WO2014193589A1 - Procédé de traitement du cancer - Google Patents

Procédé de traitement du cancer Download PDF

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Publication number
WO2014193589A1
WO2014193589A1 PCT/US2014/035991 US2014035991W WO2014193589A1 WO 2014193589 A1 WO2014193589 A1 WO 2014193589A1 US 2014035991 W US2014035991 W US 2014035991W WO 2014193589 A1 WO2014193589 A1 WO 2014193589A1
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WIPO (PCT)
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combination
tafinlar
human
trametinib
patients
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PCT/US2014/035991
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English (en)
Inventor
Roya Behbahani
Robin L. CARSON
Mark J. CORNFELD
Christine E. DABROWSKI
Tona M. Gilmer
Vicki L. GOODMAN
Mary E. GUCKERT
Angela HUGHES-EARLE
Stephen R. LANE
Jeffrey J. Legos
Anne-Marie MARTIN
Daniele OUELLET
Kiran A. PATEL
Eric M. RICHARDS
Lauren E. RICHARDS-PETERSON
Sharon RUDO
Peng Sun
R. Suzanne SWANN
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Glaxosmithkline Llc
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Publication of WO2014193589A1 publication Critical patent/WO2014193589A1/fr

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    • 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
    • A61K31/395—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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • This invention relates to a method of treating cancer in a human by the in vivo administration of: N- ⁇ 3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7- trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin- 1 -yljphenyl ⁇ acetamide dimethyl sulfoxide solvate, represented r referred to as Compound A:
  • cancer results from the deregulation of the normal processes that control cell division, differentiation and apoptotic cell death.
  • Apoptosis (programmed cell death) plays essential roles in embryonic development and pathogenesis of various diseases, such as degenerative neuronal diseases, cardiovascular diseases and cancer.
  • One of the most commonly studied pathways, which involves kinase regulation of apoptosis, is cellular signaling from growth factor receptors at the cell surface to the nucleus (Crews and Erikson, Cell, 74:215-17, 1993).
  • MEK Mitogen-activated protein
  • MAP Mitogen-activated protein
  • ERK extracellular signal-regulated kinase
  • MEK Mitogen-activated protein
  • the Raf family (B-Raf, C-Raf etc.) activates the MEK family (MEK- 1 , MEK-2 etc.) and the MEK family activates the ERK family (ERK- 1 and ERK-2).
  • the signaling activity of the RAF/MEK/ERK pathway controls mRNA translation. This includes genes related to the cell cycle. Hence, hyperactivation of this pathway can lead to uncontrolled cell proliferation.
  • RAF/MEK/ERK pathway by ERK hyperactivation is seen in approximately 30% of all human malignancies (Allen, LF, et al. Semin. Oncol. 2003. 30(5 Suppl 16): 105-16).
  • RAS which can signal through both the PI3K/AKT and RAF/MEK/ERK, has a mutated oncogenic protein in 15% of all cancers (Davies, H. et al. Nature. 2002. 417:949-54).
  • activating BRAF mutations have been identified at a high frequency in specific tumor types (e.g., melanomas) (Davies, H. et al. Nature. 2002. 417:949-54).
  • MEK inhibitory activity effectively induces inhibition of ERK 1/2 activity and suppression of cell proliferation (The Journal of Biological Chemistry, vol. 276, No. 4, pp. 2686-2692, 2001), and the compound is expected to show effects on diseases caused by undesirable cell proliferation, such as tumor genesis and/or cancer.
  • Compound B is a compound which is disclosed and claimed, along with
  • Compound B is the compound of Example 4-1.
  • Compound B can be prepared as described in International Application No. PCT/JP2005/01 1082. Compound B can be prepared as described in United States Patent Publication No. US
  • Compound B is the compound of Example 4-1.
  • Compound B is in the form of a dimethyl sulfoxide solvate, or Compound A as defined herein.
  • Compound B is in the form of a solvate selected from: hydrate, acetic acid, ethanol, nitromethane, chlorobenzene, 1-pentanol, isopropyl alcohol, ethylene glycol and 3- methyl- 1 -butanol.
  • Solvates and salt forms can be prepared by one of skill in the art, for example from the description in International Application No. PCT/JP2005/01 1082 or United States Patent Publication No. US 2006/0014768.
  • Compound A is prepared in Example 4- 149 of United States Patent Publication No. US 2006/0014768.
  • cholangiocarcinoma Tetracranial pressure (Tannapfel et al Gut (2003) 52(5) 706-712), central nervous system tumors including primary CNS tumors such as glioblastomas, astrocytomas and ependymomas (Knobbe et al Acta Neuropathol. (Berl.) (2004) 108(6) 467-470, Davies (2002) supra, and Garnett et al., Cancer Cell (2004) supra) and secondary CNS tumors (i.e., metastases to the central nervous system of tumors originating outside of the central nervous system), colorectal cancer, including large intestinal colon carcinoma (Yuen et al Cancer Res.
  • leukemias Garnett et al., Cancer Cell (2004) supra, particularly acute lymphoblastic leukemia (Garnett et al., Cancer Cell (2004) supra and Gustafsson et al Leukemia (2005) 19(2) 310-312
  • AML acute myelogenous leukemia
  • AML acute myelogenous leukemia
  • myelodysplasia syndromes Christiansen et al Leukemia (2005) supra
  • chronic myelogenous leukemia Mizuchi et al Biochem.
  • Raf family kinases By virtue of the role played by the Raf family kinases in these cancers and exploratory studies with a range of preclinical and therapeutic agents, including one selectively targeted to inhibition of B-Raf kinase activity (King A.J., et al., (2006) Cancer Res. 66: 1 1 100- 1 1 105), it is generally accepted that inhibitors of one or more Raf family kinases will be useful for the treatment of such cancers or other condition associated with Raf kinase.
  • B-Raf has also been implicated in other conditions, including cardio-facio cutaneous syndrome (Rodriguez-Viciana et al Science (2006) 31 1(5765) 1287- 1290) and polycystic kidney disease (Nagao et al Kidney Int. (2003) 63(2) 427-437).
  • methanesulfonate salt (Collectively used herein as Compound C) are compounds which are disclosed and claimed, along with pharmaceutically acceptable salts thereof, as being useful as inhibitors of BRAF activity, particularly in treatment of cancer, in PCT application
  • PCT/US09/42682 Compound C is embodied by Examples 58a through 58e of the application.
  • the PCT application was published on 12 November 2009 as publication WO2009/137391, and is hereby incorporated by reference.
  • This invention comprises a method of administering Compound A, or Compound B or a pharmaceutically acceptable salt or solvate thereof, in combination with Compound C; which method takes into account adverse reactions of the compound.
  • This invention comprises a method of administering Compound A, or Compound B or a pharmaceutically acceptable salt or solvate thereof, in combination with Compound C; which method takes into account the toxicology of the compound.
  • This invention comprises a method of administering Compound A, or Compound B or a pharmaceutically acceptable salt or solvate thereof, in combination with Compound C; which method takes into account the risk for Retinal Vein Occlusion caused by the combination.
  • This invention comprises a method of administering Compound A, or Compound B or a pharmaceutically acceptable salt or solvate thereof, in combination with Compound C; which method takes into account use in specific populations for the combination.
  • This invention comprises a method of administering Compound A, or Compound B or a pharmaceutically acceptable salt or solvate thereof, in combination with Compound C; which method takes into account Skin Toxicity caused by the combination.
  • This invention comprises a method of administering Compound A, or Compound B or a pharmaceutically acceptable salt or solvate thereof, in combination with Compound C; which method takes into account Retinal Pigment Epithelial Detachment caused by the combination.
  • This invention comprises a method of administering Compound A, or Compound B or a pharmaceutically acceptable salt or solvate thereof, in combination with Compound C; which method takes into account Cardiomyopathy caused by the combination.
  • This invention comprises a method of administering Compound A, or Compound B or a pharmaceutically acceptable salt or solvate thereof, in combination with Compound C; which method takes into account Interstitial Lung Disease and/or pneumonitis caused by the combination.
  • This invention comprises a method of administering Compound A, or Compound B or a pharmaceutically acceptable salt or solvate thereof, in combination with Compound C; which method takes into account the clinical pharmacology of the combination.
  • This invention comprises a method of administering Compound A, or Compound B or a pharmaceutically acceptable salt or solvate thereof, in combination with Compound C; which method takes into account Drug Interactions of the compound.
  • This invention comprises a method of administering Compound A, or Compound B or a pharmaceutically acceptable salt or solvate thereof, in combination with Compound C; which method takes into account febrile reactions caused by the combination.
  • This invention comprises a method of administering Compound A, or Compound B or a pharmaceutically acceptable salt or solvate thereof, in combination with Compound C; which method takes into account thromboembolic events caused by the combination.
  • TAFINLAR is a kinase inhibitor indicated as single agent for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA- approved test. (1.1, 2.1)
  • TAFINLAR in combination with trametinib is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutation as detected by an FDA-approved test. (1.2, 2.1) This indication is based on the demonstration of durable response rate. Improvement in disease-related symptoms or overall survival has not been demonstrated with TAFINLAR in combination with trametinib. (1.2, 14.1) Limitation of use: TAFINLAR is not indicated for treatment of patients with wild- type BRAF melanoma. (1.3, 5.2)
  • the recommended dose as a single agent or in combination with trametinib is 150 mg orally twice daily taken at least 1 hour before or at least 2 hours after a meal.
  • New Primary Malignancies New primary malignancies, cutaneous and non-cutaneous, can occur when TAFINLAR is administered as a single agent or when used in combination with trametinib. Monitor patients for cutaneous and non-cutaneous malignancies prior to initiation of therapy, every 2 months while on therapy, and for up to 6 months following discontinuation of TAFINLAR. (5.1)
  • Hemorrhage Major hemorrhagic events can occur in patients receiving TAFINLAR in combination with trametinib. Monitor for signs and symptoms of bleeding. (5.3, 2.3)
  • ⁇ Thromboembolic Events Deep vein thrombosis and pulmonary embolism can occur in patients receiving TAFINLAR in combination with trametinib. (5.4, 2.3)
  • Hyperglycemia Monitor serum glucose levels in patients with pre-existing diabetes or hyperglycemia. (5.9)
  • Embryofetal Toxicity Can cause fetal harm. Advise females of reproductive potential of potential risk to a fetus. TAFINLAR may render hormonal contraceptives less effective and an alternative method of contraception should be used. (5.1 1, 8.1)
  • TAFINLAR ® as a single agent is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test.
  • TAFINLAR in combination with trametinib, is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test. This indication is based on the demonstration of durable response rate [see
  • TAFINLAR The recommended dosage regimens of TAFINLAR are:
  • TAFINLAR as a single agent, or TAFINLAR in combination with trametinib, at least 1 hour before or 2 hours after a meal [see Clinical Pharmacology (12.3)] . Do not take a missed dose of TAFINLAR within 6 hours of the next dose. Do not open, crush, or break TAFINLAR Capsule.
  • trametinib When administered in combination with trametinib, take the once-daily dose of trametinib at the same time each day with either the morning dose or the evening dose of TAFINLAR.
  • TAFINLAR is used in combination with trametinib, do not modify the dose of either TAFINLAR or trametinib.
  • TAFINLAR is used in combination with trametinib, withhold trametinib for up to 3 weeks and also interruption of TAFINLAR should be considered for recurrent events.
  • TAFINLAR is administered as a or 4 skin toxicity that does not single agent, permanently discontinue improve within 3 weeks despite TAFINLAR.
  • TAFINLAR is used in combination baseline and is below LLN that with trametinib, resume trametinib at a improves to normal LVEF value reduced dose level. Do not modify the within 4 weeks following dose of TAFINLAR.
  • TAFINLAR is used in combination with trametinib, withhold trametinib for up to 3 weeks. Do not modify the dose of TAFINLAR
  • TAFINLAR is used in combination with trametinib, do not modify the trametinib dose.
  • CCAE National Cancer Institute Common Terminology Criteria for Adverse Events
  • Capsules Dark red capsule imprinted with 'GS TEW and '50 mg'.
  • Capsules Dark pink capsule imprinted with 'GS LHF' and '75 mg'.
  • TAFINLAR is used in combination with trametinib, are not described in the TAFINLAR Full Prescribing Information:
  • New primary malignancies cutaneous and non-cutaneous, can occur when TAFINLAR is administered as a single agent or when used in combination with trametinib.
  • TAFINLAR as single-agent results in an increased incidence of cutaneous squamous cell carcinoma, keratoacanthoma, and melanoma.
  • TAFINLAR when used in combination with trametinib results in an increased incidence of basal cell carcinoma.
  • Cutaneous squamous cell carcinoma occurred in 7% of patients receiving TAFINLAR in combination with trametinib and 19% of patients receiving single-agent TAFINLAR.
  • the range of time to diagnosis of cuSCC was 136 tol97 days in the combination arm and was 9 to - 197 days in the single-agent TAFINLAR arm.
  • New primary melanoma occurred in 2% (1/53) of patients receiving single-agent TAFINLAR and in none of the 55 patients receiving TAFINLAR in combination with trametinib.
  • Non-cutaneous Malignancies Based on its mechanism of action, TAFINLAR may promote the growth and development of malignancies associated with activation of RAS through mutation or other mechanisms [see Warnings and Precautions (5.2)].
  • TAFINLAR may promote the growth and development of malignancies associated with activation of RAS through mutation or other mechanisms [see Warnings and Precautions (5.2)].
  • Monitor patients receiving the combination closely for signs or symptoms of other malignancies. Permanently discontinue TAFINAR for RAS mutation-positive non-cutaneous malignancies. If used in combination with trametinib, no dose modification is needed for trametinib in patients who develop non-cutaneous malignancies.
  • Hemorrhages including major hemorrhages, defined as symptomatic bleeding in a critical area or organ, can occur when TAFINLAR is used in combination with trametinib.
  • TAFINLAR The major hemorrhagic events of intracranial or gastric hemorrhage occurred in 5% (3/55) of patients treated with TAFINLAR in combination with trametinib compared with none of the 53 patients treated with single-agent TAFINLAR. Intracranial hemorrhage was fatal in two (4%) patients receiving the combination of TAFINLAR and trametinib.
  • Venous thromboembolism can occur when TAFINLAR is used in combination with trametinib.
  • Cardiomyopathy can occur when TAFINLAR is used in combination with trametinib and with trametinib as a single-agent [refer to the trametinib Full Prescribing Information] .
  • cardiomyopathy occurred in 9% (5/55) of patients treated with TAFINLAR in combination with trametinib and in none of patients treated with single-agent TAFINLAR.
  • the median time to onset of cardiomyopathy in patients treated with TAFINLAR in combination with trametinib was 86 days (range: 27 to 253 days).
  • Cardiomyopathy was identified within the first month of treatment with TAFINLAR in combination with trametinib in 2 of 5 patients. In all five patients, cardiomyopathy resolved and resulted in dose reduction.
  • Retinal Pigment Epithelial Detachment Retinal pigment epithelial detachments (RPED) can occur when TAFINLAR is used in combination with trametinib and with single-agent trametinib [refer to the trametinib Full Prescribing Information] .
  • Retinal detachments resulting from trametinib are often bilateral and multifocal, occurring in the macular region of the retina.
  • Uveitis and Iritis can occur when TAFINLAR is administered as a single agent or when used in combination with trametinib.
  • Uveitis occurred in 1% (6/586) of patients treated with single-agent TAFINLAR and uveitis occurred in 1% (2/202) of patients treated with TAFINLAR in combination with trametinib.
  • Symptomatic treatment employed in clinical trials included steroid and mydriatic ophthalmic drops. Monitor patients for visual signs and symptoms of uveitis (e.g., change in vision, photophobia, eye pain). If diagnosed, withhold TAFINLAR until uveitis/iritis resolves to Grade 0- 1. If TAFINLAR is used in combination with trametinib, do not modify the dose of trametinib.
  • the incidence of fever (serious and non-serious) was 28% in patients treated with TAFINLAR and 10% in patients treated with dacarbazine.
  • TAFINLAR the median duration of fever was 6 days with the combination compared with 4 days with single- agent TAFINLAR.
  • Withhold TAFINLAR for fever of 101.3°F or for any serious febrile reaction or fever a by accompanied hypotension, rigors or chills, dehydration, or renal failure and evaluate for signs and symptoms of infection.
  • withhold trametinib if used in combination with TAFINLAR for any fever higher than 104°F or any serious febrile drug reaction.
  • Prophylaxis with antipyretics may be required when resuming TAFINLAR.
  • Use of oral corticosteroids should be considered in patients with recurrent pyrexia for whom anti-pyretics are insufficient.
  • Serious skin toxicity can occur when TAFINLAR is used in combination with trametinib and with single-agent trametinib [refer to the trametinib Full Prescribing Information] .
  • the median time to onset of skin toxicity in patients treated with TAFINLAR in combination with trametinib was 37 days (range 1 to 225 days) and median time to resolution of skin toxicity was 33 days (range: 3 to 421 days). No patient required reduction in the dose of TAFINLAR and trametinib or permanent discontinuation of TAFINLAR and trametinib for skin toxicity.
  • Hyperglycemia can occur when TAFINLAR is administered as a single agent or when used in combination with trametinib.
  • TAFINLAR which contains a sulfonamide moiety, confers a potential risk of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Closely observe patients with G6PD deficiency for signs of hemolytic anemia.
  • G6PD glucose-6-phosphate dehydrogenase
  • TAFINLAR can cause fetal harm when administered to a pregnant woman.
  • Dabrafenib was teratogenic and embryotoxic in rats at doses three times greater than the human exposure at the recommended clinical dose. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)].
  • BRAF V600 E Unresectable or Metastatic Melanoma The safety of TAFINLAR as a single agent was evaluated in 586 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma, previously treated or untreated, who received TAFINLAR 150 mg orally twice daily until disease progression or unacceptable toxicity, including 181 patients treated for at least 6 months and 86 additional patients treated for more than 12 months.
  • TAFINLAR was studied in open-label, single-arm trials and in an open-label, randomized, active-controlled trial. The median daily dose of TAFINLAR was 300 mg (range: 1 18 to 300 mg).
  • Table 3 and Table 4 present adverse drug reactions and laboratory abnormalities identified from analyses of Trial 1 [see Clinical Studies (14)].
  • the trial excluded patients with abnormal left ventricular ejection fraction or cardiac valve morphology (>Grade 2), corrected QT interval >480 milliseconds on electrocardiogram, or a known history of glucose-6-phosphate dehydrogenase deficiency.
  • the median duration on treatment was 4.9 months for patients treated with TAFINLAR and 2.8 months for dacarbazine-treated patients.
  • the population exposed to TAFINLAR was 60% male, 99% white, and had a median age of 53 years.
  • TAFINLAR The most commonly occurring adverse reactions (>20%) in patients treated with TAFINLAR were, in order of decreasing frequency: hyperkeratosis, headache, pyrexia, arthralgia, papilloma, alopecia, and palmar-plantar erythrodysesthesia syndrome (PPES).
  • d Includes squamous cell carcinoma of the skin and keratoacanthoma.
  • Gastrointestinal Disorders Pancreatitis.
  • Immune System Disorders Hypersensitivity manifesting as bullous rash.
  • BRAF V600 E or V600K Unresectable or Metastatic Melanoma The safety of TAFINLAR in combination with trametinib was evaluated in Trial 2 and other trials consisting of a total of 202 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma who received
  • TAFINLAR 150 mg orally twice daily in combination with trametinib 2 mg orally once daily until disease progression or unacceptable toxicity Among these 202 patients, 66 (33%) were exposed to TAFINLAR and 68 (34%) were exposed to trametinib for greater than 6 to 12 months while 40 (20%) were exposed to TAFINLAR and 36 (18%) were exposed to trametinib for greater than one year. The median age was 54 years, 57% were male, and >99% were white.
  • LVEF history of acute coronary syndrome within 6 months, current evidence of Class II or greater congestive heart failure (New York Heart Association), history RVO or RPED, QTc interval >480 msec, treatment refractory hypertension, uncontrolled arrhythmias, history of pneumonitis or interstitial lung disease, or a known history of G6PD deficiency were excluded.
  • the median duration of treatment was 10.9 months for both TAFINLAR and trametinib (2 mg orally once daily treatment group) when used in combination, 10.6 months for both TAFINLAR and trametinib (1 mg orally once daily treatment group) when used in combination, and 6.1 months for single-agent TAFINLAR.
  • abdominal pain Includes the following terms: abdominal pain, abdominal pain upper, abdominal pain lower, and abdominal discomfort.
  • peripheral edema Includes the following terms: peripheral edema, edema, and lymphedema.
  • renal failure and renal failure acute Includes the following terms: renal failure and renal failure acute.
  • brain stem hemorrhage cerebral hemorrhage, gastric hemorrhag epistaxis, gingival hemorrhage, hematuria, vaginal hemorrhage, hemorrhage intracranial, eye hemorrhage, and vitreous hemorrhage.
  • Neoplasms Benign, Malignant, and Unspecified including cvsts and polyps: Skin papilloma.
  • Vascular Disorders Hypertension.
  • Skin and Subcutaneous Tissue Disorders Palmar-plantar erythrodysesthesia syndrome, hyperkeratosis, hyperhidrosis.
  • Gastrointestinal Disorders Stomatitis, pancreatitis.
  • ALT Alanine aminotransferase
  • AST Aspartate aminotransferase
  • GGT Gamma glutamyltransferase. 7 DRUG INTERACTIONS
  • Dabrafenib is primarily metabolized by CYP2C8 and CYP3A4. Strong inhibitors of CYP3A4 or CYP2C8 may increase concentrations of dabrafenib and strong inducers of CYP3A4 or CYP2C8 may decrease concentrations of dabrafenib [see Clinical Pharmacology (12.3)]. Substitution of strong inhibitors or strong inducers of CYP3A4 or CYP2C8 is recommended during treatment with TAFINLAR.
  • CYP3A4 or CYP2C8 If concomitant use of strong inhibitors (e.g., ketoconazole, nefazodone, clarithromycin, gemfibrozil) or strong inducers (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, St John's wort) of CYP3A4 or CYP2C8 is unavoidable, monitor patients closely for adverse reactions when taking strong inhibitors or loss of efficacy when taking strong inducers.
  • strong inhibitors e.g., ketoconazole, nefazodone, clarithromycin, gemfibrozil
  • strong inducers e.g., rifampin, phenytoin, carbamazepine, phenobarbital, St John's wort
  • Drugs that alter the pH of the upper GI tract may alter the solubility of dabrafenib and reduce its bioavailability.
  • proton pump inhibitors e.g., proton pump inhibitors, H 2 -receptor antagonists, antacids
  • TAFINLAR coadministered with a proton pump inhibitor, H 2 -receptor antagonist, or antacid
  • systemic exposure of dabrafenib may be decreased and the effect on efficacy of TAFINLAR is unknown.
  • Dabrafenib induces CYP3A4 and CYP2C9. Dabrafenib decreased the systemic exposures of midazolam (a CYP3A4 substrate), S-warfarin (a CYP2C9 substrate), and R-warfarin (a
  • CYP3A4/CYP1A2 substrate [see Clinical Pharmacology (12.3)] .
  • Coadministration of TAFINLAR with other substrates of these enzymes, including dexamethasone or hormonal contraceptives, can result in decreased concentrations and loss of efficacy [see Use in Specific Populations (8.1, 8.6)]. Substitute for these medications or monitor patients for loss of efficacy if use of these medications is unavoidable.
  • Pregnancy Category D Risk Summary: Based on its mechanism of action, TAFINLAR can cause fetal harm when administered to a pregnant woman. Dabrafenib was teratogenic and embryotoxic in rats at doses 3 times greater than the human exposure at the recommended clinical dose of 150 mg twice daily based on AUC. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Warnings and Precautions (5.7)] .
  • Contraception Females: Advise female patients of reproductive potential to use highly effective contraception during treatment and for at least 2 week after the last dose of TAFINLAR or at least 4 months after the last dose of TAFINLAR taken in combination with trametinib. Counsel patients to use a non-hormonal method of contraception since TAFINLAR can render hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR [see Warnings and Precautions (5.7), Drug Interactions (7.1), Use in Specific Populations (8.1)] .
  • Infertility Females: Increased follicular cysts and decreased corpora lutea were observed in female rats treated with trametinib. Advise female patients of reproductive potential that
  • TAFINLAR taken in combination with trametinib may impair fertility in female patients.
  • Dabrafenib mesylate is a kinase inhibitor.
  • the chemical name for dabrafenib mesylate is N- ⁇ 3-[5- (2-Amino-4-pyrimidinyl)-2-(l , 1-dimethylethyl)- 1 ,3-thiazol-4-yl]-2-fluorophenyl ⁇ -2,6- difluorobenzene sulfonamide, methanesulfonate salt. It has the molecular formula C 23 H 2 oF 3 N 5 0 2 S 2 »CH 4 0 3 S and a molecular wei ht of 615.68. Dabrafenib mesylate has the
  • Dabrafenib mesylate is a white to slightly colored solid with three pK a s: 6.6, 2.2, and -1.5. It is very slightly soluble at pH 1 and practically insoluble above pH 4 in aqueous media.
  • TAFINLAR (dabrafenib) capsules are supplied as 50-mg and 75-mg capsules for oral
  • Each 50-mg capsule contains 59.25 mg dabrafenib mesylate equivalent to 50 mg of dabrafenib free base.
  • Each 75-mg capsule contains 88.88 mg dabrafenib mesylate equivalent to 75 mg of dabrafenib free base.
  • the inactive ingredients of TAFINLAR are colloidal silicon dioxide, magnesium stearate, and microcrystalline cellulose.
  • Capsule shells contain hypromellose, red iron oxide (El 72), and titanium dioxide (El 71).
  • Dabrafenib is an inhibitor of some mutated forms of BRAF kinases with in vitro IC 50 values of 0.65, 0.5, and 1.84 nM for BRAF V600E, BRAF V600K, and BRAF V600D enzymes, respectively. Dabrafenib also inhibits wild-type BRAF and CRAF kinases with IC 5 o values of 3.2 and 5.0 nM, respectively, and other kinases such as SIK1, NEK1 1, and LIMK1 at higher concentrations. Some mutations in the BRAF gene, including those that result in BRAF V600E, can result in constitutively activated BRAF kinases that may stimulate tumor cell growth [see Indications and Usage (I)].
  • Dabrafenib inhibits BRAF V600 mutation-positive melanoma cell growth in vitro and in vivo. Dabrafenib and trametinib target two different tyrosine kinases in the RAS/RAF/MEK/ERK pathway. Use of dabrafenib and trametinib in combination resulted in greater growth inhibition of BRAF V600 mutation-positive melanoma cell lines in vitro and prolonged inhibition of tumor growth in BRAF V600 mutation positive melanoma xenografts compared with either drug alone. 12.3 Pharmacokinetics
  • Dabrafenib is 99.7% bound to human plasma proteins.
  • the apparent volume of distribution (V c /F) is 70.3 L.
  • Metabolism The metabolism of dabrafenib is primarily mediated by CYP2C8 and CYP3A4 to form hydroxy-dabrafenib. Hydroxy-dabrafenib is further oxidized via CYP3A4 to form carboxy- dabrafenib and subsequently excreted in bile and urine. Carboxy-dabrafenib is decarboxylated to form desmethyl-dabrafenib; desmethyl-dabrafenib may be reabsorbed from the gut. Desmethyl- dabrafenib is further metabolized by CYP3A4 to oxidative metabolites.
  • Hydroxy-dabrafenib terminal half- life (10 hours) parallels that of dabrafenib while the carboxy- and desmethyl- dabrafenib metabolites exhibited longer half- lives (21 to 22 hours).
  • Mean metabolite-to-parent AUC ratios following repeat-dose administration are 0.9, 1 1, and 0.7 for hydroxy-, carboxy-, and desmethyl-dabrafenib, respectively. Based on systemic exposure, relative potency, and pharmacokinetic properties, both hydroxy- and desmethyl-dabrafenib are likely to contribute to the clinical activity of dabrafenib.
  • Fecal excretion is the major route of elimination accounting for 71% of radioactive dose while urinary excretion accounted for 23% of total radioactivity as metabolites only.
  • Age has no effect on dabrafenib pharmacokinetics. Pharmacokinetic differences based on gender and on weight are not clinically relevant.
  • Renal No formal pharmacokinetic trial in patients with renal impairment has been conducted.
  • the pharmacokinetics of dabrafenib were evaluated using a population analysis in 233 patients with mild renal impairment (GFR 60 to 89 mL/min/1.73 m 2 ) and 30 patients with moderate renal impairment (GFR 30 to 59 mL/min/1.73 m 2 ) enrolled in clinical trials.
  • Mild or moderate renal impairment has no effect on systemic exposure to dabrafenib and its metabolites. No data are available in patients with severe renal impairment.
  • Hepatic No formal pharmacokinetic trial in patients with hepatic impairment has been conducted. The pharmacokinetics of dabrafenib was evaluated using a population analysis in 65 patients with mild hepatic impairment enrolled in clinical trials. Mild hepatic impairment has no effect on systemic exposure to dabrafenib and its metabolites. No data are available in patients with moderate to severe hepatic impairment.
  • dabrafenib is a substrate of CYP3A4 and CYP2C8 while hydroxy- dabrafenib and desmethyl-dabrafenib are CYP3A4 substrates.
  • Coadministration of dabrafenib 75 mg twice daily and ketoconazole 400 mg once daily (a strong CYP3A4 inhibitor) for 4 days increased dabrafenib AUC by 71%, hydroxy-dabrafenib AUC by 82%, and desmethyl-dabrafenib AUC by 68%.
  • Dabrafenib is a substrate of human P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in vitro.
  • P-gp human P-glycoprotein
  • BCRP breast cancer resistance protein
  • dabrafenib is an inducer of CYP3A4 and CYP2B6 via activation of the pregnane X receptor (PXR) and constitutive androstane receptor (CAR) nuclear receptors. Dabrafenib may also induce CYP2C enzymes via the same mechanism. Coadministration of dabrafenib 150 mg twice daily for 15 days and a single dose of midazolam 3 mg (a CYP3A4 substrate) decreased midazolam AUC by 74%.
  • Dabrafenib and its metabolites, hydroxy-dabrafenib, carboxy-dabrafenib, and desmethyl- dabrafenib are inhibitors of human organic anion transporting polypeptide OATPIBI, OATP1B3 and organic anion transporter OAT1 and OAT3 in vitro. Dabrafenib and desmethyl-dabrafenib are inhibitors of BCRP in vitro.
  • TAFINLAR increased the risk of cutaneous squamous cell carcinomas in patients in clinical trials.
  • Dabrafenib was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay, and was not clastogenic in an in vivo rat bone marrow micronucleus test.
  • Randomization was stratified by disease stage at baseline [unresectable stage III (regional nodal or in- transit metastases), Mia (distant skin, subcutaneous, or nodal metastases), or Mlb (lung metastases) vs. Mlc melanoma (all other visceral metastases or elevated serum LDH)].
  • the main efficacy outcome measure was progression- free survival (PFS) as assessed by the investigator.
  • PFS progression- free survival
  • IRRC independent radiology review committee assessed the following efficacy outcome measures in pre- specified supportive analyses: PFS, confirmed objective response rate (ORR), and duration of response.
  • the median age of patients in Trial 1 was 52 years. The majority of the trial population was male (60%), white (99%), had an ECOG performance status of 0 (67%), Mlc disease (66%), and normal LDH (62%). All patients had tumor tissue with mutations in BRAF V600E as determined by a clinical trial assay at a centralized testing site. Tumor samples from 243 patients (97%) were tested retrospectively, using an FDA-approved companion diagnostic test, THxIDTM-BRAF assay.
  • the median durations of follow-up prior to initiation of alternative treatment in the patients treated with TAFINLAR was 5.1 months and in the dacarbazine arm was 3.5 months. Twenty-eight (44%) patients crossed over from the dacarbazine arm at the time of disease progression to receive TAFINLAR.
  • Trial 1 demonstrated a statistically significant increase in progression- free survival in the patients treated with TAFINLAR.
  • Table 7 and Figure 1 summarize the PFS results.
  • CI Confidence interval
  • CR Complete response
  • HR Hazard ratio
  • NR Not reached
  • PR Partial response.
  • Cohort B patients in Cohort B were required to have evidence of disease progression in a previously treated lesion or an untreated lesion. Additional eligibility criteria were at least one measurable lesion of 0.5 cm or greater in largest diameter on contrast-enhanced MRI, stable or decreasing corticosteroid dose, and no more than two prior systemic regimens for treatment of metastatic disease.
  • the primary outcome measure was estimation of the overall intracranial response rate (OIRR) in each cohort.
  • the median age of patients in Cohort A was 50 years, 72% were male, 100% were white, 59% had a pre-treatment ECOG performance status of 0, and 57% had an elevated LDH value at baseline.
  • the median age of patients in Cohort B was 51 years, 63% were male, 98% were white, 66% had a pre-treatment ECOG performance status of 0, and 54% had an elevated LDH value at baseline.
  • Efficacy results as determined by an independent radiology review committee, masked to investigator response assessments, are provided in Table 8.
  • IRRC Independent radiology review committee
  • CI Confidence interval
  • NR Not reached. 14.2 BRAF V600E or V600K Unresectable or Metastatic Melanoma
  • Trial 2 was a multicenter, open- label, randomized (1 : 1 : 1) dose-ranging trial designed to evaluate the clinical activity and safety of TAFINLAR in combination with trametinib (at two different doses) and to compare the safety with single-agent TAFINLAR in 162 patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma. Patients were permitted to have had one prior chemotherapy regimen and prior aldesleukin; patients with prior exposure to BRAF or MEK inhibitors were ineligible.
  • the major efficacy outcome measure was investigator-assessed overall response rate (ORR). Additional efficacy outcome measures were investigator-assessed duration of response, independent radiology review committee (IRRC)-assessed ORR, and IRRC-assessed duration of response.
  • the median age of patients was 53 years, 57% were male, >99% were white, 66% of patients had a pre-treatment ECOG performance status of 0, 67% had Mlc disease, 54% had a normal LDH at baseline, and 8% had history of brain metastases. Most patients (81%) had not received prior anti- cancer therapy for unresectable or metastatic disease. Based on local laboratory or centralized testing, 85% of patients' tumors had BRAF V600E mutations and 15% had BRAF V600K mutations.
  • ORR Confirmed overall response rate
  • NR Not reported.
  • the ORR results were similar in subgroups defined by BRAF mutation subtype, i.e., in the 85% of patients with V600E mutation-positive melanoma and in the 15% of patients with V600K mutation-positive melanoma.
  • BRAF mutation subtype i.e., in the 85% of patients with V600E mutation-positive melanoma and in the 15% of patients with V600K mutation-positive melanoma.
  • the ORR results were also similar to the intent-to-treat analysis. 16 HOW SUPPLIED/STORAGE AND HANDLING
  • Capsules Dark red capsule imprinted with 'GS TEW' and '50 mg' available in bottles of 120 (NDC 0173-0846-08). Each bottle contains a silica gel desiccant. 75 mg Capsules: Dark pink capsule imprinted with 'GS LHF' and '75 mg' available in bottles of 120 (NDC 0173-0847-08). Each bottle contains a silica gel desiccant.
  • TAFINLAR administered in combination with trametinib increases the risk of intracranial and gastrointestinal hemorrhage.
  • • TAFINLAR can cause visual disturbances. Advise patients to contact their healthcare provider if they experience any changes in their vision [see Warnings and Precautions [see Warnings and Precautions (5.6)]. • TAFINLAR can cause pyrexia including serious febrile reactions. The incidence and severity of pyrexia are increased when TAFINLAR is given in combination with trametinib. Instruct patients to contact their doctor if they experience a fever while taking TAFINLAR [see Warnings and Precautions (5.7)].
  • TAFINLAR can impair glucose control in diabetic patients resulting in the need for more intensive hypoglycemic treatment. Advise patients to contact their doctor to report symptoms of severe hyperglycemia [see Warnings and Precautions (5.9)]. ⁇ TAFINLAR may cause hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Advise patients with known G6PD deficiency to contact their doctor to report signs or symptoms of anemia or hemolysis [see Warnings and Precautions (5.10)].
  • G6PD glucose-6-phosphate dehydrogenase
  • TAFINLAR can cause fetal harm if taken during pregnancy. Instruct female patients to use non-hormonal, highly effective contraception during treatment and for 4 weeks after treatment. Advise patients to contact their doctor if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR [see Warnings and Precautions (5.11) and Use in Specific
  • TAFINLAR should be taken either at least 1 hour before or at least 2 hours after a meal [see Dosage and Administration (2.1)].
  • TAFINLAR is a registered trademark of the Glaxo SmithKline group of companies.
  • THxID is a trademark of bioMerieux.
  • TAFINLAR used by itself or in combination with trametinib may cause serious side effects, including:
  • TAFINLAR may cause new cancers, including cutaneous squamous cell carcinoma (cuSCC) that can spread to other parts of the body. Talk with your healthcare provider about your risk for developing skin cancers or other cancers.
  • cuSCC cutaneous squamous cell carcinoma
  • Your healthcare provider should check your skin before you start taking TAFINLAR, and every two months while taking TAFINLAR to look for any new skin cancers. Your healthcare provider may continue to check your skin for up to six months after you stop taking TAFINLAR, or until you start another therapy for your cancer.
  • Your healthcare provider should also check for cancers that may not occur on the skin. Tell your healthcare provider about any new symptoms that have developed while taking TAFINLAR.
  • TAFINLAR is a prescription medicine which is used by itself or in combination with trametinib to treat a type of skin cancer called melanoma:
  • TAFINLAR is not used to treat people with a type of skin cancer called wild-type BRAF melanoma.
  • TAFINLAR Before you start taking TAFINLAR, tell your healthcare provider if you: have liver, kidney, or heart problems, have eye problems, have lung or breathing problems, have diabetes, plan to have surgery, dental, or other medical procedures, have a deficiency of the glucose-6-phosphate dehydrogenase (G6PD) enzyme, have any other medical conditions, are pregnant or plan to become pregnant. TAFINLAR can harm your unborn baby.
  • G6PD glucose-6-phosphate dehydrogenase
  • birth control using hormones may not work as well while you are taking TAFINLAR. You should use another effective method of birth control while taking TAFINLAR. Talk to your healthcare provider about birth control methods that may be right for you.
  • TAFINLAR may cause lower sperm counts in men. This could affect the ability to father a child. Talk to your healthcare provider if this is a concern for you. Talk to your healthcare provider about family planning options that might be right for you.
  • TAFINLAR can affect each other, causing side effects.
  • TAFINLAR may affect the way other medicines work, and other medicines may affect how TAFINLAR works. You can ask your pharmacist for a list of medicines that may interact with TAFINLAR.
  • trametinib only once a day at the same each day, either in the morning or in the evening at the same time as TAFINLAR. See trametinib patient information leaflet on how to take trametinib. • Take TAFINLAR at least 1 hour before or 2 hours after a meal.
  • TAFINLAR may cause serious side effects, including:
  • Heart problems including heart failure • Heart problems including heart failure. TAFINLAR in combination with trametinib can cause heart problems including heart failure. Tell your healthcare provider right away if you develop following signs and symptoms of a heart problem:
  • TAFINLAR can cause fever, including severe fever. In some cases, too much fluid loss (dehydration), low blood pressure, dizziness, or kidney problems may happen with the fever. Tell your healthcare provider right away if you get a fever while taking TAFINLAR. More severe cases of fever may occur when TAFINLAR is used in combination with trametinib.
  • TAFINLAR Tell your healthcare provider right away if you get these symptoms during treatment with TAFINLAR:
  • TAFINLAR when used by itself include: thickening of the outer layers of the skin, headache, joint aches, warts, hair loss, redness, swelling, peeling, or tenderness of hands or feet.
  • TAFINLAR when used in combination with trametinib include: tiredness, feeling sick to your stomach (nausea) or vomiting, diarrhea, swelling of the face, arms, or legs, cough, skin rash, loss of appetite, night sweats, constipation, muscle pain
  • Inactive ingredients colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose Capsule shells contain: hypromellose, red iron oxide (El 72), titanium dioxide (El 71).
  • the amount of Compound A required to achieve the label claim of Compound B (the free or un-solvated compound) is calculated utilizing the molecular conversion factor of 0.8873 for the ratio of Compound B (un-solvated) to compound A (the DMSO solvate), and based on the purity value from the certificate of analysis. The amount of Mannitol is adjusted accordingly.
  • NP not present in formulation.
  • micronized drug substance sodium lauryl sulfate, silicon dioxide, croscarmellose sodium, microcrystalline cellulose and hypromellose are screened, if required, and transferred into a suitable bin blender and blended.
  • the magnesium stearate is screened, if required, transferred to the bin blender and blended for an additional time.
  • the lubricated blend is compressed on a rotary tablet press to the target weight for each strength (145 mg, 155 mg and 165 mg corresponding to 0.5 mg, 1 mg and 2 mg, respectively).
  • the compressed tablets are sampled for in-process monitoring of individual weight variation, appearance, hardness, thickness, friability and disintegration time.
  • Tablet cores are sprayed with an aqueous suspension of Opadry® Pink YS- 1-14762- A) (for 2 mg strength), Opadry® Yellow YS-1- 12525-A (for 0.5 mg strength) or Opadry® White OY- S-28876 (for 1 mg strength). Coating continues until a target weight gain of approximately 3% is attained. The tablets are then dried and bulk packed into HDPE containers with plastic liners and desiccant bags, and stored until packaged.
  • TAFINLAR is a well known marketed product.
  • Pharmaceutical dosages of Tafinlar are made by methods well known to those of skill in the art.

Abstract

La présente invention concerne des procédés de traitement du cancer chez un humain nécessitant un tel traitement qui comprend l'administration d'une quantité thérapeutiquement efficace d'une combinaison de : N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phénylamino)-6,8-diméthyl-2,4,7-trioxo-3,4,6,7-tétrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phényl}acétamide, ou un sel ou solvate associé ; et N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-diméthyléthyl)-1,3-thiazol-4-yl]-2-fluorophényl}-2,6-difluorobenzènesulfonamide ou un sel ou solvate associé, à un tel humain. La présente invention concerne en outre des procédés de traitement du cancer chez un humain nécessitant un tel traitement qui comprend l'administration d'une quantité thérapeutiquement efficace d'une combinaison de : diméthylsulfoxyde de N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phénylamino)-6,8-diméthyl-2,4,7-trioxo-3,4,6,7-tétrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phényl}acétamide et méthanesulfonate de N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-diméthyléthyl)-1,3-thiazol-4-yl]-2-fluorophényl}-2,6-difluorobenzènesulfonamide, à un tel humain.
PCT/US2014/035991 2013-05-29 2014-04-30 Procédé de traitement du cancer WO2014193589A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012068468A1 (fr) * 2010-11-19 2012-05-24 Glaxosmithkline Llc Méthode de traitement utilisant un inhibiteur de la braf

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012068468A1 (fr) * 2010-11-19 2012-05-24 Glaxosmithkline Llc Méthode de traitement utilisant un inhibiteur de la braf

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"Australia and New Zealand Consumer Medicine Information. MEKANIST trametinib (as dimethyl sulfoxide", 6 February 2013 (2013-02-06), Retrieved from the Internet <URL:http://www.***.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=1&ved=0CB4QFjAA&url=http%3A%2F%2Fwww.gsk.com.au%2Fresources.ashx%2Fprescriptionmedicinesproductschilddatadownloads%2F2818%2FFile%2FC7AB994046B5DF387A74CAA6E07B46DF%2FTrametinibTablet_AU_NZ_CMI_001_Approved.pdf&ei=sZXzU4zYJNbioASa2oG> [retrieved on 20140818] *
"LOOKCHEM.com Dabrafenib", 2008, pages 1 - 2, Retrieved from the Internet <URL:http://www.lookchem.com/Dabrafenib> [retrieved on 20140818] *
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FLAHERTY ET AL.: "Combined BRAF and MEK Inhibition in Melanoma with BRAF V600 Mutations .", N ENGL J MED, vol. 367, no. 18, November 2012 (2012-11-01), pages 1694 - 1703, XP002725869, doi:10.1056/NEJMoa1210093 *
KIM ET AL.: "Phase II study of the MEK1/MEK2 inhibitor Trametinib in patients with metastatic BRAF-mutant cutaneous melanoma previously treated with or without a BRAF inhibitor.", J CLIN ONCOL, vol. 31, no. 4, 1 February 2013 (2013-02-01), pages 482 - 489, XP055131610, Retrieved from the Internet <URL:http://www.lookchem.com/GSK-1120212> [retrieved on 20140818], doi:10.1200/JCO.2012.43.5966 *

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