types
integrated immunogenomics methods using a CIBERSORT- based approach, which, of note, identified six immune subtypes of cancer
can be used to estimate the abundance of intra-tumoral immune infiltrates by using deconvolution of bulk gene expression data see Newman et al., Robust enumeration of cell subsets from tissue expression profiles, Nat.
the cancer to be treated has a high immunoscore.
Immunoscore is a digital pathology, H4C -based immune assay measuring the densities of CD3+ and CD8+ T cells at different tumor locations.
the Immunoscore scoring has been defined in a large international SITC-led retrospective validation study conducted on more than 2500 St I-III colon cancer patients (see Pages et al, International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study, The Lancet Volume 391, ISSUE 10135, P2128- 2139, May 26, 2018, incorporated herein by reference).
Commercial Immunoscore assays are available through, for example, HalioDx, Inc. (Richmond, Va).
FFPE paraffin-embedded
Image analysis is performed via a dedicated software (Immunoscore Analyzer, HalioDx): automatic detection of the tissue histologic structure is followed by an operator-guided definition of the tumor, healthy tissue (submucosa, muscularis intestinal, serosa), and the epithelium (mucosa). The operator also excludes all areas of necrosis, abscess, and artifacts (bubbles folds, tom areas, background) to avoid false positives.
the IM spanning 360 pm into the healthy tissue and 360 pm into the tumor, is calculated automatically by the software. In the presence of multiple FFPE blocks, the one to select for the Immunoscore evaluation is the one containing the IM.
the cancer to be treated has a high IFN-y Signature of Expanded Immune Signature, for example as described in Ayers et al. Ayers M, et al. “IFN-y-Related MRNA Profile Predicts Clinical Response to PD-1 Blockade.” Journal of Clinical Investigation, vol. 127, no. 8, 2017, pp. 2930-2940., doi : 10.1172/j ci91190 (incorporated herein by reference in its entirety), who outline a thorough, iterative approach to building a gene expression signature predictive of response to immune checkpoint inhibitors (e.g., pembrolizumab).
IFN-y Signature of Expanded Immune Signature for example as described in Ayers et al. Ayers M, et al. “IFN-y-Related MRNA Profile Predicts Clinical Response to PD-1 Blockade.” Journal of Clinical Investigation, vol. 127, no. 8, 2017, pp. 2930-2940., doi : 10.1172/j ci91
the IFN-y Signature analysis consists of determining the expression profile of six genes: IDO1, CXCL10, CXCL9, HLA-DRA; STAT1, and IFN-y.
the Expanded Immune Signature analysis consists of determining the expression profile of 18 genes: CCL5, CD27, CD274, CD276, CD8A, CMKLR1, CXCL9, CXCR6, HLA-DRB1, HLA-DQA1, HLA-E, IDO1, LAG3, NKG7, PDCD1LG2, PSMB10, STAT1, and TIGIT.
Ayers et al. performed sequencing quantitation using a 680 gene panel on the Nanostring platform. To compute a sample’s score for either multi -gene signature (IFN-y Signature or Expanded Immune Signature), quantile normalization is performed prior to a loglO transformation and subsequent averaging across the gene-set. Calculation of the area under the ROC curve was used as a measure of discriminatory ability for the signature scores.
the Youden index a summary measure of the ROC curve (see Youden WJ. Index for rating diagnostic tests. Cancer. 1950;3 (1): 32— 35, incorporated herein by reference), was used as an agnostic method for choosing an “optimal” cutoff, that is “high’7”low” on the signature scores to illustrate potential clinical usefulness.
a “high” IFN-y Signature or Expanded Immune Signature can be determined based on comparison to scores of known immunogenic samples.
a “high” IFN-y Signature or Expanded Immune Signature score is one that is scored greater than at least 2.25, 2.5, or 2.75.
a “high” IFN-y Signature or Expanded Immune Signature score is one that is scored greater than at least 2.5.
the cancer to be treated is IFN-y Dominant in a Six Class Immune Signature category as described in as described by Thorsson et al., “The Immune Landscape of Cancer.” Immunity, vol 51, no. 2, 2018, pp. 812-830 (incorporated herein by reference in its entirety).
Thorsson et al. performed an extensive literature search for expression signatures which characterized various facets of the immune response. This search resulted in 160 signatures for examination. Weighted Gene Correlation Network Analysis (WGCNA) over the entire TCGA (The Cancer Genome Atlas) dataset was used to cluster these 160 signatures into 9 distinguishable signature-modules, or collections of signatures purported to measure consistent immune phenomena.
WGCNA Weighted Gene Correlation Network Analysis
TCGA The Cancer Genome Atlas
the cancer to be treated is programmed death-1 ligand (PD-L1) positive.
PD-L1 is a transmembrane protein that down-regulates immune responses through binding to its two inhibitory receptors, programmed death-1 (PD-1) and B7.1.
PD-1 is an inhibitory receptor expressed on T cells following T-cell activation, which is sustained in states of chronic stimulation such as in chronic infection or cancer (Blank, C and Mackensen, A, Contribution of the PD-L1/PD-1 pathway to T-cell exhaustion: an update on implications for chronic infections and tumor evasion. Cancer Immunol Immunother, 2007. 56(5): p. 739-745).
B7.1 is a molecule expressed on antigen presenting cells and activated T cells.
PD-L1 binding to B7.1 on T cells and antigen presenting cells can mediate down-regulation of immune responses, including inhibition of T-cell activation and cytokine production (see Butte MJ, Keir ME, Phamduy TB, et al.
Programmed death- 1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity. 2007;27(l): 111-122).
PD-L1 expression has been observed in immune cells and tumor cells.
interruption of the PD-L1/PD-1 pathway represents an attractive strategy to reinvigorate tumor-specific T cell immunity suppressed by the expression of PD-L1 in the tumor microenvironment.
the upregulation of PD-L1 may allow cancers to evade the host immune system.
PD-L1 expression can be determined by methods known in the art. For example, PD-L1 expression can be detected using PD-L1 IHC 22C3 pharmDx, the FDA-approved in vitro diagnostic immunohistochemistry (IHC) test developed by Dako and Bristol-Meyers Squibb as a companion test for treatment with pembrolizumab.
IHC in vitro diagnostic immunohistochemistry
PD-L1 expression can also be detected using PD-L1 IHC 28-8 pharmDx, the FDA- approved in vitro diagnostic immunohistochemistry (IHC) test developed by Dako and Merck as a companion test for treatment with nivolumab.
IHC in vitro diagnostic immunohistochemistry
This qualitative assay uses the Monoclonal rabbit anti-PD-Ll, Clone 28-8 and EnVision FLEX visualization system on Autostainer Lin 48 to detect PD-L1 in formalin-fixed, paraffin-embedded (FFPE) human non-small cell lung cancer tissue.
FFPE paraffin-embedded
PD-L1 detection include the Ventana SP263 assay (developed by Ventana in collaboration with AstraZeneca) that utilizes monoclonal rabbit anti- PD-Ll, Clone SP263 and the Ventana SP142 Assay (developed by Ventana in collaboration with Genentech/Roche) that uses rabbit monoclonal anti-PD-Ll clone SP142. Determination of PD- L1 status is indication-specific, and evaluation is based on either the proportion of tumor area occupied by PD-L1 expressing tumor-infiltrating immune cells (% IC) of any intensity or the percentage of PD-L1 expressing tumor cells (% TC) of any intensity.
% IC proportion of tumor area occupied by PD-L1 expressing tumor-infiltrating immune cells
% TC percentage of PD-L1 expressing tumor cells
PD-L1 expression in > 5% IC determined by, for example, the Ventana PD-L1 (SP142) Assay in urothelial carcinoma tissue, whereas a PD-L1 positive status in TNBC is considered > 1% IC and NSCLC is considered > 50% TC or > 10% IC.
SP142 Ventana PD-L1
the colorectal cancer to be treated is a PD-L1 positive colorectal cancer having PD-L1 expression > 1% IC. In some embodiments, the colorectal cancer to be treated is a PD-L1 positive colorectal cancer having PD-L1 expression > 5% IC
Trilaciclib Trilaciclib (2'-((5-(4-methylpiperazin- 1 -yl)pyri din-2 -yl)amino)-7',8'-dihydro-6'H- spiro(cyclohexane-l,9'-pyrazino(r,2': l,5)pyrrolo(2,3-d)pyrimidin)-6'-one) is a highly selective
CDK4/6 inhibitor having the structure:
trilaciclib or its pharmaceutically acceptable salt, composition, isotopic analog, or prodrug thereof is administered in a suitable carrier.
Trilaciclib has been approved by the U.S. FDA for the treatment of extensive-stage small cell lung cancer to decrease the incidence of chemotherapy-induced myelosuppression in patients when administered prior to a platinum/etoposide-containing regimen or topotecan-containing regimen, and marketed as under the brand name Cosela® by G1 Therapeutics, Inc.
trilaciclib is provided as a hydrochloride salt, for example, a dihydrochloride salt.
the trilaciclib is reconstituted form the dihydrochloride dihydrate, which may be in lypholized form.
Trilaciclib is described in US 2013-0237544, incorporated herein by reference in its entirety. Trilaciclib can be synthesized as described in or US 2019-0135820, incorporated herein by reference in its entirety. Trilaciclib can be administered in any manner that achieves the desired outcome, including systemically, parenterally, intravenously, intramuscularly, subcutaneously, or intradermally.
trilaciclib may be provided, in some embodiments, for example, as a 300 mg/vial as a sterile, lyophilized, yellow cake providing 300 mg of trilaciclib (equivalent to 349 mg of trilaciclib dihydrochloride, dihydrate).
the product may be supplied in single-use 20-mL clear glass vials which does not contain a preservative.
trilaciclib for injection 300 mg/vial may be reconstituted with 19.5 ml of 0.9% sodium chloride injection or 5% dextrose injection. This reconstituted solution has a trilaciclib concentration of 15 mg/mL and would typically be subsequently diluted prior to intravenous administration.
Trilaciclib can be administered intravenously as described herein. In some embodiments, trilaciclib is administered at between about 180 mg/m 2 and 300 mg/m 2 .
trilaciclib is administered at about 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 285, or about 300 mg/m 2 .
trilaciclib is administered at about 240 mg/m 2 , prior to administration of the other fluorouracil-based multi -agent chemotherapeutic agents, for example prior to about 4 hours or less, for example about 4 hours or less, 3 hours or less, 2 hours or less, about 1 hour or less, or about 30 minutes prior to administration of any of the other fluorouracil-based multi-agent chemotherapeutic agents.
trilaciclib is administered intravenously over a period of about 30 minutes.
trilaciclib is administered on day 1 of each 14-day cycle during the induction and maintenance phase, or as otherwise provided herein.
Trilaciclib is administered prior to the initiation of administration of the other chemotherapeutic agents, generally via intravenous injection/infusion over about 30 minutes about 4 hours or less, for example about 3 hours or less, 2 hours or less, 1 hour or less, or about 30 minutes prior to the initiation of the administration of the other agents in the protocol.
the trilaciclib is completely administered on day 1 prior to initiation of the administration any of the other fluorouracil -based multi -agent chemotherapy agents.
Trilaciclib is also administered on day 2 of each 14-day cycle during the induction and optionally during the maintenance phase, if 5-FU is administered over a two-day period as a continuous infusion, or as otherwise provided herein.
Trilaciclib can be administered on day 2 between about 16 and 26 hours after its administration on day 1.
trilaciclib is administered on day 2 within about 24 hours after administration of trilaciclib on day 1.
trilaciclib is administered on day 2 about 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 hours after its administration on day 2.
the trilaciclib is administered on day 2 of each cycle between about 20 and 22 hours after its administration on day 1 of each cycle.
a different CDK4/6 inhibitor is administered.
the CDK4/6 inhibitor used instead of trilaciclib in the protocols described herein is ribociclib (Novartis), palbociclib (Pfizer), or abemaciclib (Eli Lily), or pharmaceutically acceptable salts thereof.
the CDK4/6 inhibitor is lerociclib, which has the structure: or a pharmaceutically acceptable composition, salt, isotopic analog, or prodrug thereof, which is described in US 2013-0237544, incorporated herein by reference in its entirety, and can be synthesized as described in US 2019-0135820, incorporated herein by reference in its entirety.
the CDK4/6 inhibitor is lerociclib, which has the structure: or a pharmaceutically acceptable composition, salt, isotopic analog, or prodrug thereof, which is described in US 2013-0237544, incorporated herein by reference in its entirety, and can be synthesized as described in US 2019-0135820, incorporated herein by reference in its entirety.
Fluorouracil also known as FU, 5FU, or 5-FU
Fluorouracil is one of the most commonly used drugs to treat colorectal cancer, and forms the basis of many of the multi-agent chemotherapies used in colorectal treatment.
Fluorouracil is an antimetabolite fluoropyrimidine analog of the nucleoside pyrimidine with antineoplastic activity. Fluorouracil and its metabolites possess a number of different mechanisms of action. In vivo, fluorouracil is converted to the active metabolite 5- fluoroxyuridine monophosphate (F-UMP); replacing uracil, F-UMP incorporates into RNA and inhibits RNA processing, thereby inhibiting cell growth.
F-UMP active metabolite 5- fluoroxyuridine monophosphate
fluorouracil is a fluorinated pyrimidine and has the chemical designation 5-fluoro-2,4 (lH,3H)-pyrimidinedione.
the structure of fluorouracil is:
Fluorouracil is contra-indicated for patients with low or absent dipyrimidine dehydrogenase (DPD) activity and is associated with a host of toxicities, including:
Cardiotoxicity Fluorouracil can cause cardiotoxicity, including angina, myocardial infarction/ischemia, arrhythmia, and heart failure;
Hyperammonemic Encephalopathy Altered mental status, confusion, disorientation, coma, or ataxia with elevated serum ammonia level can occur within 72 hours of initiation of fluorouracil;
Neurologic Toxicity Fluorouracil can cause acute cerebellar syndrome, confusion, disorientation, ataxia, or visual disturbances.
HFS Palmar-Plantar Erythrodysesthesia
the use of 5-FU in the described embodiments is substituted with an alternative fluoropyrimidine.
a 5-FU prodrug is administered instead of 5-FU.
a 5-FU prodrug is selected from mono, di, or tri-phosphate 5-FU prodrug, capecitabine, tegafur, tegafur-uracil, tegafur/gimeracil/oteracil, carmofur, doxifluridine, or 5-fluoro-2’ -deoxyuridine.
a 5-FU prodrug is an FUDR-phosphoramidate.
the use of 5-FU in the described embodiments is substituted with capecitabine.
the use of 5-FU in the described embodiments is substituted with tegafur. In some embodiments, the , the use of 5-FU in the described embodiments is substituted with tegafur-uracil (UFT). In some embodiments, the , the use of 5-FU in the described embodiments is substituted with S-l (tegafur, gimeracil, and oteracil). In some alternative embodiments, the use of 5-FU in the described embodiments is substituted with carmofur (HCFU). In some alternative embodiments, the use of 5-FU in the described embodiments is substituted with doxifluridine. In some alternative embodiments, the use of 5-FU in the described embodiments is substituted with 5-fluoro-2’- deoxyuridine (5FUdR).
UFT tegafur-uracil
S-l tegafur, gimeracil, and oteracil
the use of 5-FU in the described embodiments is substituted with carmofur (HCFU).
HCFU carmofur
the fluorouracil-based multi-agent chemotherapies provided herein generally include the use of a folinic acid.
Folinic acid is a 5-FU modulating agent which inhibits thymidylate synthase.
Leucovorin also known as folinic acid, citrovorum factor, calcium folinate, or 5-formyl- 5,6,7,8-tetrahydrofolic acid, or leucovorin calcium
Leucovorin calcium has the chemical designation of Calcium N- [p-[[[(6RS)-2-amino-5-formyl-5,6,7,8-tetrahydro-4-hydroxy-6- pteridinyl]methyl]amino]benzoyl]-L-glutamate (1 : 1).
Leucovorin is sold under such brand names as Wellcovorin among others.
the structural formula of leucovorin calcium is:
Leucovorin is a mixture of the diastereoisomers of the 5-formyl derivative of tetrahydrofolic acid (THF).
the biologically active compound of the mixture is the (-)-l-isomer, known as Citrovorum factor or (-)-folinic acid.
Leucovorin potentiates the cytotoxic effects of 5- FU in the cell (de Gramont et al., Leucovorin and fluorouracil with or without oxaliplatin as first- line treatment in advanced colorectal cancer. J. Clin. Oncol. 2000 Aug;18(16):2938-47).
5-FU converts to fluoro-deoxy uridylic acid, a molecule that functions to inhibit thymidylate synthase.
Thymidylate synthase is an enzyme that is important in DNA repair and replication.
the functional derivative of folinic acid, 5,10 methylenetetrahydrofolate stabilizes the bound fluorodeoxy uridylic acid to thymidylate synthase. This interaction yields a ternary complex known as the thymidylate synthase 5-fluorodeoxyuridine monophosphate-methylenetetrahydrofolate complex, which ultimately functions to inhibit thymidylate synthase.
Leucovorin can also be administered as the disodium salt sodium leucovorin.
Levoleucovorin is the levo isomeric form of racemic d,l-leucovorin.
Levoleucovorin is the pharmacologically active isomer of leucovorin [(6-S)-leucovorin], Levoleucovorin is sold under such brand names as Fusilev and Kapzory.
Levoleucovorin when substituted in place of leucovorin, is generally dosed at one-half the usual dose of leucovorin.
Levoleucovorin can be administered as a calcium or disodium salt.
a folinate salt with a similar mechanism of action to the folinic acid compounds above are administered.
Oxaliplatin also sold under various brand names such as Eloxatin, is an antineoplastic agent with the molecular formula CsHi4N2O4Pt and the chemical name of cis-[(l R,2 R)- l,2-cyclohexanediamine-N,N’] [oxalato(2-)-O,O’] platinum.
Oxaliplatin is an organoplatinum complex in which the platinum atom is complexed with 1,2-diaminocyclohexane (DACH) and with an oxalate ligand as a leaving group, and has the chemical structure:
Oxaliplatin undergoes nonenzymatic conversion in physiologic solutions to active derivatives via displacement of the labile oxalate ligand.
Several transient reactive species are formed, including mono-aquo and di-aquo DACH platinum, which covalently bind with macromolecules.
Both inter-and intra-strand Pt-DNA crosslinks are formed.
Crosslinks are formed between the N7 positions of two adjacent guanines (GG), adjacent adenine-guanines (AG), and guanines separated by an intervening nucleotide (GNG). These crosslinks inhibit DNA replication and transcription. Cytotoxicity is cell-cycle nonspecific.
Oxaliplatin is associated with high rates of gastrointestinal toxicity such as nausea/vomiting, diarrhea, abdominal pain and stomatitis. Additionally, the following are important risks related to oxaliplatin use:
Oxaliplatin is associated with two types of neuropathy: o An acute, reversible, primarily peripheral, sensory neuropathy that is of early onset, occurring within hours or one to two days of dosing, that resolves within 14 days, and that frequently recurs with further dosing. o A persistent (> 14 days), primarily peripheral, sensory neuropathy that is usually characterized by paresthesias, dysesthesias, hypoesthesias, but may also include deficits in proprioception that can interfere with daily activities (e.g., writing, buttoning, swallowing, and difficulty walking from impaired proprioception).
RPLS Posterior Leukoencephalopathy Syndrome
PRES Posterior Reversible Encephalopathy Syndrome
Irinotecan also sold under various brand names such as Campostar, is an antineoplastic agent of the topoisomerase I inhibitor class.
the chemical name is (S)-4,l l-diethyl-3,4,12,14- tetrahydro-4-hydroxy-3,14-dioxolH-pyrano[3’,4’ :6,7]-indolizino[l,2-b]quinolin-9-yl- [l,4’bipiperidine]-r-carboxylate, monohydrochloride, trihydrate, and has the structure:
Irinotecan is a derivative of camptothecin. Camptothecins interact specifically with the enzyme topoisomerase I, which relieves torsional strain in DNA by inducing reversible singlestrand breaks. Irinotecan and its active metabolite SN-38 bind to the topoisomerase LDNA complex and prevent re-ligation of these single-strand breaks. Current research suggests that the cytotoxicity of irinotecan is due to double-strand DNA damage produced during DNA synthesis when replication enzymes interact with the ternary complex formed by topoisomerase I, DNA, and either irinotecan or SN-38. Mammalian cells cannot efficiently repair these double-strand breaks.
irinotecan is administered as a liposomal dispersion (irinotecan liposomal; Onivyde).
Anti-VEGF monoclonal antibodies include bevacizumab (Avastin, Genentech) or bevacizumab-awwb (Mvasi, Amgen).
Bevacizumab is vascular endothelial growth factor directed antibody.
Bevacizumab is a recombinant humanized monoclonal IgGl antibody that contains human framework regions and murine complementarity-determining regions (CDRs).
Bevacizumab binds VEGF and prevents the interaction of VEGF to its receptors (Fit- 1 and KDR) on the surface of endothelial cells.
the interaction of VEGF with its receptors leads to endothelial cell proliferation and new blood vessel formation in in vitro models of angiogenesis.
Administration of bevacizumab causes reduction of microvascular growth and inhibition of metastatic disease progression.
Bevacizumab-awwb has a similar mechanism of action and is a biosimilar of bevacizumab.
bevacizumab is generally administered on day 1 of each 14-day cycle of the induction phase and maintenance phase, or once every 2 weeks, as an intravenous injection at a dose of between about 4 and 12 mg/kg, with dosing adjustments as required. In some embodiments, bevacizumab is administered at about 5 mg/kg. In some embodiments, bevacizumab is administered at about 10 mg/kg.
Bevacizumab has been associated with GI toxicity including nausea, diarrhea, and stomatitis as well as bone marrow suppression. The following are important risks related to bevacizumab use:
the anti-VEGF compound is QL1101A (produced by Qilu Pharmaceutical Co., Ltd.), a biosimilar of bevacizumab.
the anti-VEGF compound ziv-afilbercept (Ziltrap; Sanofi/Genzyme) is a vascular endothelial growth factor inhibitor. It is a recombinant fusion protein consisting of Vascular Endothelial Growth Factor (VEGF)-binding portions from the extracellular domains of human VEGF Receptors 1 and 2 fused to the Fc portion of the human IgGl.
VEGF Vascular Endothelial Growth Factor
Ziv-afhbercept is produced by recombinant DNA technology in a Chinese hamster ovary (CHO) K-l mammalian expression system.
Ziv-aflibercept is a dimeric glycoprotein with a protein molecular weight of 97 kilodaltons (kDa) and contains glycosylation, constituting an additional 15% of the total molecular mass, resulting in a total molecular weight of 115 kDa.
ZALTRAP (ziv-afhbercept) injection is a sterile, clear, colorless to pale-yellow, non-pyrogenic, preservative-free, solution for intravenous use.
ZALTRAP is supplied in single-dose vials of 100 mg/4 mL and 200 mg/8 mL formulated as 25 mg/mL ziv-aflibercept in polysorbate 20 (1 mg/mL), sodium chloride (5.84 mg/mL), sodium citrate (1.45 mg/mL), sodium phosphate (0.8 mg/mL), and sucrose (200 mg/mL), in Water for Injection, USP, at a pH of 6.2.
ziv-aflibercept When used in fluorouracil-based multi-agent chemotherapies, ziv-aflibercept is generally administered on day 1 of each 14-day cycle of the induction and maintenance phase, or once every two weeks, as an intravenous infusion at a dose of between about 2 and 10 mg/kg, with dosing adjustments as required. In some embodiments, ziv-aflibercept is administered as an intravenous infusion at about 4 mg/kg over 1 hour.
Ziv-aflibercept acts as a soluble receptor that binds to human VEGF -A (equilibrium dissociation constant KD of 0.5 pM for VEGF-Aies and 0.36 pM for VEGF -Am), to human VEGF- B (KD of 1.92 pM), and to human P1GF (KD of 39 pM for P1GF-2).
VEGF -A Equilibrium dissociation constant KD of 0.5 pM for VEGF-Aies and 0.36 pM for VEGF -Am
KD 0.5 pM for VEGF-Aies and 0.36 pM for VEGF -Am
human VEGF- B KD of 1.92 pM
human P1GF KD of 39 pM for P1GF-2
ziv-aflibercept can inhibit the binding and activation of their cognate receptors. This inhibition can result in decreased neovascularization and decreased vascular permeability.
aflibercept is administered as the anti-VEGF compound.
Ramucirumab (Cyramza; Eli Lily) is a human vascular endothelial growth factor receptor 2 (VEGFR2) antagonist that specifically binds VEGFR2 and blocks binding of VEGFR ligands, VEGF-A, VEGF-C, and VEGF-D.
VEGFR2 vascular endothelial growth factor receptor 2
ramucirumab inhibits ligand-stimulated activation of VEGFR2, thereby inhibiting ligand-induced proliferation, and migration of human endothelial cells.
Ramucirumab is a recombinant human IgGl monoclonal antibody.
Ramucirumab has an approximate molecular weight of 147 kDa.
Ramucirumab is produced in genetically engineered mammalian NS0 cells.
Ramucirumab injection for intravenous use is a sterile, preservative-free, clear to slightly opalescent and colorless to slightly yellow solution.
Ramucirumab is supplied at a concentration of 10 mg/mL in either 100 mg (10 mL) or 500 mg (50 mL) single-dose vials.
Ramucirumab is formulated in glycine (9.98 mg/mL), histidine (0.65 mg/mL), histidine monohydrochloride (1.22 mg/mL), polysorbate 80 (0.1 mg/mL), sodium chloride (4.383 mg/mL), and Water for Injection, USP, pH 6.0.
ramucirumab When used in fluorouracil-based multi-agent chemotherapies, ramucirumab is generally administered on day 1 of each 14-day cycle of the induction and maintenance phase, or once every two weeks, as an intravenous infusion at a dose of between about 5 and 15 mg/kg, with dosing adjustments as required. In some embodiments, ramucirumab is administered at about 8 mg/kg as an intravenous infusion over 1 hour.
the anti-VEGF compound is apatinib.
the apatinib is administered at a dose of between about 100 and 400 mg QD on days 1-14. In some embodiments, the apatinib is administered at a dose of about 250 mg QD on days 1-14.
the anti-VEGF compound is selected from axitinib (Inlyta), dovitinib, fruquintinib (Elunate), pazopanib (Votrient), sunitinib (Sutent), sorafenib (Nexavar), regorafenib (Stivarga), cabozantinib (Cabometyx), lenvatinib (Lenvima), ponatinib (Iclusig), cabozatinib (Cometriq), tivozanib (Fotivda), or vandetanib (Caperlsa).
Anti-EGFR Monoclonal Antibodies An anti-EGFR monoclonal antibody or compound is also routinely incorporated in fluorouracil -based multi-agent chemotherapy protocols in patients having colorectal cancer with RAS (including KRAS and NRAS) and BRAF wild-type tumors.
RAS including KRAS and NRAS
Commonly used anti-EGFR monoclonal antibodies include cetuximab (Erbitux; Eli Lilly) and panitumumab (Vectibix; Amgen).
EGFR is overexpressed in certain human cancers, including colon and rectum cancers. Interaction of EGFR with its normal ligands (e.g., EGF, transforming growth factor-alpha) leads to phosphorylation and activation of a series of intracellular proteins, which in turn regulate transcription of genes involved with cellular growth and survival, motility, and proliferation.
EGF transforming growth factor-alpha
KRAS Kirsten rat sarcoma 2 viral oncogene homologue
NRAS Neuroroblastoma RAS viral oncogene homologue
Panitumumab binds specifically to EGFR on both normal and tumor cells, and competitively inhibits the binding of ligands for EGFR. binding of the anti-EGFR antibody to the EGFR prevents ligand-induced receptor autophosphorylation and activation of receptor-associated kinases, resulting in inhibition of cell growth, induction of apoptosis, decreased proinflammatory cytokine and vascular growth factor production, and internalization of the EGFR.
Panitumumab is a human IgG2 kappa monoclonal antibody with an approximate molecular weight of 147 kDa that is produced in genetically engineered mammalian (Chinese hamster ovary) cells. In fluorouracil -based multi -agent chemotherapy protocols, panitumumab is generally administered on day 1 of each 14-day cycle of the induction phase and maintenance, or once every two weeks, as an intravenous injection at a dose of between about 2 and 10 mg/kg, with dosing adjustments as required. In some embodiments, panitumumab is administered at about 5 mg/kg.
Cetuximab is a recombinant, human/mouse chimeric monoclonal antibody that binds specifically to the extracellular domain of the human epidermal growth factor receptor (EGFR).
Cetuximab is composed of the Fv regions of a murine anti-EGFR antibody with human IgGl heavy and kappa light chain constant regions and has an approximate molecular weight of 152 kDa. Cetuximab is produced in mammalian (murine myeloma) cell culture.
cetuximab is generally administered on day 1 of each 14-day cycle of the induction and maintenance phase, or once every two weeks, as an intravenous injection at a dose of between about 200 mg/m 2 and 1000 mg/m 2 with dosing adjustments as required. In some embodiments, cetuximab is administered at about 500 mg/m 2 .
anti-EGFR monoclonal antibodies has been associated with several risks and toxicities, including diarrhea and stomatitis.
the anti-EGFR compound is nimotuzumab. In alternative embodiments, the anti-EGFR compound is necitumumab. In alternative embodiments, the anti- EGRR compound is Mab A13, AMG595, depatuxizumab mafodotin, duligotuzumab (MEHD7945A, RG7597), futuximab (Sym004), GC1118, imgatuzumab (GA201), matuzumab (EMD 72000), anitumumab (Vectibix, ABX-EGF), zalutumumab, humMRl, tomuzotuximab, erlotinib (Tarceva), gefitinib (Iressa), afatinib (Gilotrif), rociletinib (CO-1686), osimertinib (Tagrisso), olmutinib (Olita),
Trilaciclib is a highly potent and selective, reversible, CDK4/6 inhibitor that is administered intravenously (IV) on day 1 at between about 200 mg/m 2 and 280 mg/m 2 , and preferably at about 240 mg/m 2 no more than about 4 hours prior to the initiation of FOLFOX administration, and administered intravenously (IV) on day 2 at the same dose either about 18 to 26 hours or about 22 to 24 hours or about 20 to 22 hours after its administration on day 1 if fluorouracil is continuously infused over the two days, or on day 2 no more than about 4 hours prior to the initiation of 5 -fluorouracil and, if applicable, folinic acid (e.g., leucovorin or levoleucovorin) administration if fluorouracil is administered as an infusion on day one (for example, over about 22 hours) and another infusion on day 2 (for
the trilaciclib is administered on day 2 of each cycle between about 20 and 22 hours after its administration on day 1 of each cycle.
the day 2 infusion of trilaciclib is being administered to ensure that synchronization and release of the HSPC G1 arrest (-24-32 hours after a single dose of trilaciclib) does not occur while 5FU is at sufficient concentrations such that 5FU-related myelosuppression is exacerbated rather than mitigated.
This administration cycle for trilaciclib is designed to preserve HSPCs during chemotherapy (myelo-preservation), enhance anti-tumor immunity (anti-tumor efficacy), and reduce other toxicities associated with administration of the protocol such as stomatitis and mucostitis.
FOLFOX is a three-drug regimen composed of fluorouracil (5-FU), folinic acid (e.g., leucovorin or levoleucovorin), and oxaliplatin commonly used in the treatment of mCRC (National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology Colon Cancer. Version 2. 2019. NCCN, Fort Washington, PA). Versions of FOLFOX include FOLFOX4, FOLFOX6, modified FOLFOX6 (mFOLFOX6), FOLFOX7, and modified FOLFOX7 (mFOLFOX7).
5-FU fluorouracil
folinic acid e.g., leucovorin or levoleucovorin
oxaliplatin commonly used in the treatment of mCRC (National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology Colon Cancer. Version 2. 2019. NCCN, Fort Washington, PA). Versions of FOLFOX include FOLFOX4, FOLFOX6, modified FOLFOX6
FOLFOX is administered for a maximum of 12 induction cycles (every 14 days) followed by maintenance consisting of intravenous-5-FU and folinic acid administered in 14-day cycles until disease progression, unacceptable toxicity, etc.
FOLFOX is commonly administered in further combination with an anti-VEGF antibody, for example bevacizumab (Avastin, Genentech) or bevacizumab-awwb (Mvasi, Amgen), ramucirumab (Cyramza, Eli Lilly), or ziv-aflibercept (Zaltrap, Sanofi/Regeneron), or an anti-EGFR monoclonal antibody, for example panitumumab (Vectibix, Amgen) (for RAS wild-type (both KRAS and NRAS) CRC) or cetuximab (Erbitux, Lily) (RAS wild-type (both KRAS and NRAS) CRC).
an anti-VEGF antibody for example bevacizumab (Avast
oxaliplatin is generally administered on day 1 of each 14- day cycle of the induction phase as an intravenous infusion over about, for example, 2 hours at a dose of between about 85 mg/m 2 and 130 mg/m 2 , with dosing adjustments as required.
oxaliplatin is administered as an intravenous infusion over about, for example, 2 hours at about 85 mg/m 2 , for example FOLFOX4, mFOLFOX6, and mFOLFOX7.
oxaliplatin is administered as an intravenous infusion over about, for example, 2 hours at about 100 mg/m 2 (e.g., FOLFOX6 and mFOLFOX6).
oxaliplatin is administered as an intravenous infusion over about, for example, 2 hours at about 130 mg/m 2 (e.g., FOLFOX7).
oxaliplatin is administered simultaneously with folinic acid (e.g., leucovorin or levoleucovorin).
folinic acid e.g., leucovorin or levoleucovorin.
oxaliplatin is administered prior to 5FU administration.
leucovorin is generally administered on day 1 of each 14-day cycle of the induction and maintenance phase as an intravenous infusion over about, for example, 2 hours at a dose of between about 50 mg/m 2 to about 400 mg/m 2 , with dosing adjustments as required.
leucovorin is administered as an intravenous infusion over about, for example, 2 hours on day 1 at about 400 mg/m 2 (e.g., FOLFOX6, mFOLFOX6, FOLFOX7).
leucovorin is administered as an intravenous infusion over about, for example, 2 hours at about 200 mg/m 2 on both day 1 and day 2 (e.g., FOLFOX 4).
leucovorin is administered as an intravenous infusion over about, for example, 2 hours on day 1 at about 200 mg/m 2 (e.g., mFOLFOX7). In some embodiments, leucovorin is administered simultaneously with oxaliplatin. In some embodiments leucovorin is administered prior to 5FU.
levoleucovorin is generally dosed at one-half the racemic d,l-leucovorin, for example, in the FOLFOX protocol, on day 1 of each 14-day cycle of the induction and maintenance phase as an intravenous infusion over about, for example, 2 hours at a dose of between about 25 mg/m2 to about 200 mg/m 2 , with dosing adjustments as required.
levoleucovorin is administered as an intravenous infusion over about, for example, 2 hours on day 1 at about 200 mg/m 2 (e.g., FOLFOX6, mFOLFOX6, FOLFOX7).
levoleucovorin is administered as an intravenous infusion over about, for example, 2 hours at about 100 mg/m2 on both day 1 and day 2 (e.g., FOLFOX 4). In some embodiments, levoleucovorin is administered as an intravenous infusion over about, for example, 2 hours on day 1 at about 100 mg/m 2 (e.g., mFOLFOX7). In some embodiments, levoleucovorin is administered simultaneously with oxaliplatin. In some embodiments levoleucovorin is administered prior to 5FU. In alternative embodiments, a folinate salt with a similar mechanism of action as leucovorin or levoleucovorin is administered in place of leucovorin or levoleucovorin.
fluorouracil is administered initially as a bolus intravenous injection of 400 mg/m 2 on day 1 followed by administration as a continuous infusion (CI) over about 22 hours on Day 1 and a separate continuous infusion over about 22 hours on day 2 (e.g., F0LF0X4), or a single continuous infusion over about 46-48 hours beginning on Day 1 (e.g., FOLFOX6, mFOLFOX6, and FOLFOX7) of each 14-day cycle in the induction and maintenance phase.
CI continuous infusion
F0LF0X4 separate continuous infusion over about 22 hours on day 2
fluorouracil is administered initially as a bolus intravenous injection of about 400 mg/m2 on day 1 followed by administration as a continuous infusion (CI) over about 22 hours on Day 1 and a separate continuous infusion over about 22 hours on day 2 (e.g., FOLFOX4), or a single continuous infusion over about, for example, 46 hours beginning on Day 1 (e.g., FOLFOX6, mFOLFOX6, and FOLFOX7) of each 14-day cycle in the induction and maintenance phase.
the bolus dose of fluorouracil can vary, from about 240 mg/m 2 to about 400 mg/m 2 , with dosing adjustments as required.
the continuous infusion dose of fluorouracil can vary, from about 600 mg/m 2 to about 2400 mg/m 2 , with dosing adjustments as required.
the fluorouracil is administered only as a continuous infusion (CI) of about 2400 mg/m 2 over 46 hours with dosing adjustments as required (e.g., mFOLFOX7).
a 5-FU prodrug is administered instead of 5-FU.
an anti-VEGF or anti-EGFR monoclonal antibody or compound as described herein is administered on day 1. In some embodiments, the anti-VEGF or anti-EGFR monoclonal antibody or compound is administered at a dose according to the approved label.
Non-limiting representative examples of the administration of trilaciclib and FOLFOX4 protocol is provided in Table 3 and Figure 1 A.
Non-limiting representative examples of the administration of trilaciclib and FOLFOX6 protocol is provided in Table 4 and Figure IB.
Table 4 - Trilaciclib + FOLFOX6 Protocol Non-limiting representative examples of the administration of trilaciclib and mFOLFOX6 protocol is provided in Table 5 and Figure 1C.
Non-limiting representative examples of the administration of trilaciclib and FOLFOX7 protocol is provided in Table 6 and Figure ID.
Non-limiting representative examples of the administration of trilaciclib and mFOLFOX7 protocol is provided in Table 7 and Figure IE.
trilaciclib is administered intravenously (IV) on day 1 at between about 200 mg/m 2 and 280 mg/m 2 , and preferably at about 240 mg/m 2 no more than about 4 hours prior to the initiation of FOLFIRI administration, for example about 1 hour or less prior to the initiation of FOLFIRI, and administered intravenously (IV) on day 2 about 18 to 26 hours or about 22 to 24 hours after its administration on day 1.
the trilaciclib is administered on day 2 of each cycle between about 20 and 22 hours after its administration on day 1 of each cycle.
Trilaciclib can be administered at a dose of between about 200 mg/m2 to about 280 mg/m2, but preferably at about 240 mg/m2 as an intravenous injection or infusion over about 30 minutes. Trilaciclib can be administered at a dose of between about 200 mg/m 2 to about 280 mg/m 2 , but preferably at about 240 mg/m 2 .
This administration cycle for trilaciclib can be incorporated into any of the various FOLFIRI protocols, and is designed to preserve HSPCs during chemotherapy (myelo-preservation), enhance antitumor immunity (anti-tumor efficacy), and reduce other toxicities associated with administration of the protocol such as stomatitis and mucostitis.
FOLFIRI is a three-drug regimen composed of fluorouracil (5-FU), folinic acid (e.g., leucovorin or levoleucovorin), and irinotecan commonly used in the treatment of mCRC (National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology Colon Cancer. Version 2. 2019. NCCN, Fort Washington, PA). FOLFIRI is administered for a maximum of 12 induction cycles (every 14 days) followed by maintenance consisting of 5-FU and folinic acid administered in 14-day cycles until disease progression, unacceptable toxicity, etc.
5-FU fluorouracil
folinic acid e.g., leucovorin or levoleucovorin
irinotecan commonly used in the treatment of mCRC (National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology Colon Cancer. Version 2. 2019. NCCN, Fort Washington, PA).
FOLFIRI is administered for a maximum of 12 induction cycles (every 14 days) followed by maintenance consist
FOLFIRI is commonly administered in further combination with an anti-VEGF antibody, for example bevacizumab (Avastin, Genentech) or bevacizumab-awwb (Mvasi, Amgen), ramucirumab (Cyramza, Eli Lilly), or ziv-aflibercept (Zaltrap, Sanofi/Regeneron) or an anti-EGFR monoclonal antibody, for example panitumumab (Vectibix, Amgen) (for RAS wild-type (both KRAS and NRAS) CRC) or cetuximab (Erbitux, Lily) (RAS wild-type (both KRAS and NRAS) CRC).
an anti-VEGF antibody for example bevacizumab (Avastin, Genentech) or bevacizumab-awwb (Mvasi, Amgen), ramucirumab (Cyramza, Eli Lilly), or ziv-aflibercept (Zaltrap, San
irinotecan is generally administered on day 1 of each 14-day cycle of the induction phase as an intravenous infusion over about, for example, 90 minutes at a dose of between about 120 mg/m 2 and 180 mg/m 2 , with dosing adjustments as required.
irinotecan is administered as an intravenous infusion over about, for example, 90 minutes at about 180 mg/m 2 .
irinotecan is administered as an intravenous infusion over about, for example, 90 minutes at about 150 mg/m 2 .
irinotecan is administered as an intravenous infusion over about, for example, 90 minutes at about 120 mg/m 2 .
irinotecan is administered simultaneously with leucovorin.
irinotecan is administered prior to 5FU.
leucovorin is generally administered on day 1 of each 14-day cycle of the induction phase as an intravenous infusion over about, for example, 2 hours at a dose of between about 200 mg/m 2 and 400 mg/m 2 .
leucovorin is administered as an intravenous infusion over about, for example, 2 hours at about 200 mg/m 2 .
leucovorin is administered as an intravenous infusion over about, for example, 2 hours at about 400 mg/m 2 .
leucovorin is administered simultaneously as irinotecan.
leucovorin is administered prior to 5FU.
levoleucovorin is generally dosed at one-half the dose of racemic d, /-leucovorin.
levoleucovorin is generally administered on day 1 of each 14-day cycle of the induction phase as an intravenous infusion over about, for example, 2 hours at a dose of between about 100 mg/m2 and 200 mg/m2.
leucovorin is administered as an intravenous infusion over about, for example, 2 hours at about 100 mg/m2.
leucovorin is administered as an intravenous infusion over about, for example, 2 hours at about 200 mg/m2.
leucovorin is administered simultaneously as irinotecan. In some embodiments, leucovorin is administered prior to 5-FU. In alternative embodiments, a folinate salt with a similar mechanism of action as leucovorin or levoleucovorin is administered in place of leucovorin or levoleucovorin.
fluorouracil is administered either as a bolus intravenous injection, e.g., about 400 mg/m 2 , on day 1 followed by administration as a continuous infusion (CI) over about 46 hours beginning on Day 1 of each 14-day cycle in the induction and maintenance phase (e.g., FOLFIRI), or only as a continuous infusion (CI) over about 46-48 hours beginning on Day 1 of each 14-day cycle in the induction and maintenance phase (e.g., mFOLFIRI).
the bolus dose of fluorouracil can vary, from about 240 mg/m 2 to about 400 mg/m 2 , with dosing adjustments as required.
the bolus dose is about 400 mg/m 2 . In some embodiments, the bolus dose is about 320 mg/m 2 .
the continuous infusion dose of fluorouracil can vary, from about 1600 mg/m 2 to about 2800 mg/m 2 over about 46-48 hours, with dosing adjustments as required. In some embodiments, the continuous infusion dose is about 2800 mg/m 2 . In some embodiments, the continuous infusion dose is about 2400 mg/m 2 . In some embodiments, the continuous infusion dose is about 2000 mg/m 2 . In some embodiments, the continuous infusion dose is about 1600 mg/m 2 .
the fluorouracil is administered as a bolus intravenous injection of about 400 mg/m 2 on day 1 followed by administration as a continuous infusion (CI) of about 2400 mg/m 2 over about 46-48 hours. In some embodiments, the fluorouracil is administered as a bolus intravenous injection of about 320 mg/m 2 on day 1 followed by administration as a continuous infusion (CI) of about 2000 mg/m 2 over about 46-48 hours. In some embodiments, the fluorouracil is administered as a bolus intravenous injection of about 240 mg/m 2 on day 1 followed by administration as a continuous infusion (CI) of about 1600 mg/m 2 over about 46 hours. In some alternative embodiments, a 5- FU prodrug is administered instead of 5-FU.
an anti-VEGF or anti-EGFR monoclonal antibody or compound as described herein is administered on day 1.
the anti-VEGF or anti-EGFR monoclonal antibody or compound is administered at a dose according to the approved label.
Non-limiting representative examples of the administration of trilaciclib and FOLFIRI protocol is provided in Table 8 and Figure 2A.
Non-limiting representative examples of the administration of trilaciclib and mFOLFIRI protocol is provided in Table 9 and Figure 2B.
an improved FOLFOXIRI treatment protocol that includes administration of the CDK4/6 inhibitor trilaciclib.
trilaciclib is administered intravenously (IV) on day 1 no more than about 4 hours prior to the initiation of FOLFOXIRI administration, for example about 1 hour or less prior to the initiation of FOLFOXIRI, and administered intravenously (IV) on day 2 about 18 to 26 hours or about 22 to 24 hours after its administration on day 1.
the trilaciclib is administered on day 2 of each cycle between about 20 and 22 hours after its administration on day 1 of each cycle.
Trilaciclib can be administered at a dose of between about 200 mg/m 2 to about 280 mg/m 2 , but preferably at about 240 mg/m 2 as an intravenous injection or infusion over about 30 minutes.
This administration cycle for trilaciclib can be incorporated into any variation of the FOLFOXIRI protocol, and is designed to preserve HSPCs during chemotherapy (myelo-preservation), enhance anti-tumor immunity (anti-tumor efficacy), reduce other toxicities associated with administration of the protocol such as stomatitis and mucostitis, and, importantly, extend the availability of FOLFOXIRI treatment to previously excluded patients.
the trilaciclib- FOLFOXIRI protocol described herein is administered to a patient greater than 70 years of age with an ECOG of > 1.
FOLFOXIRI is a four-drug regimen composed of infusional fluorouracil (5-FU), folinic acid (e.g., leucovorin or levoleucovorin), oxaliplatin, and irinotecan commonly used in the treatment of mCRC (National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology Colon Cancer. Version 2. 2019. NCCN, Fort Washington, PA). FOLFOXIRI is administered for a maximum of 12 induction cycles (every 14 days) followed by maintenance cycles consisting of infusional-5-FU and folinic acid (leucovorin or levoleucovorin) administered in 14-day cycles until disease progression, unacceptable toxicity, etc.
5-FU infusional fluorouracil
folinic acid e.g., leucovorin or levoleucovorin
oxaliplatin e.g., oxaliplatin
irinotecan commonly used in the treatment of mCRC
FOLFOXIRI is commonly administered in further combination with an anti-VEGF antibody, for example bevacizumab (Avastin, Genentech) or bevacizumab-awwb (Mvasi, Amgen), ramucirumab (Cyramza, Eli Lilly), or ziv-aflibercept (Zaltrap, Sanofi/Regeneron) or an anti-EGFR monoclonal antibody, for example panitumumab (Vectibix, Amgen) (for RAS wild-type (both KRAS and NRAS) CRC) or cetuximab (Erbitux, Lily) (RAS wild-type (both KRAS and NRAS) CRC).
an anti-VEGF antibody for example bevacizumab (Avastin, Genentech) or bevacizumab-awwb (Mvasi, Amgen), ramucirumab (Cyramza, Eli Lilly), or ziv-aflibercept (Zaltrap
irinotecan is generally administered on day 1 of each 14-day cycle of the induction phase as an intravenous infusion over about, for example, 2 hours at a dose of between about 125 mg/m 2 and 200 mg/m 2 , with dosing adjustments as required.
irinotecan is administered as an intravenous infusion over about, for example, 2 hours at about 165 mg/m 2 .
irinotecan is administered as an intravenous infusion over about, for example, 2 hours at about 175 mg/m 2 .
irinotecan is administered prior to leucovorin and oxaliplatin administration.
leucovorin is generally administered on day 1 of each 14-day cycle of the induction and maintenance phase as an intravenous infusion over about, for example, 2 hours at a dose of between about 140 mg/m 2 to about 400 mg/m 2 , with dosing adjustments as required.
leucovorin is administered as an intravenous infusion over about, for example, 2 hours at about 200 mg/m 2 .
leucovorin is administered as an intravenous infusion over about, for example, 2 hours at about 400 mg/m 2 .
leucovorin is administered simultaneously with oxaliplatin.
leucovorin is administered after irinotecan.
leucovorin is administered prior to fluorouracil. If levoleucovorin is used, it is generally dosed at one-half the dose of racemic d,l- leucovorin, for example in FOLFOXIRI, , levoleucovorin is generally administered on day 1 of each 14-day cycle of the induction and maintenance phase as an intravenous infusion over about, for example, 2 hours at a dose of between about 70 mg/m2 to about 200 mg/m2, with dosing adjustments as required. In some embodiments, levoleucovorin is administered as an intravenous infusion over about, for example, 2 hours at about 100 mg/m2.
levoleucovorin is administered as an intravenous infusion over about, for example, 2 hours at about 200 mg/m2. In some embodiments, levoleucovorin is administered simultaneously with oxaliplatin. In some embodiments, levoleucovorin is administered after irinotecan. In some embodiments, levoleucovorin is administered prior to fluorouracil. In alternative embodiments, a folinate salt with a similar mechanism of action as leucovorin or levoleucovorin is administered in place of leucovorin or levoleucovorin.
oxaliplatin is generally administered on day 1 of each 14-day cycle of the induction phase as an intravenous infusion over about, for example, 2 hours at a dose of between about 50 mg/m 2 and 100 mg/m 2 , with dosing adjustments as required.
oxaliplatin is administered as an intravenous infusion over about, for example, 2 hours at about 85 mg/m 2 .
oxaliplatin is administered as an intravenous infusion over about, for example, 2 hours at about 100 mg/m 2 .
oxaliplatin is administered simultaneously as leucovorin.
oxaliplatin is administered after irinotecan.
oxaliplatin is administered prior to fluorouracil.
fluorouracil is administered as a continuous infusion (CI) over 48 hours beginning on Day 1 on each 14-day cycle in the Induction and Maintenance phase.
the dose of fluorouracil can vary, from about 1200 mg/m 2 to about 4000 mg/m 2 , with dosing adjustments as required.
the fluorouracil is administered as a continuous infusion over about, for example, 46-48 hours at a dose of between about 2400 mg/m 2 to about 3200 mg/m 2 , with dosing adjustments as required.
the fluorouracil is administered as a continuous infusion over about, for example, 46-48 hours at a dose of 3200 mg/m 2 .
the fluorouracil is administered as a continuous infusion over about, for example, 46-48 hours at a dose of 3800 mg/m 2 .
a 5-FU prodrug is administered instead of 5-FU.
an anti-VEGF or anti-EGFR monoclonal antibody or compound as described herein is administered on day 1. In some embodiments, the anti-VEGF or anti-EGFR monoclonal antibody or compound is administered at a dose according to the approved label.
Non-limiting representative examples of the administration of trilaciclib and FOLFOXIRI protocol is provided in Table 10 and Figure 3A.
Non-limiting representative examples of the administration of trilaciclib and an alternative FOLFOXIRI protocol is provided in Table 11 and Figure 3B.
the 5-FU is administered at a dose of about 75% of the above, that is about 1800-2400 mg/m 2 . In some embodiments of the above protocol, the 5-FU is administered at a dose of about 50% of the above, that is about 1200-1600 mg/m 2 .
the irinotecan is administered at a dose of about 75% of the above, that is about 125 mg/m 2 . In some embodiments of the above protocol, the irinotecan is administered at a dose of about 50% of the above, that is about 80 mg/m 2 . In some embodiments of the above protocol, the oxaliplatin is administered at a dose of about 75% of the above, that is about 65 mg/m 2 . In some embodiments of the above protocol, the oxaliplatin is administered at a dose of about 50% of the above, that is about 40 mg/m 2 .
the 5-FU is administered at a dose of about 75% of the above, that is about 1800-2400 mg/m 2 . In some embodiments of the above protocol, the 5-FU is administered at a dose of about 50% of the above, that is about 1200-1600 mg/m 2 . In some embodiments of the above protocol, the irinotecan is administered at a dose of about 75% of the above, that is about 125 mg/m 2 . In some embodiments of the above protocol, the irinotecan is administered at a dose of about 50% of the above, that is about 80 mg/m 2 .
the oxaliplatin is administered at a dose of about 75% of the above, that is about 65 mg/m 2 . In some embodiments of the above protocol, the oxaliplatin is administered at a dose of about 50% of the above, that is about 40 mg/m 2 .
an improved FOLFIRINOX treatment protocol that includes administration of the CDK4/6 inhibitor trilaciclib.
trilaciclib is administered intravenously (IV) on day 1 no more than about 4 hours prior to the initiation of FOLFIRINOX administration, for example about 1 hour or less, and administered intravenously (IV) on day 2 about 18 to 26 hours or about 22 to 24 hours after its administration on day 1.
the trilaciclib is administered on day 2 of each cycle between about 20 and 22 hours after its administration on day 1 of each cycle.
trilaciclib The day 2 infusion of trilaciclib is being administered to ensure that synchronization and release of the HSPC G1 arrest (-24-32 hours after a single dose of trilaciclib) does not occur while 5FU is at sufficient concentrations such that 5FU- related myelosuppression is exacerbated rather than mitigated.
This administration cycle for trilaciclib can be incorporated into any variation of the FOLFIRINOX protocol, and is designed to preserve HSPCs during chemotherapy (myelo-preservation), enhance anti-tumor immunity (antitumor efficacy), reduce other toxicities associated with administration of the protocol such as stomatitis and mucostitis, and, importantly, extend the availability of FOLFIRINOX treatment to previously excluded patients.
FOLFIRINOX is a four-drug regimen composed of bolus + intravenous fluorouracil (5- FU), intravenous folinic acid (e.g., leucovorin or levoleucovorin), intravenous oxaliplatin, and intravenous irinotecan commonly used in the treatment of mCRC (National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology Colon Cancer. Version 2. 2019. NCCN, Fort Washington, PA). FOLFIRINOX is administered for a maximum of 12 induction cycles (every 14 days) followed by maintenance cycles consisting of intravenous-5 -FU and leucovorin (folinic acid) administered in 14-day cycles until disease progression, unacceptable toxicity, etc.
5- FU intravenous fluorouracil
folinic acid e.g., leucovorin or levoleucovorin
intravenous oxaliplatin e.g., leucovorin or levoleucovorin
FOLFIRINOX is commonly administered in further combination with an anti-VEGF antibody, for example bevacizumab (Avastin, Genentech), bevacizumab-awwb (Mvasi, Amgen), ramucirumab (Cyramza, Eli Lilly), or ziv-aflibercept (Zaltrap, Sanofi/Regeneron) or an anti-EGFR monoclonal antibody, for example panitumumab (Vectibix, Amgen) (for RAS wild-type (both KRAS and NRAS) CRC) or cetuximab (Erbitux, Lily) (RAS wild-type (both KRAS and NRAS) CRC).
an anti-VEGF antibody for example bevacizumab (Avastin, Genentech), bevacizumab-awwb (Mvasi, Amgen), ramucirumab (Cyramza, Eli Lilly), or ziv-aflibercept (Zaltrap, San
oxaliplatin is generally administered on day 1 of each 14- day cycle of the induction phase as an intravenous infusion over about, for example, 2 hours at a dose of between about 60 mg/m 2 and 85 mg/m 2 , with dosing adjustments as required.
oxaliplatin is administered as an intravenous infusion over about, for example, 2 hours at about 85 mg/m 2 .
oxaliplatin is administered as an intravenous infusion over about, for example, 2 hours at about 60 mg/m 2 .
oxaliplatin is administered prior to irinotecan and leucovorin.
irinotecan is generally administered on day 1 of each 14- day cycle of the Induction phase as an intravenous infusion over about, for example, 90 minutes at a dose of between about 120 mg/m 2 and 180 mg/m 2 , with dosing adjustments as required.
irinotecan is administered as an intravenous infusion over about, for example, 90 minutes at about 180 mg/m 2 .
irinotecan is administered as an intravenous infusion over about, for example, 90 minutes at about 150 mg/m 2 .
irinotecan is administered as an intravenous infusion over about, for example, 90 minutes at about 120 mg/m 2 .
irinotecan is administered simultaneously as leucovorin.
irinotecan is administered after oxaliplatin.
irinotecan is administered prior to 5FU.
leucovorin is generally administered on day 1 of each 14- day cycle of the induction phase as an intravenous infusion over about, for example, 2 hours at a dose of between about 200 mg/m 2 and 400 mg/m 2 .
leucovorin is administered as an intravenous infusion over about, for example, 2 hours at about 200 mg/m 2 .
leucovorin is administered as an intravenous infusion over about, for example, 2 hours at about 400 mg/m 2 .
leucovorin is administered simultaneously with irinotecan.
leucovorin is administered after oxaliplatin.
leucovorin is administered prior to 5FU. If levoleucovorin is administered, it is generally administered at one-half the dose of d,l-leucovorin. For example, in the FOLFIRINOX protocol, levoleucovorin is generally administered on day 1 of each 14-day cycle of the induction phase as an intravenous infusion over about, for example, 2 hours at a dose of between about 100 mg/m 2 and 200 mg/m 2 . In some embodiments, levoleucovorin is administered as an intravenous infusion over about, for example, 2 hours at about 100 mg/m2.
levoleucovorin is administered as an intravenous infusion over about, for example, 2 hours at about 100 mg/m 2 . In some embodiments, levoleucovorin is administered simultaneously with irinotecan. In some embodiments, levoleucovorin is administered after oxaliplatin. In some embodiments, levoleucovorin is administered prior to 5FU. In alternative embodiments, a folinate salt with a similar mechanism of action as leucovorin or levoleucovorin is administered in place of leucovorin or levoleucovorin.
fluorouracil is administered initially as a bolus intravenous injection of about 400 mg/m 2 on day 1 followed by administration as a continuous infusion (CI) over about 46 hours beginning on Day 1 of each 14-day cycle in the induction and maintenance cycles.
the bolus dose of fluorouracil can vary, from about 200 mg/m 2 to about 400 mg/m 2 , with dosing adjustments as required.
the bolus dose is about 400 mg/m 2 .
the bolus dose is about 300 mg/m 2 .
the bolus dose is about 200 mg/m 2 .
the continuous infusion dose of fluorouracil can vary, from about 1200 mg/m 2 to about 2400 mg/m 2 over about 46-48 hours, with dosing adjustments as required.
the continuous infusion dose is about 2400 mg/m 2 .
the continuous infusion dose is about 1800 mg/m 2 .
the continuous infusion dose is about 1200 mg/m 2 .
the fluorouracil is administered as a bolus intravenous injection of about 400 mg/m 2 on day 1 followed by administration as a continuous infusion (CI) of about 2400 mg/m 2 over about 46-48 hours.
the fluorouracil is administered as a bolus intravenous injection of about 300 mg/m 2 on day 1 followed by administration as a continuous infusion (CI) of about 1800 mg/m 2 over about 46-48 hours. In some embodiments, the fluorouracil is administered as a bolus intravenous injection of about 200 mg/m 2 on day 1 followed by administration as a continuous infusion (CI) of about 1200 mg/m 2 over about 46-48 hours. In some alternative embodiments, a 5-FU prodrug is administered instead of 5-FU.
an anti-VEGF or anti-EGFR monoclonal antibody or compound as described herein is administered on day 1. In some embodiments, the anti-VEGF or anti-EGFR monoclonal antibody or compound is administered at a dose according to the approved label.
Non-limiting representative examples of the administration of trilaciclib and FOLFIRINOX protocol is provided in Table 12 and Figure 4.
Trilaciclib + FLOX colorectal Treatment Using Trilaciclib + FLOX
Trilaciclib is a highly potent and selective, reversible, CDK4/6 inhibitor that is administered intravenously (IV) on day 1, day 8, day 15, day 22, day 29, and day 36 of each 8-week cycle (56 days) at between about 200 mg/m 2 and 280 mg/m 2 , and preferably at about 240 mg/m 2 no more than about 4 hours prior to the initiation of FLOX administration.
This administration cycle for trilaciclib can be incorporated into any of the various FLOX protocols, and is designed to preserve HSPCs during chemotherapy (myelo-preservation), enhance anti-tumor immunity (anti-tumor efficacy), and reduce other toxicities associated with administration of the protocol such as stomatitis and mucostitis.
FLOX is a three-drug regimen composed of fluorouracil (5-FU), folinic acid (leucovorin or levoleucovorin), and oxaliplatin commonly used in the treatment of CRC (National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology Colon Cancer. Version 2. 2019. NCCN, Fort Washington, PA).
FLOX is administered for a maximum of 3 induction cycles (every 8 weeks).
FLOX can be administered in further combination with an anti-VEGF antibody, for example bevacizumab (Avastin, Genentech) or bevacizumab-awwb (Mvasi, Amgen), ramucirumab (Cyramza, Eli Lilly), or ziv-aflibercept (Zaltrap, Sanofi/Regeneron), or an anti-EGFR monoclonal antibody, for example panitumumab (Vectibix, Amgen) (for RAS wild-type (both KRAS and NRAS) CRC) or cetuximab (Erbitux, Lily) (RAS wild-type (both KRAS and NRAS) CRC).
an anti-VEGF antibody for example bevacizumab (Avastin, Genentech) or bevacizumab-awwb (Mvasi, Amgen), ramucirumab (Cy
oxaliplatin is generally administered on day 1, day 15, and day 29 of an 8-week cycle of the induction phase as an intravenous infusion over about, for example, 2 hours at a dose of between about 65 mg/m 2 and 105 mg/m 2 , with dosing adjustments as required.
oxaliplatin is administered as an intravenous infusion over about, for example, 2 hours at about 85 mg/m 2 .
oxaliplatin is administered simultaneously with leucovorin.
oxaliplatin is administered prior to leucovorin and 5FU administration.
leucovorin is generally administered on day 1, day 8, day 15, day 22, day 29, and day 36 of each 8-week cycle of the induction phase as an intravenous infusion over about, for example, 2 hours at a dose of between about 25 mg/m 2 to about 600 mg/m 2 , with dosing adjustments as required.
leucovorin is administered as an intravenous infusion over about, for example, 2 hours on day 1 at about 500 mg/m 2 .
leucovorin is administered as an intravenous infusion over about, for example, 2 hours on day 1 at about 50 mg/m 2 .
leucovorin is administered simultaneously with oxaliplatin.
leucovorin is administered after 5-FU is administered. If levoleucovorin is administered, it is generally administered at one-half the dose of d,l-leucovorin.
levoleucovorin is generally administered on day 1, day 8, day 15, day 22, day 29, and day 36 of each 8-week cycle of the induction phase as an intravenous infusion over about, for example, 2 hours at a dose of between about 12.5 mg/m 2 to about 300 mg/m 2 , with dosing adjustments as required.
levoleucovorin is administered as an intravenous infusion over about, for example, 2 hours on day 1 at about 250 mg/m 2 .
levoleucovorin is administered as an intravenous infusion over about, for example, 2 hours on day 1 at about 25 mg/m 2 .
levoleucovorin is administered simultaneously with oxaliplatin.
levoleucovorin is administered after 5-FU is administered.
a folinate salt with a similar mechanism of action as leucovorin or levoleucovorin is administered in place of leucovorin or levoleucovorin.
fluorouracil is administered as a bolus intravenous injection on day 1, day 8, day 15, day 22, day 29, and day 36 of each 8-week cycle.
the bolus dose of fluorouracil can vary, from about 200 mg/m 2 to about 1000 mg/m 2 , with dosing adjustments as required.
the fluorouracil is administered at about 500 mg/m 2 .
a 5-FU prodrug is administered instead of 5-FU.
an anti-VEGF or anti-EGFR monoclonal antibody or compound as described herein is administered on day 1, day 15, and day 29 of each 8-week cycle. In some embodiments, an anti-VEGF or anti-EGFR monoclonal antibody or compound as described herein is administered at a dose according to the approved label.
Non-limiting representative examples of the administration of trilaciclib and FLOX protocol is provided in Table 13 and Figure 5.
the inclusion of trilaciclib in a fluorouracil-based multi-agent chemotherapy protocol described herein provides for an increased anti-tumor efficacy compared to those subjects receiving a fluorouracil-based multi-agent chemotherapy protocols without trilaciclib.
Methods of accessing tumor response are well known in the art and include, for example RECIST vl .1 (Eisenhauer et al. New response evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer. 2009; 45: 228-247).
the fluorouracil -based multi-agent chemotherapy protocol is FOLFOXIRI or FOLFOXIRI + an anti- VEGF or anti-EGFR antibody or compound.
the inclusion of trilaciclib in a fluorouracil-based multi-agent chemotherapy protocol described herein provides for an increased or extended progression free survival (PFS) compared to those subjects not receiving trilaciclib.
PFS is generally defined as the time (number of months) from date of protocol administration until the date of documented radiologic disease progression or death from any cause. Methods of accessing increased PFS are well known in the art and include, for example RECIST vl. l (Eisenhauer et al. New response evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer. 2009; 45: 228-247).
the fluorouracil-based multi-agent chemotherapy protocol is FOLFOXIRI or FOLFOXIRI + an anti-VEGF or anti-EGFR antibody or compound.
the inclusion of trilaciclib in a fluorouracil-based multi-agent chemotherapy protocol described herein provides for an increased or extended overall survival (OS) compared to those subjects not receiving trilaciclib.
OS is generally calculated as the time (months) from the date of the onset of protocol administration to the date of death due to any cause.
the inclusion of trilaciclib in a fluorouracil-based multi-agent chemotherapy protocol described herein provides for an improved objective response rate (ORR) compared to those subjects not receiving trilaciclib.
ORR is generally defined as the proportion of patients with tumor size reduction of a predefined amount and for a minimum time period.
Objective response (OR) includes a complete response (CR), which is the disappearance of all signs of the tumor in response to treatment and a partial response (PR), which is a decrease in the size of a tumor in response to treatment.
the objective response (OR) is a complete response (CR).
the objective response (OR) is a partial response (PR).
ORR is an important parameter to demonstrate the efficacy of a treatment and it serves as a primary or secondary end-point in clinical trials.
Methods of assessing ORR are well known in the art and include, for example RECIST vl. l (Eisenhauer et al. New response evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer. 2009; 45: 228-247) and World Health Organization (WHO) (World Health Organization. WHO Handbook for Reporting Results of Cancer Treatment. World Health Organization Offset Publication No. 48; Geneva (Switzerland), 1979).
Statistical methods of measuring objective response rate are well known in the art and include, for example, the Clopper-Pearson Method (Clopper, C.; Pearson, E. S. (1934).
the fluorouracil -based multi-agent chemotherapy protocol is FOLFOXIRI or FOLFOXIRI + an anti- VEGF or anti-EGFR antibody or compound.
the inclusion of trilaciclib in a fluorouracil-based multi-agent chemotherapy protocol described herein provides for an improved Duration of Objective Response (DOR) compared to those subjects not receiving trilaciclib.
DOR is generally defined as the time between first objective response of CR or PR and the first date that progressive disease is objectively documented or death, whichever comes first.
Methods of assessing improved DOR are well known in the art and include, for example RECIST vl.l (Eisenhauer et al. New response evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer. 2009; 45: 228-247).
the fluorouracil-based multi-agent chemotherapy protocol is FOLFOXIRI or FOLFOXIRI + an anti-VEGF or anti-EGFR antibody or compound.
the use of trilaciclib in a fluorouracil-based multi-agent chemotherapy protocol described herein results in improved myelopreservation of hematopoietic stem and progenitor cells (HSPCs) and immune effector cells such as lymphocytes including T- lymphocytes, as well as enhanced anti -tumor efficacy in subjects compared to those receiving a fluorouracil -based multi-agent chemotherapy protocol without trilaciclib.
HSPCs hematopoietic stem and progenitor cells
lymphocytes including T- lymphocytes
HSPCs hematopoietic stem and progenitor cells
immune effector cells such as lymphocytes including T-lymphocytes
CBC complete blood count
RBC red blood cell count
WBC platelet count
WBC white blood cell count
ANC absolute neutrophil count
AEs severe adverse events
PROs patient recorded outcomes
the fluorouracil-based multi-agent chemotherapy protocol is FOLFOXIRI or FOLFOXIRI + an anti-VEGF or anti-EGFR antibody or compound.
the use of trilaciclib in a fluorouracil-based multi-agent chemotherapy protocol described herein results in myelopreservation of the neutrophil lineage in subjects compared to those receiving a fluorouracil-based multi-agent chemotherapy protocol without trilaciclib.
Endpoints to measure myelopreservation of the neutrophil lineage include a reduction in duration of severe neutropenia, for example after induction cycle 1, and the reduction in the occurrence of severe neutropenia.
Neutropenia is generally defined as a condition that results when the body does not have enough neutrophils, an important white blood cell that fights infections. The lower the neutrophil count, the more vulnerable one is to infectious diseases.
Neutropenia is generally quantified as an absolute neutrophil count (ANC) of less than 1500 per microliter (1500/pL).
Severe neutropenia is generally quantified as an absolute neutrophil count (ANC) of less than 500 per microliter (500/ pL).
Methods of calculating absolute neutrophil count (ANC) are well known in the art and include multiplying the WBC count times the percent of neutrophils in the differential WBC count. The percent of neutrophils consists of the segmented (fully mature) neutrophils) + the bands (almost mature neutrophils).
the fluorouracil -based multi-agent chemotherapy protocol is FOLFOXIRI or FOLFOXIRI + an anti- VEGF or anti-EGFR antibody or compound.
the use of trilaciclib in a fluorouracil-based multi-agent chemotherapy protocol described herein results in a reduction in the duration of severe (Grade 4) neutropenia (DSN) in subjects compared to those receiving a fluorouracil-based multi -agent chemotherapy protocol without trilaciclib.
the duration of SN (DSN) is generally defined as the number of days from the date of the first ANC value of ⁇ 0.5 x 10 9 /L to the date of the first ANC value >0.5 x 10 9 /L where no additional ANC values ⁇ 0.5 x 10 9 /L are observed for the remainder of that cycle.
Severe neutropenia is generally quantified as an absolute neutrophil count (ANC) of less than 500 per microliter (500/microL).
ANC absolute neutrophil count
Methods of calculating absolute neutrophil count (ANC) are well known in the art and include multiplying the WBC count times the percent of neutrophils in the differential WBC count.
the percent of neutrophils consists of the segmented (fully mature) neutrophils) + the bands (almost mature neutrophils).
the fluorouracilbased multi-agent chemotherapy protocol is FOLFOXIRI or FOLFOXIRI + an anti-VEGF or anti- EGFR antibody or compound.
the use of trilaciclib in a fluorouracil-based multi-agent chemotherapy protocol described herein results in a reduction of chemotherapy-induced fatigue (CIF) in subjects compared to those receiving a fluorouracil-based multi-agent chemotherapy protocol without trilaciclib.
the reduction of CIF is a reduction in the time to first confirmed deterioration of fatigue (TTCD-fatigue), as measured by the Functional Assessment of Cancer Therapy-Fatigue (FACIT-F).
FACIT-F is a 13-item subscale that measures fatigue severity and the impact of fatigue on functioning and is described in Yellen et al., Measuring fatigue and other anemia-related symptoms with the Functional Assessment of Cancer Therapy (FACT) measurement system.
the fluorouracil-based multi-agent chemotherapy protocol is FOLFOXIRI or FOLFOXIRI + an anti-VEGF or anti-EGFR antibody or compound.
the use of trilaciclib in a fluorouracil-based multi-agent chemotherapy protocol described herein results in a reduction in severe neutropenia events, a reduction in granulocyte-colony stimulating factor (G-CSF) treatment, or a reduction in febrile neutropenia (FN) adverse events (AEs).
G-CSF treatment will be utilized according to the treatment guidelines outlined in Aapro et al.
the fluorouracil-based multi-agent chemotherapy protocol is FOLFOXIRI or FOLFOXIRI + an anti-VEGF or anti-EGFR antibody or compound.
the use of trilaciclib in a fluorouracil-based multi-agent chemotherapy protocol described herein results in a reduction in Grade 3 or 4 decreased hemoglobin laboratory values, red blood cell (RBC) transfusions, or erythropoiesis-stimulating agent (ESA) administration.
the fluorouracil-based multi-agent chemotherapy protocol is FOLFOXIRI or FOLFOXIRI + an anti-VEGF or anti-EGFR antibody or compound.
the use of trilaciclib in a fluorouracil-based multi-agent chemotherapy protocol described herein results in a reduction in Grade 3 or 4 decreased platelet count laboratory values and/or the number of platelet transfusions.
platelets are generally transfused at a threshold of ⁇ 10,000/pL. Platelets are also generally transfused in any patient who is bleeding with a platelet count ⁇ 50,000/pL (100,000/pL for central nervous system or ocular bleeding).
the fluorouracil -based multi-agent chemotherapy protocol is FOLFOXIRI or FOLFOXIRI + an anti- VEGF or anti-EGFR antibody or compound.
the use of trilaciclib in a fluorouracil-based multi-agent chemotherapy protocol described herein results in a reduction in Grade 3 or 4 hematologic laboratory values.
the use of trilaciclib in a fluorouracil-based multi-agent chemotherapy protocol described herein results in a reduction in all-cause dose reductions or cycle delays and relative dose intensity or a fluorouracil-based multi-agent chemotherapy protocol described herein .
the fluorouracil-based multi-agent chemotherapy protocol is FOLFOXIRI or FOLFOXIRI + an anti-VEGF or anti-EGFR antibody or compound.
the use of trilaciclib in a fluorouracil-based multi-agent chemotherapy protocol described herein results in a reduction in i) hospitalizations, including but not limited to those due to all causes, febrile neutropenia/neutropenia, anemia/RBC transfusion, thrombocytopenia/bleeding and infections) or ii) antibiotic use, including but not limited to intravenous (IV), oral, and oral and IV administered antibiotics.
the fluorouracil -based multi-agent chemotherapy protocol is FOLFOXIRI or FOLFOXIRI + an anti- VEGF or anti-EGFR antibody or compound.
the use of trilaciclib in a fluorouracil-based multi-agent chemotherapy protocol described herein results in an improvement to one or more of: Functional Assessment of Cancer Therapy-General (FACT-G) domain scores (physical, social/family, emotional, and functional well-being); Functional Assessment of Cancer Therapy -Anemia (FACT-An): Anemia; Functional Assessment of Cancer Therapy -colorectal cancer (FACT-C) : Colorectal Cancer Subscale; 5-level EQ-5D (EQ-5D-5L); Patient Global Impression of Change (PGIC) fatigue item; or Patient Global Impression of Severity (PGIS) fatigue item.
the fluorouracil-based multi-agent chemotherapy protocol is FOLFOXIRI or FOLFOXIRI + an anti-VEGF or anti-EGFR antibody or compound.
the use of trilaciclib in a fluorouracil-based multi-agent chemotherapy protocol described herein results in a reduction in the number of severe diarrhea episodes (Grade 3 or greater) experienced by a subject compared to those a fluorouracil-based multi-agent chemotherapy protocol described herein without trilaciclib.
the fluorouracil-based multi-agent chemotherapy protocol is FOLFOXIRI or FOLFOXIRI + an anti-VEGF or anti-EGFR antibody or compound.
the use of trilaciclib in a fluorouracil-based multi-agent chemotherapy protocol described herein results in a reduction in the development of, severity of, or episodes of mucositis experienced by a subject compared to those receiving a fluorouracil-based multi-agent chemotherapy protocol described herein without trilaciclib.
the fluorouracil-based multi-agent chemotherapy protocol is FOLFOXIRI or FOLFOXIRI + an anti-VEGF or anti-EGFR antibody or compound.
the use of trilaciclib in a fluorouracil-based multi-agent chemotherapy protocol described herein results in a reduction in the development of, severity of, or episodes of stomatitis experienced by a subject compared to those receiving a fluorouracil-based multi-agent chemotherapy protocol described herein without trilaciclib.
the fluorouracil-based multi-agent chemotherapy protocol is FOLFOXIRI or FOLFOXIRI + an anti-VEGF or anti-EGFR antibody or compound.
the fluorouracil-based multi-agent chemotherapy protocols for administration to a subject with colorectal cancer, or other cancer described herein further includes the administration of an immune-checkpoint inhibitor or immune modulating agent.
the immune checkpoint inhibitor or immune modulating agent is administered on day 1 of each 14-day cycle, or every two weeks.
Example of immune checkpoint inhibitors and immune modulating agents include, but are not limited to , a PD-1 inhibitor, PD-L1 inhibitor, PD-L2 inhibitor, CTLA-4 inhibitor, LAG-3 inhibitor, TIM-3 inhibitor, V-domain Ig suppressor of T-cell activation (VISTA) inhibitors, TIGIT inhibitor, Siglec-15 inhibitor, B7-H3 (CD272) inhibitor, BTLA inhibitor (CD272), small molecule, peptide, nucleotide, or other inhibitor.
the immune modulator is an antibody, such as a monoclonal antibody.
the immune checkpoint inhibitor is a PD-1 inhibitor that blocks the interaction of PD-1 and PD-L1 by binding to the PD-1 receptor, and in turn inhibits immune suppression.
the immune checkpoint inhibitor is a PD- 1 immune checkpoint inhibitor selected from, but not limited to, nivolumab (Opdivo®), pembrolizumab (Keytruda®), pidilizumab (Medivation), AMP -224 (Amplimmune); sasanlimab (PF-06801591; Pfizer), spartalizumab (PDR001; Novartis), cemiplimab (Libtayo®; REGN2810; Regeneron), retifanlimab (MGA012; MacroGenics), tislelizumab (BGB-A317; BeiGene), camrelizumab (SHR-1210; Jiangsu Hengrui Medicine Company and Incyte Corporation
the immune checkpoint inhibitor is a PD-L1 inhibitor that blocks the interaction of PD-1 and PD-L1 by binding to the PD-L1 receptor, and in turn inhibits immune suppression.
PD-L1 inhibitors include, but are not limited to, atezolizumab (Tecentriq®, Genentech), durvalumab (Imfinzi®, AstraZeneca); avelumab (Bavencio®; Merck), envafolimab (KN035; Alphamab), BMS-936559 (Bristol-Myers Squibb), lodapolimab (LY3300054; Eli Lilly), cosibelimab (CK-301; Checkpoint Therapeutics), sugemalimab (CS- 1001; Cstone Pharmaceuticals), adebrelimab (SHR-1316; Jiangsu HengRui Medicine), CBT-502 (CBT Pharma), and BGB-A333 (BeiGene).
the immune checkpoint inhibitor is a PD-L1/VISTA inhibitor.
PD-L1-VISTA inhibitors include, but are not limited to, CA-170 (Curis Inc.).
the immune checkpoint inhibitor is a VISTA immune checkpoint inhibitor.
VISTA inhibitors include, but are not limited to, JNJ-61610588 (Johnson & Johnson).
the immune checkpoint inhibitor is a CTLA-4 immune checkpoint inhibitor that binds to CTLA-4 and inhibits immune suppression.
CTLA-4 inhibitors include, but are not limited to, ipilimumab (Yervoy®, Bristol Myers Squibb); tremelimumab (AstraZeneca/Medlmmune), zalifrelimab (AGEN1884; Agenus) and AGEN2041 (Agenus).
the immune checkpoint inhibitor is a LAG-3 immune checkpoint inhibitor.
LAG-3 immune checkpoint inhibitors include, but are not limited to, relatlimab (BMS-986016; Bristol-Myers Squibb), GSK2831781 (GlaxoSmithKline), eftilagimod alpha (IMP321; Prima BioMed), leramilimab (LAG525; Novartis), MK-4280 (Merck), REGN3767 (Regeneron), TSR-033 (Tesaro), BI754111 (Bohringer Ingelheim), Sym022 (Symphogen).
the dual PD-1 and LAG-3 inhibitor tebotelimab MMD013; MacroGenics
the dual PD-L1 and LAG-3 inhibitor FS118 F-Star
the immune checkpoint inhibitor is a TIM-3 immune checkpoint inhibitor.
TIM-3 inhibitors include, but are not limited to, TSR-022 (Tesaro), MBG453 (Novartis), Sym023 (Symphogen), INCAGN2390 (Incyte), LY3321367 (Eli Lilly and Company), BMS-986258 (BMS), SHR-1702 (Jiangsu HengRui), and RO7121661 (Roche).
the immune checkpoint inhibitor is a TIGIT (T cell immunoreceptor with Ig and ITIM domains) immune checkpoint inhibitor.
TIGIT immune checkpoint inhibitors include, but are not limited to, MK-7684 (Merck), Etigilimab /OMP- 313 M32 (OncoMed), Tiragolumab/MTIG7192A/RG-6058 (Genentech), BMS-986207 (BMS), AB-154 (Arcus Biosciences), and ASP-8374 (Potenza).
immune checkpoint inhibitors for use in the invention described herein include, but are not limited to, B7-H3/CD276 immune checkpoint inhibitors such as enoblituzumab (MGA217, Macrogenics) MGD009 (Macrogenics), 131I-8H9/omburtamab (Y-mabs), and I- 8H9/omburtamab (Y-mabs), indoleamine 2,3-dioxygenase (IDO) immune checkpoint inhibitors such as Indoximod and INCB024360, killer immunoglobulin-like receptors (KIRs) immune checkpoint inhibitors such as Lirilumab (BMS-986015), carcinoembryonic antigen cell adhesion molecule (CEACAM) inhibitors (e.g., CEACAM-1, -3 and/or -5).
B7-H3/CD276 immune checkpoint inhibitors such as enoblituzumab (MGA217, Macrogenics) MGD009 (
anti-CEACAM-1 antibodies are described in WO 2010/125571, WO 2013/082366 and WO 2014/022332, e.g., a monoclonal antibody 34B1, 26H7, and 5F4; or a recombinant form thereof, as described in, e.g., US 2004/0047858, U.S. Pat. No. 7,132,255 and WO 99/052552.
the anti- CEACAM antibody binds to CEACAM-5 as described in, e.g., Zheng et al. PLoS One. 2010 September 2; 5(9). pii: el2529 (DOI: 10: 1371/journal. pone.0021146), or cross-reacts with CEACAM-1 and CEACAM-5 as described in, e.g., WO 2013/054331 and US 2014/0271618.
Still other checkpoint inhibitors can be molecules directed to B and T lymphocyte attenuator molecule (BTLA), for example as described in Zhang et al., Monoclonal antibodies to B and T lymphocyte attenuator (BTLA) have no effect on in vitro B cell proliferation and act to inhibit in vitro T cell proliferation when presented in a cis, but not trans, format relative to the activating stimulus, Clin Exp Immunol. 2011 Jan; 163(1): 77-87, and TAB004/JS004 (Junshi Biosciences).
B and T lymphocyte attenuator molecule BTLA
the immune checkpoint inhibitor is a sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) inhibitor, including, but not limited to, NC318 (an anti- Siglec-15 mAb).
Siglec-15 sialic acid-binding immunoglobulin-like lectin 15
the fluorouracil-based multi-agent chemotherapy protocol administered to the subject does not include an immune checkpoint inhibitor or immune modulatory agent other than trilaciclib.
the selected compounds of the protocols described herein or their pharmaceutically acceptable salts can be administered as the neat chemical, but is more typically administered as a pharmaceutical composition, that includes an effective amount for a patient, typically a human, in need of such treatment in a pharmaceutically acceptable carrier.
the pharmaceutical composition may contain a compound or salt thereof as the only active agent, or, in an alternative embodiment, the compound or its salt and at least one additional active agent for the disease to be treated.
the pharmaceutical compositions may be administered in a therapeutically effective amount by any desired mode of administration, but is typically administered as an intravenous injection or infusion.
the compounds or pharmaceutically acceptable salts are delivered in an effective amount with a pharmaceutically acceptable carrier for oral delivery.
the pharmaceutical composition one suitable for oral (including buccal and sub-lingual), rectal, nasal, topical, transdermal, pulmonary, vaginal or parenteral (including intramuscular, intra-arterial, intrathecal, subcutaneous and intravenous), injections, inhalation or spray, intra-aortal, intracranial, subdermal, intraperitioneal, subcutaneous, or by other means of administration containing conventional pharmaceutically acceptable carriers.
Suitable dosage ranges depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, and the preferences and experience of the medical practitioner involved.
One of ordinary skill in the art of treating such diseases will be able, without undue experimentation and in reliance upon personal knowledge and the disclosure of this application, to ascertain a therapeutically effective amount of the compositions of the disclosure for a given disease.
the pharmaceutical composition is in a dosage form that contains from about 0.01 mg to about 1000 mg, from about 0.1 mg to about 750 mg, from about 1 mg to about 500 mg, or from about 5, 10, 15, or 20 mg to about 250 mg of the active compound or its pharmaceutically acceptable salt.
dosage forms are those delivering at least 0.01, 0.05, 0.1, 1, 5, 10, 25, 50, 100, 200, 250, 300, 400, 500, 600, 700, or 750 mg of active compound, or its salt.
the weight can refer to either the compound alone or the compound in combination with its pharmaceutially acceptable salt.
an effective amount of the disclosed compound or its salt may be administered based on the weight, size or age of the patient.
a therapeutic amount may for example be in the range of about 0.01 mg/kg to about 250 mg/kg body weight, or about 0.1 mg/kg to about 10 mg/kg, in at least one dose.
the patient can be administered as many doses as are required to reduce and/or alleviate and/or cure the disorder in question.
formulations can be prepared with enteric coatings adapted for sustained or controlled release administration of the active ingredient.
the dose ranges from about 0.01-100 mg/kg of patient body weight, for example about 0.01 mg/kg, about 0.05 mg/kg, about 0.1 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 1.5 mg/kg, about 2 mg/kg, about 2.5 mg/kg, about 3 mg/kg, about 3.5 mg/kg, about 4 mg/kg, about 4.5 mg/kg, about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 55 mg/kg, about 60 mg/kg, about 65 mg/kg, about 70 mg/kg, about 75 mg/kg, about 80 mg/kg, about 85 mg/kg, about 90 mg/kg, about 95 mg/kg, or about 100 mg/kg.
the pharmaceutical preparations are preferably in unit dosage forms.
the preparation is subdivided into unit doses containing appropriate quantities of the active component.
the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packed tablets, capsules, and powders in vials or ampoules.
the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
the compound is administered as a pharmaceutically acceptable salt.
pharmaceutically acceptable salts include: acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nit
alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethyl ammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine.
the pharmaceutical compositions can be in the form of solid, semi-solid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, syrup, suspensions, creams, ointments, lotions, paste, gel, spray, aerosol, foam, or oil, injection or infusion solution, a transdermal patch, a subcutaneous patch, an inhalation formulation, in a medical device, suppository, buccal, or sublingual formulation, parenteral formulation, or an ophthalmic solution, or the like, preferably in unit dosage form suitable for single administration of a precise dosage.
solid, semi-solid or liquid dosage forms such as, for example, tablets, suppositories, pills, capsules, powders, liquids, syrup, suspensions, creams, ointments, lotions, paste, gel, spray, aerosol, foam, or oil, injection or infusion solution, a transdermal patch, a subcutaneous patch, an inhalation formulation, in a medical device,
compositions will include an effective amount of the selected drug in combination with a pharmaceutically acceptable carrier and, in addition, can include other pharmaceutical agents, adjuvants, diluents, buffers, and the like.
Carriers include excipients and diluents and should be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the patient being treated.
the carrier can be inert or it can possess pharmaceutical benefits of its own.
the amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound.
Classes of carriers include, but are not limited to adjuvants, binders, buffering agents, coloring agents, diluents, disintegrants, excipients, emulsifiers, flavorants, gels, glidents, lubricants, preservatives, stabilizers, surfactants, solubilizer, tableting agents, wetting agents or solidifying material.
Some carriers may be listed in more than one class, for example vegetable oil may be used as a lubricant in some formulations and a diluent in others.
Exemplary pharmaceutically acceptable carriers include sugars, starches, celluloses, powdered tragacanth, malt, gelatin; talc, petroleum jelly, lanoline, polyethylene glycols, alcohols, transdermal enhancers and vegetable oils.
Optional active agents may be included in a pharmaceutical composition, which do not substantially interfere with the activity of the compound of the present invention.
excipients include, but are not limited, to liquids such as water, saline, glycerol, polyethylene glycol, hyaluronic acid, ethanol, and the like.
the compound can be provided, for example, in the form of a solid, a liquid, spray dried material, a microparticle, nanoparticle, controlled release system, etc., as desired according to the goal of the therapy.
Suitable excipients for non-liquid formulations are also known to those of skill in the art. A thorough discussion of pharmaceutically acceptable excipients and salts is available in Remington’s Pharmaceutical Sciences, 18th Edition (Easton, Pennsylvania: Mack Publishing Company, 1990).
a biological buffer can be any solution which is pharmacologically acceptable, and which provides the formulation with the desired pH, i.e., a pH in the physiologically acceptable range.
buffer solutions include saline, phosphate buffered saline, Tris buffered saline, Hank’s buffered saline, and the like.
conventional nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like.
Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, and the like, an active compound as described herein and optional pharmaceutical adjuvants in an excipient, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form a solution or suspension.
the pharmaceutical composition to be administered can also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, and the like.
auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, and the like.
permeation enhancer excipients including polymers such as: polycations (chitosan and its quaternary ammonium derivatives, poly-L- arginine, aminated gelatin); polyanions (N-carboxymethyl chitosan, poly-acrylic acid); and, thiolated polymers (carboxymethyl cellulose-cysteine, polycarbophil-cysteine, chitosanthiobutylamidine, chitosan-thioglycolic acid, chitosan-glutathione conjugates).
polycations chitosan and its quaternary ammonium derivatives, poly-L- arginine, aminated gelatin
polyanions N-carboxymethyl chitosan, poly-acrylic acid
thiolated polymers carboxymethyl cellulose-cysteine, polycarbophil-cysteine, chitosanthiobutylamidine, chitosan-thioglycoli
the excipient is selected from butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and x
compositions/combinations can be formulated for oral administration.
the composition may take the form of a tablet, capsule, a softgel capsule or can be an aqueous or nonaqueous solution, suspension or syrup.
Tablets and capsules are typical oral administration forms.
Tablets and capsules for oral use can include one or more commonly used carriers such as lactose and com starch.
Lubricating agents such as magnesium stearate, are also typically added.
compositions of the disclosure can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like.
an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like.
suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture.
suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, com sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like.
Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.
Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
the active agent can be combined with any oral, nontoxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like and with emulsifying and suspending agents. If desired, flavoring, coloring and/or sweetening agents can be added as well.
suitable inert carrier such as ethanol, glycerol, water, and the like
flavoring, coloring and/or sweetening agents can be added as well.
Other optional components for incorporation into an oral formulation herein include, but are not limited to, preservatives, suspending agents, thickening agents, and the like.
the compound can be administered, as desired, for example, via intravitreal, intrastromal, intracameral, sub-tenon, sub-retinal, retro-bulbar, peribulbar, suprachorodial, conjunctival, subconjunctival, episcleral, periocular, transscleral, retrobulbar, posterior juxtascleral, circumcomeal, or tear duct injections, or through a mucus, mucin, or a mucosal barrier, in an immediate or controlled release fashion or via an ocular device.
Parenteral formulations can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solubilization or suspension in liquid prior to injection, or as emulsions.
sterile injectable suspensions are formulated according to techniques known in the art using suitable carriers, dispersing or wetting agents and suspending agents.
the sterile injectable formulation can also be a sterile injectable solution or a suspension in a acceptably nontoxic parenterally acceptable diluent or solvent.
acceptable vehicles and solvents that can be employed are water, Ringer’s solution and isotonic sodium chloride solution.
sterile, fixed oils, fatty esters or polyols are conventionally employed as solvents or suspending media.
parenteral administration can involve the use of a slow release or sustained release system such that a constant level of dosage is maintained.
Parenteral administration includes intraarticular, intravenous, intramuscular, intradermal, intraperitoneal, and subcutaneous routes, and include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
aqueous and non-aqueous, isotonic sterile injection solutions which can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient
aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
Administration via certain parenteral routes can involve introducing the formulations of the disclosure into the body of a patient through a needle or a catheter, propelled by a sterile syringe or some other mechanical device such as a continuous infusion system.
a formulation provided by the disclosure can be administered using a syringe, injector, pump, or any other device recognized in the art for parenteral administration.
a method of treating a human having colorectal cancer comprising administering to the human an effective amount of a CDK4/6 inhibitor having the structure: , or a pharmaceutically acceptable salt thereof, wherein the CDK4/6 inhibitor is administered in a FOLFOXIRI chemotherapy protocol, and wherein the CDK4/6 inhibitor is administered i) a first time 4 hours or less prior to the initiation of FOLFOXIRI chemotherapy administration and ii) a second time between 18 hours and 26 hours after the first CDK4/6 inhibitor administration.
FOLFOXIRI chemotherapy protocol for the treatment of colorectal cancer comprising administering to the human an effective amount of a CDK4/6 inhibitor having the structure: pharmaceutically acceptable salt thereof, and wherein the CDK4/6 inhibitor is administered i) a first time 4 hours or less prior to the initiation of FOLFOXIRI chemotherapy administration and ii) a second time between 18 hours and 26 hours after the first CDK4/6 inhibitor administration.
a method of treating colorectal cancer in a human comprising: vi) administering to the human an effective amount of a CDK4/6 inhibitor having the structure: , or a pharmaceutically acceptable salt thereof; vii) administering to the human an effective amount of 5-FU; viii) administering to the human an effective amount of folinic acid; ix) administering to the human an effective amount of oxaliplatin; x) administering to the human an effective amount of irinotecan; and, xi) optionally administering to the human an anti-VEGF or anti-EGFR monoclonal antibody or compound; and wherein the CDK4/6 inhibitor is administered i) a first time 4 hours or less prior to the first to be administered of 5-FU, folinic acid, oxaliplatin, or irinotecan, and ii) a second time between 18 hours and 26 hours after the first CDK4/6 inhibitor administration.
a method of treating colorectal cancer in a human comprising i) administering to the human on day 1 and day 2 of each 14-day cycle an effective amount of a CDK4/6 inhibitor of structure: ii) administering to the human starting on day 1 of each 14-day cycle an effective amount of fluorouracil (5-FU), wherein the 5-FU is administered as a continuous infusion (CI) over a period of between about 44 and 48 hours; iii) administering to the human on day 1 of each 14-day cycle an effective amount of folinic acid; iv) administering to the human on day 1 of each 14-day cycle an effective amount of oxaliplatin; and, v) administering to the human on day 1 of each 14-day cycle an effective amount of irinotecan; and, vi) optionally administering to the human on day 1 of each 14-day cycle an anti-VEGF or anti-EGFR monoclonal antibody or compound; wherein the CDK4/6
a method of treating a human having colorectal cancer comprising administering to the human an effective amount of a CDK4/6 inhibitor having the structure: , or a pharmaceutically acceptable salt thereof, wherein the CDK4/6 inhibitor is administered in a FOLFIR.INOX chemotherapy protocol, and wherein the CDK4/6 inhibitor is administered i) a first time 4 hours or less prior to the initiation of FOLFIRINOX chemotherapy administration and ii) a second time between 18 hours and 26 hours after the first CDK4/6 inhibitor administration.
a method of reducing chemotherapy induced myelosuppression in a human undergoing a FOLFIRINOX chemotherapy protocol for the treatment of colorectal cancer comprising administering to the human an effective amount of a CDK4/6 inhibitor having the structure: pharmaceutically acceptable salt thereof, and wherein the CDK4/6 inhibitor is administered i) a first time 4 hours or less prior to the initiation of FOLFIRINOX chemotherapy administration and ii) a second time between 18 hours and 26 hours after the first CDK4/6 inhibitor administration.
a method of treating colorectal cancer in a human comprising: i) administering to the human an effective amount of a CDK4/6 inhibitor having the structure: , or a pharmaceutically acceptable salt thereof; ii) administering to the human an effective amount of 5-FU, wherein the 5-FU is administered as a bolus injection; iii) administering to the human an effective amount of 5-FU, wherein the 5-FU is administered as a continuous infusion (CI); iv) administering to the human an effective amount of folinic acid; v) administering to the human an effective amount of oxaliplatin; and, vi) administering to the human an effective amount of irinotecan; and, vii) optionally administering to the human an anti-VEGF or anti-EGFR monoclonal antibody or compound; wherein the CDK4/6 inhibitor is first administered about 4 hours or less prior to administration of the first to be administered of 5-FU, folinic acid, oxaliplatin, or irinotecan, and wherein the
a method of treating colorectal cancer in a human comprising i) administering to the human on day 1 and day 2 of each 14-day cycle an effective amount of a CDK4/6 inhibitor having the structure: or a pharmaceutically acceptable salt thereof; ii) administering to the human on day 1 of each 14-day cycle an effective amount of 5-FU, wherein the 5-FU is administered as a bolus injection; iii) administering to the human starting on day 1 of each 14-day cycle an effective amount of 5-FU, wherein the 5-FU is administered as a continuous infusion (CI) over a period of between about 44 and 48 hours beginning on day 1; iv) administering to the human on day 1 of each 14-day cycle an effective amount of
a method of treating a human having colorectal cancer comprising administering to the human an effective amount of a CDK4/6 inhibitor having the structure: or a pharmaceutically acceptable salt thereof, wherein the CDK4/6 inhibitor is administered in a FOLFOX-based chemotherapy protocol, and wherein the CDK4/6 inhibitor is administered i) a first time 4 hours or less prior to the initiation of the FOLFOX-based chemotherapy administration and ii) a second time between 18 hours and 26 hours after the first CDK4/6 inhibitor administration.
a method of reducing chemotherapy induced myelosuppression in a human undergoing a FOLFOX-based chemotherapy protocol for the treatment of colorectal cancer comprising administering to the human an effective amount of a CDK4/6 inhibitor having the structure: pharmaceutically acceptable salt thereof, and wherein the CDK4/6 inhibitor is administered i) a first time 4 hours or less prior to the initiation of FOLFOX-based chemotherapy administration and ii) a second time between 18 hours and 26 hours after the first CDK4/6 inhibitor administration.
a method of treating colorectal cancer in a human comprising: i) administering to the human an effective amount of a CDK4/6 inhibitor having the structure; , or a pharmaceutically acceptable salt thereof, ii) administering to the human an effective amount of 5-FU, wherein the 5-FU is administered as a continuous infusion (CI); iii) administering to the human an effective amount of 5-FU, wherein the 5-FU is administered as a bolus dose; iv) administering to the human an effective amount of a folinic acid; and, v) administering to the human an effective amount of oxaliplatin; and, vi) optionally administering to the human an anti-VEGF or anti-EGFR monoclonal antibody or compound; wherein the CDK4/6 inhibitor is first administered about 4 hours or less prior to administration of the first to be administered of 5-FU, folinic acid, or oxaliplatin, and wherein the CDK4/6 inhibitor is administered a second time between about 18 and 26 hours after its first administration.
a method of treating colorectal cancer in a human comprising: i) administering to the human on day 1 and day 2 of each 14-day cycle an effective amount of a CDK4/6 inhibitor having the structure; or a pharmaceutically acceptable salt thereof, ii) administering to the human on day 1 and day 2 of each 14-day cycle an effective amount of 5-FU, wherein the 5-FU is administered as a continuous infusion (CI) over a period of between about 20 and 24 hours; iii) administering on day 1 of each 14-day cycle an effective amount of 5-FU, wherein the 5-FU is administered as a bolus dose; iv) administering to the human on day 1 and day 2 of each 14-day cycle an effective amount of a folinic acid; and, v) administering to the human on day 1 of each 14-day cycle an effective amount of oxaliplatin; and, vi) optionally administering to the human on day 1 of each 14-day cycle an anti-
a method of treating colorectal cancer in a human comprising: i) administering to the human on day 1 and day 2 of each 14-day cycle an effective amount of a CDK4/6 inhibitor having the structure: or a pharmaceutically acceptable salt thereof; ii) administering to the human on day 1 of each 14-day cycle an effective amount of 5-FU, wherein the 5-FU is administered as a bolus intravenous injection; iii) administering to the human starting on day 1 of each 14-day cycle an effective amount of 5-FU, wherein the 5-FU is administered as a continuous infusion (CI) over a period of between about 44 and 48 hours; iv) administering to the human on day 1 of each 14-day cycle an effective amount of folinic acid; and, v) administering to the human on day 1 of each 14-day cycle an effective amount of oxaliplatin; and, vi) optionally administering to the human on day 1 of each 14-day cycle an anti-VEGF or anti
a method of treating a human having colorectal cancer comprising administering to the human an effective amount of a CDK4/6 inhibitor having the structure: or a pharmaceutically acceptable salt thereof, wherein the CDK4/6 inhibitor is administered in a FOLFIRI-based chemotherapy protocol, and wherein the CDK4/6 inhibitor is administered i) a first time 4 hours or less prior to the initiation of the FOLFIRI-based chemotherapy administration and ii) a second time between 18 hours and 26 hours after the first CDK4/6 inhibitor administration.
a method of reducing chemotherapy induced myelosuppression in a human undergoing a FOLFIRI-based chemotherapy protocol for the treatment of colorectal cancer comprising administering to the human an effective amount of a CDK4/6 inhibitor having the structure: pharmaceutically acceptable salt thereof, and wherein the CDK4/6 inhibitor is administered i) a first time 4 hours or less prior to the initiation of FOLFIRI-based chemotherapy administration and ii) a second time between 18 hours and 26 hours after the first CDK4/6 inhibitor administration.
a method of treating colorectal cancer in a human comprising: i) administering to the human an effective amount of a CDK4/6 inhibitor having the structure; , or a pharmaceutically acceptable salt thereof, ii) administering to the human an effective amount of 5-FU, wherein the 5-FU is administered as a continuous infusion (CI); iii) administering to the human an effective amount of a folinic acid; and, iv) administering to the human an effective amount of irinotecan; and, v) optionally administering to the human an anti-VEGF or anti-EGFR monoclonal antibody or compound; wherein the CDK4/6 inhibitor is first administered about 4 hours or less prior to administration of the first to be administered of 5-FU, folinic acid, or irinotecan, and wherein the CDK4/6 inhibitor is administered a second time between about 18 and 26 hours
a method of treating colorectal cancer in a human wherein the treatment comprises one or more 14-day cycles comprising: i) administering to the human on day 1 and day 2 of each 14-day cycle an effective amount of a CDK4/6 inhibitor having the structure: or a pharmaceutically acceptable salt thereof; ii) administering to the human starting on day 1 of each 14-day cycle an effective amount of 5-FU, wherein the 5-FU is administered as a continuous infusion (CI) over a period of between about 44 and 48 hours; iii) administering to the human on day 1 of each 14-day cycle an effective amount of folinic acid; and, iv) administering to the human on day 1 of each 14-day cycle an effective amount of irinotecan; and, v) optionally administering to the human on day 1 of each 14-day cycle an anti-VEGF or anti-EGFR monoclonal antibody or compound; wherein the
a method of treating a human with colorectal cancer comprising i) administering to the human on day 1, day 8, day 15, day 22, day 29, and day 36 of each 56-day cycle an effective amount of a CDK4/6 inhibitor having the structure: or a pharmaceutically acceptable salt thereof; ii) administering to the human on day 1, day 8, day 15, day 22, day 29, and day 36 of each 56-day cycle an effective amount of 5-FU, wherein the 5-FU is administered as a bolus injection; iii) administering to the human on day 1, day 8, day 15, day 22, day 29, and day 36 of each 56-day cycle an effective amount of folinic acid; iv) administering to the human on day 1, day 15, and day 29 of each 56-day cycle an effective amount of oxaliplatin; and, v) optionally administering to the human on day 1, day 15, and day 29 of each 56-day cycle an anti-VEGF or anti-EGFR monoclonal antibody; wherein the CDK4/6 inhibitor having the structure: or a pharmaceutically acceptable salt thereof;
CDK4/6 inhibitor is administered about 4 hour or less prior to the administration of the 5-FU.
166 The method of any of embodiments 164-165, wherein the human is further administered an anti-VEGF or an anti-EGFR antibody or compound.
HSPCs hematopoietic stem and progenitor cells
the cancer treated is not colorectal cancer but instead advanced or metastatic pancreatic cancer.
the cancer treated is not colorectal cancer but instead advanced or metastatic gastric cancer.
the cancer treated is not colorectal cancer but instead advanced or metastatic gastroesophageal junction adenocarcinoma.
the cancer treated is not colorectal cancer but instead advanced or metastatic biliary tract cancer.
the cancer treated is not colorectal cancer but instead advanced or metastatic neuroendocrine carcinoma.
the cancer treated is not colorectal cancer but instead advanced or metastatic peritoneal carcinosis.
the cancer treated is not colorectal cancer but instead advanced or metastatic liver cancer.
Example 1 A Phase 3 Randomized, Double-blind Trial of Trilaciclib versus Placebo in Patients Receiving FOLFOXIRI/Bevacizumab for Metastatic Colorectal Cancer
mCRC metastatic colorectal cancer
trilaciclib 240 mg/m 2 or placebo IV on Day 1 and Day 2 of each 14-day Induction cycle (up to 12 cycles in total).
trilaciclib/placebo will be administered no more than 4 hours prior to the start of chemotherapy administration; the second dose of trilaciclib/placebo should be administered on Day 2.
FOLFOXIREbevacizumab should not be administered until after the completion of the trilaciclib or placebo infusion on Day 1. Patients should meet the requirements to proceed before initiation of Cycle 2 and each subsequent induction cycle.
induction refers to any cycles of therapy where 5-FU and either oxaliplatin or irinotecan is also being administered, e.g., 5-FU + oxaliplatin + bevacizumab; 5-FU+ irinotecan + bevacizumab; 5-FU + oxaliplatin; or 5-FU + irinotecan.
Trilaciclib (240 mg/m 2 ) or placebo: In each 14-day cycle in Induction and Maintenance, a dose of trilaciclib 240 mg/m 2 diluted in 250 mL of dextrose 5% in water or sodium chloride solution 0.9% will be administered by IV infusion over approximately 30 ( ⁇ 10) minutes no more than 4 hours prior to each Day 1 FOUFOXIRI/bevacizumab administration. The second dose of trilaciclib should be administered on Day 2.
o 5-FU Fluorouracil 2400 - 3200 mg/m 2 - continuous infusion (CI) over 48 hours beginning on Day 1; this dose range is provided to reflect geographic variations in prescribed fluorouracil (5-FU) dose; however, the same dose should be continued throughout the study for each patient, except where dose modifications are required for toxicity management.
trilaciclib is planned to be administered on both Day 1 and Day 2 of each 14-day cycle.
the Day 2 infusion of trilaciclib is being administered to ensure that synchronization and release of the HSPC G1 arrest (-24-32 hours after a single dose of Trilaciclib) does not occur while 5FU is at sufficient concentrations such that 5FU-related myelosuppression is exacerbated rather than mitigated.
Patients who complete induction without radiographic or clinical disease progression and remain eligible to receive 5-FU/folinic acid (leucovorin or levoleucovorin)/bevacizumab will continue with maintenance. These patients include those who were able to complete the maximum of 12 induction cycles as well as those who were unable to complete 12 cycles due to toxicity (without documented disease progression) when the treating physician feels the patient will receive additional clinical benefit by transitioning to maintenance therapy. Patients will receive trilaciclib or placebo (per same randomization allocation at study entry) prior to infusional-5-FU/folinic acid (leucovorin or levoleucovorin)/bevacizumab at the same dose and schedule in each 14-day cycle during maintenance.
Infusional 5-FU/folinic acid (leucovorin or levoleucovorin)/bevacizumab should not be administered on Day 1 until after the completion of administration of the trilaciclib or placebo infusion. Patients should meet the requirements before initiation of each maintenance cycle. Since individual drugs may be discontinued for toxicity, maintenance refers to any cycles of therapy where only 5FU/folinic acid (leucovorin or levoleucovorin) or 5FU/folinic acid (leucovorin or levoleucovorin) + bevacizumab is administered. Treatment cycles will occur consecutively without interruption, except when necessary to manage toxicities or for administrative reasons.
patients Upon discontinuation of study treatment, patients will be followed for survival, i.e., patients or their caregivers will be contacted approximately every 2 months until the end of the trial (or death) to record their status (alive or dead) as well as details of any subsequent systemic anti -cancer therapy initiated.
Myelopreservation efficacy will be assessed based on reported hematology assessments, severe adverse event (AE) details, and supportive care interventions (including transfusions). Fatigue will be assessed with the Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F). Tumor response criteria including PFS, OS, duration of objective response (DOR) and best overall response (BOR) will be based on RECIST vl.l.
Safety will be evaluated by monitoring AEs, clinical laboratory test results (hematology, clinical chemistry, coagulation [international normalized ratio, activated partial thromboplastin time], and urinalysis), vital sign measurements (blood pressure, heart rate [HR], and oral body temperature), 12 lead safety electrocardiogram (ECG) results, dose modifications, and physical examination findings.
clinical laboratory test results hematology, clinical chemistry, coagulation [international normalized ratio, activated partial thromboplastin time], and urinalysis
vital sign measurements blood pressure, heart rate [HR], and oral body temperature
ECG electrocardiogram
a fixed-sequence procedure will be used for assessing treatment effects on the two primary endpoints and then the key PRO secondary endpoint, while a hierarchical testing strategy from PFS to OS is assumed. If the analyses on DSN in Cycle 1 and occurrence of SN have demonstrated statistically significant results at the 2-sided 0.04 level, the analysis for TTCD- fatigue will then be performed.
the primary myelosuppression endpoints are DSN in Cycle 1 and occurrence of SN during Induction.
Severe neutropenia is defined as the absolute neutrophil count (ANC) laboratory value that meets the common terminology criteria for adverse events (CTCAE) criteria for > Grade 4 toxicity (i.e., ANC ⁇ 0.5 x 10 9 /L in SI Unit).
CCAE common terminology criteria for adverse events
Grade 4 toxicity i.e., ANC ⁇ 0.5 x 10 9 /L in SI Unit.
the duration of SN is defined as the number of days from the date of the first ANC value of ⁇ 0.5 x 10 9 /L to the date of the first ANC value >0.5 x 10 9 /L where no additional ANC values ⁇ 0.5 x 10 9 /L are observed for the remainder of that cycle.
the occurrence of SN during Induction is defined as having SN in at least one cycle in Induction and is thus a binary variable (yes vs no).
This co-primary endpoint will be analyzed using a modified Poisson regression model with the same terms as used in the non-parametric ANCOVA model for DSN in Cycle 1 with baseline ANC value as a covariate.
the log-transformed number of cycles will be used as the offset in the model.
the adjusted relative risk (aRR) (trilaciclib vs placebo) and its 96% confidence interval will be calculated and reported along with the 2-sided p-value.
Time Months to first deterioration of fatigue (confirmed at two consecutive visits) is calculated as the duration of time from date of randomization to the date of first confirmed deterioration.
Patients who do not experience confirmed deterioration will be censored at the date of the last instrument completion (i.e., date of the last non-missing value).
Patients with no baseline assessment will be censored at the date of the baseline assessment.
the Kaplan Meier method will be used to estimate the median, 25% and 75% percentile duration of TTCD-fatigue with their corresponding 96% confidence interval.
Treatment group difference in TTCD-fatigue will be evaluated using a stratified log-rank test with the same terms as used in the non-parametric ANCOVA model for DSN in Cycle 1.
the hazard ratio (HR) between the 2 treatment groups (trilaciclib vs placebo), together with its 96% confidence intervals, will be calculated from a Cox proportional hazard model using the same terms as included in the stratified log-rank test.
Treatment effects on PFS and OS will be evaluated using the stratified log-rank test controlling for three factors of region, history of systemic cytotoxic therapy in the adjuvant/neoadjuvant setting, and presence of BRAF V600E mutation (yes, or no).
a Cox proportional hazard model with the same covariate terms as in the stratified log-rank test will be used to estimate the HR between the 2 treatment groups (trilaciclib vs placebo) for PFS and OS along with its (l-a)xl00% confidence interval, respectively.
AEs are defined as those events occurring or worsening after treatment has begun on this study. AE data will be coded to system organ class and preferred term using the Medical Dictionary for Regulatory Activities (MedDRA). The number and percentage of patients experiencing any AE overall, and by system organ class and preferred term will be tabulated for each treatment group. Adverse events considered by the investigator to be related to treatment will also be summarized by the treatment to which it is attributed (e.g., trilaciclib/placebo, fluorouracil, leucovorin, irinotecan, oxaliplatin, bevacizumab) for each treatment group. Severity of AEs will be tabulated based on greatest severity observed for each patient.
MedDRA Medical Dictionary for Regulatory Activities
Observed values and change (including maximum and minimum values) from baseline to each visit in vital signs, ECG intervals, and laboratory assessments of hematology, clinical chemistry, urinalysis, and liver function parameters will be tabulated, as appropriate.
Toxicity grades for clinical lab parameters (ego, hematology, chemistry) will be characterized according to National Cancer Institute (NCI) CTCAE v5.0, when possible. Shifts in toxicity grades from baseline to each visit, and from baseline to the worst grade during the study will be summarized. Both scheduled and unscheduled data will be included in safety evaluation. Graphical presentations of safety data will be presented as is deemed appropriate.
the pharmacokinetics of trilaciclib will be determined using a non-linear mixed effects modeling approach.
Population pharmacokinetic parameters including clearance (CL), volume of distribution (V), and other parameters will be estimated as data permit.
Tumor lesions will be categorized as follows:
Measurable lesions tumor lesions with a longest diameter (measured in at least 1 dimension) with a minimum size as follows:
- Measurable lymph nodes must be > 15 mm on the short axis by CT or MRI (with a scan slice thickness of no greater than 5 mm); only the short axis is to be measured at baseline and follow-up.
- Lytic bone lesions or mixed lytic-blastic lesions with a soft tissue component meeting the definition of measurability above can be considered measurable lesions.
Cystic lesions representing cystic metastases that meet the definition of measurability described above can be considered measurable lesions. If present, noncystic lesions should be selected as target lesions for this study.
a tumor lesion that has been previously irradiated may be considered measurable if unequivocal growth of the lesion has been demonstrated.
Target lesions At baseline, up to 5 measurable tumor lesions/lymph nodes (with a maximum of 2 lesions per organ) should be identified as target lesions. Lesions with the longest diameter, that are representative of all involved organs, and for which reproducible repeated measurements can be obtained should be selected as the target lesions. Malignant lymph node is considered an organ in this study, therefore only 2 malignant lymph nodes (regardless of location) may be selected as target lesions and all others should be entered as nontarget lesions.
Non-measurable Lesions tumor lesions with a longest diameter ⁇ 10 mm, lymph nodes with > 10 to ⁇ 15 mm short axis, or non-measurable lesions such as leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, or abdominal masses/abdominal organomegaly identified by physical exam that is not measurable by CT scan or MRI.
Nontarget lesions All other lesions (or sites of disease) identified at baseline should be identified as nontarget lesions and recorded in the eCRF. Measurements of these lesions are not required, but the presence, absence, or unequivocal progression of each nontarget lesion should be recorded in the eCRF at each follow up time point. Multiple nontarget lesions in the same organ may be noted as a single item on the eCRF.
the definitions for tumor response for the target lesion per RECIST vl .1 are as follows:
Non-CR/Non-PD Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits.
- Progressive Disease Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. ‘Unequivocal progression’ represents a substantial increase in overall tumor burden such that treatment should be discontinued even in the setting of stable disease (SD) or PR in the target disease. Although a clear progression of “non-target” lesions only is rare, the opinion of the treating physician should prevail in such circumstances.

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