WO2018060833A1

WO2018060833A1 - Dosage regimen for alpha-isoform selective phosphatidylinositol 3-kinase inhibitor alpelisib

Info

Publication number: WO2018060833A1
Application number: PCT/IB2017/055814
Authority: WO
Inventors: Marie-Caroline GERMA; Cristina Karen RODRIGUEZ LORENC
Original assignee: Novartis Ag
Priority date: 2016-09-27
Filing date: 2017-09-26
Publication date: 2018-04-05

Abstract

Methods of treating or preventing a proliferative disease in a human in need thereof by orally administering to said human a daily dose of about 100 mg to about 450 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof each day for a period of three weeks and then not administering said compound to said human for one week immediately thereafter and then repeating this cycle for one to several cycles; use of said compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing a proliferative disease administered in accordance with said dosage regimen; a therapeutic regimen comprising administration of said compound of formula (I) or a pharmaceutically acceptable salt thereof in accordance with said dosage regimen; and related pharmaceutical compositions and packages thereof.

Description

DOSAGE REGIMEN FOR ALPHA-ISOFORM SELECTIVE PHOSPHATIDYLINOSITOL 3-KINASE INHIBITOR ALPELISIB

Field of the Invention

The present invention relates to a method of treating or preventing a proliferative disease in a human in need thereof by orally administering to said human a daily dose of about 100 mg to about 450 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof each day for a period of three weeks and then not administering said compound to said human for one week immediately thereafter and then repeating this cycle for one to several cycles; use of said compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing a proliferative disease administered in accordance with said dosage regimen; a therapeutic regimen comprising administration of said compound of formula (I) or a pharmaceutically acceptable salt thereof in accordance with said dosage regimen; and related pharmaceutical compositions and packages thereof.

Background of the Invention

Phosphatidylinositol 3-kinases ( "PI3K") comprise a family of lipid kinases that catalyze the transfer of phosphate to the D-3' position of inositol lipids to produce phosphoinositol-3- phosphate ("PIP"), phosphoinositol-3,4-diphosphate ("PIP2") and phosphoinositol-3,4,5- triphosphate ("PIP3") that, in turn, act as second messengers in signaling cascades by docking proteins containing pleckstrin-homology, FYVE, Phox and other phospholipid-binding domains into a variety of signaling complexes often at the plasma membrane (Vanhaesebroeck et al., Annu. Rev. Biochem 70:535 (2001 ); Katso et al., Annu. Rev. Cell Dev. Biol. 17:615 (2001 )). Human cells contain three genes (PIK3CA, PIK3CB and PIK3CD) encoding the catalytic p1 10 subunits (α, β, δ isoforms) of class IA PI3K enzymes. These catalytic p1 10a, p1 10β, and p1 105 subunits are constitutively associated with a regulatory subunit that can be p85a, p55a, p50a, ρ85β or ρ55γ. p1 10a and p1 10β are expressed in most tissues. Class 1 B PI3K has one family member, a heterodimer composed of a catalytic p1 10γ subunit associated with one of two regulatory subunits, either the p101 or the p84 (Fruman et al., Annu Rev. Biochem. 67:481 (1998); Suire et al., Curr. Biol. 15:566 (2005)). The modular domains of the p85/55/50 subunits include Src Homology (SH2) domains that bind phosphotyrosine residues in a specific sequence context on activated receptor and cytoplasmic tyrosine kinases, resulting in activation and localization of Class 1A PI3Ks. Class 1 B, as well as ρ1 10β in some circumstances, is activated directly by G protein-coupled receptors that bind a diverse repertoire of peptide and non-peptide ligands (Stephens et al., Cell 89: 105 (1997)); Katso et al., Annu. Rev. Cell Dev. Biol. 17:615-675 (2001)). Consequently, the resultant phospholipid products of class I PI3K link upstream receptors with downstream cellular activities including proliferation, survival, chemotaxis, cellular trafficking, motility, metabolism, inflammatory and allergic responses, transcription and translation (Cantley et al., Cell 64:281 (1991 ); Escobedo and Williams, Nature 335:85 (1988); Fantl et al., Cell 69:413 (1992)).

Aberrant regulation of PI3K, which often increases survival through Akt activation, is one of the most prevalent events in human cancer and has been shown to occur at multiple levels. The tumor suppressor gene PTEN, which dephosphorylates phosphoinositides at the 3' position of the inositol ring and in so doing antagonizes PI3K activity, is functionally deleted in a variety of tumors. In other tumors, the genes for the p1 10a isoform, PIK3CA, and for Akt are amplified and increased protein expression of their gene products has been demonstrated in several human cancers. Furthermore, mutations and translocation of p85a that serve to up-regulate the p85-p1 10 complex have been described in human cancers. Finally, somatic missense mutations in PIK3CA that activate downstream signaling pathways have been described at significant frequencies in a wide diversity of human cancers, including 32% of colorectal cancers, 27% of glioblastomas, 25% of gastric cancers, 36% of hepatocellular carcinomas, and 18-40% of breast cancers. (Samuels et al., Cell Cycle 3(10):1221 (2004); Hartmann et al, Acta Neuropathol., 109(6):639 (June 2005); Li et al, BMC Cancer 5 :29 (March 2005) ; Lee et al, Oncogene, 24(8):1477 (2005); Backman et al, Cancer Biol. Ther. 3(8): 772-775 (2004);

Campbell et al., Cancer Research, 64(21 ): 7678-7681 (2004); Levine et al., Clin. Cancer Res., 1 1 (8): 2875-2878 (2005); and Wu et al, Breast Cancer Res., 7(5):R609-R616 (2005)).

Deregulation of PI3K, including the a-isoform, is one of the most common deregulations associated with human cancers and proliferative diseases (Parsons et al., Nature 436:792 (2005); Hennessey at el., Nature Rev. Drug Disc. 4:988-1004 (2005)). SJ-Pyrrolidine-1 ,2-dicarboxylic acid 2-amide 1 -({4-methyl-5-[2-(2,2,2-trifluoro-1 , 1- dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl}-amideJ is a specific 2-carboxamide cycloamino urea derivative compound that potently and selectively targets the alpha (a)-isoform of class IA PI3K. (See, e.g., Examples A and C of PCT Application No. WO2010/029082). This compound has the following chemical structure:

(hereinafter, "compound of formula (I)" or "Compound A" or "Alpelisib"). The compound of formula (I) and pharmaceutically acceptable salts thereof, suitable formulations, and its method of preparation are described in PCT Application WO2010/029082.

In a Phase I clinical trial, this alpha-isoform selective PI3K inhibitor compound Alpelisib demonstrated clinical efficacy in the single-agent treatment of human patients having advanced solid malignancies carrying an alteration in the PIK3CA gene. In the dose escalation phase, patients were orally administered this compound either (a) at a dosage ranging from 30 mg to 450 mg once per day (q.d.) on a continuous daily schedule for 28-days, or (b) at a dosage ranging from 120 mg to 200 mg twice per day (b.i.d.) on a continuous daily schedule for 28- days, as guided by Bayesian logistic regression model with overdose control. After determination of the maximal tolerated dose (MTD), the dose expansion phase was conducted to additionally treat patients having head and neck cancer with a PIK3CA alteration, patients having solid tumors with PIK3CA alteration, and patients having PIK3CA wildtype ER+/ HER2- breast cancer. Clinical efficacy of this compound has been demonstrated preliminarily. As of February 15, 2013, confirmed partial responses have been observed in several patients treated at > 270 mg/day, including patients suffering from breast cancer (1 patient, confirmed), colorectal cancer (1 patient confirmed), endometrial cancer (1 patient, confirmed) and cervical cancer (1 patient confirmed). (Gonzalez-Angulo et al., "Safety, pharmacokinetics, and preliminary activity of the a-specific PI3K inhibitor BYL719: results from the first-in-human study", Presentation at the 2013 ASCO Annual Meeting, held May 31 -June 4, 2013 in Chicago,

IL.)

Despite the clinical efficacy of this compound in this Phase I clinical trial, some human patients administered this compound on the once per day or twice per day continuous daily schedule demonstrated at least one side effect or adverse event including, but not limited to, hyperglycemia (49% of patients), nausea (43% of patients), decreased appetite (34% of patients), diarrhea (35% of patients), rash and hypersensitivity (34% of patients), asthenia/ fatigue (34% of patients), vomiting, stomatitis, dysgeusia, and/or dyspepsia. (Gonzalez-Angulo et al., Presentation at the 2013 ASCO Annual Meeting, held May 31 -June 4, 2013 in Chicago, IL.)

In an ongoing Phase Ib/ll clinical trial, some adult post-menopausal patients having locally advanced or metastatic Hormone Receptor-positive /HER2-negative breast cancer experienced grade 3 or 4 elevations of Alanine Aminotransferase/ Glutamic Pyruvic

Transaminase/ GPT ("ALT") or Aspartate Aminotransferase/ Glutamic Oxaloacetic

Transaminase/ GOT ("AST") after administration of the combination of CDK 4/6 inhibitor Ribociclib , alpha-isoform selective PI3K inhibitor compound Alpelisib (morning dosing on continuous daily schedule), and letrozole. Such elevations of ALT and AST are associated with hepatic dysfunction and/or hepatobiliary toxicity.

Currently, there is an unmet need for a potent alpha (a)-isoform selective PI3K inhibitor which can be administered to human patients in a dosage or dosage regimen that is therapeutically effective for treatment of a proliferative disease, particularly a cancer, but also that relieves, reduces, or alleviates side effects (e.g, by severity, occurrence rate, or frequency) of the drug. It is believed that this has not been achieved for any alpha-isoform selective PI3K inhibitor prior to the present invention. It is believed that the dosage regimen of the present invention could improve safety and tolerability of the alpha-isoform selective PI3K inhibitor compound Alpelisib and may relieve, reduce or alleviate the severity, occurrence or frequency of side effects, particularly hepatobiliary toxicity, in patients administered said drug.

Summary of the Invention

The present invention relates to a method of treating or preventing a proliferative disease in a human in need thereof comprising orally administering to said human a daily dose of about 100 mg to about 450 mg of the compound of formula (I)

or a pharmaceutically acceptable salt thereof each day for a period of three weeks and then not administering said compound of formula (I) or a pharmaceutically salt thereof to said human for one week immediately thereafter and then repeating this cycle for one to several cycles.

The present invention further relates to the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing a proliferative disease, wherein said medicament is orally administered to a human in need thereof in a daily dose of about 100 mg to about 450 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof each day for a period of three weeks and then not administered to said human for one week immediately thereafter, and wherein this cycle is repeated for from one to several cycles.

The present invention further relates to the compound of formula (I) or a

pharmaceutically acceptable salt thereof is for use in the treatment or prevention of a proliferative disease, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is orally administered to a human in need thereof in a daily dose of about 100 mg to about 450 mg each day for a period of three weeks and then not administered to said human for one week immediately thereafter, and wherein this cycle is repeated for one to several cycles.

The present invention further relates to a method of treating or preventing a proliferative disease in a human in need thereof comprising orally administering to said human a daily dose of about 100 mg to about 450 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof each day for a period of three weeks and then not administering said compound of formula (I) or a pharmaceutically salt thereof to said human for one week immediately thereafter and then repeating this cycle for one cycle to several cycles until the proliferative disease is treated, or until the disease progresses, or until at least one side effect is relieved, reduced, or alleviated in severity, occurrence rate, or frequency in the human.

The present invention further relates to a method of treating or preventing a proliferative disease in a human in need thereof comprising orally administering to said human a daily dose of about 100 mg to about 450 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof each day for a period of three weeks and then not administering said compound of formula (I) or a pharmaceutically salt thereof to said human for one week immediately thereafter and then repeating this cycle for one to several cycles, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with at least one additional therapeutic agent. The present invention further relates to a therapeutic regimen comprising orally administering to a human suffering from a proliferative disease a daily dose of about 100 mg to about 450 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof each day for a period of three weeks and then not administering said compound of formula (I) or a pharmaceutically acceptable salt thereof to said human for one week immediately thereafter, and then repeating this cycle for one to several cycles.

The present invention further relates to a package comprising a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients together with instructions to orally administer said pharmaceutical composition at a daily dose of about 100 mg to about 450 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof each day for a period of three weeks and then to not administer said pharmaceutical composition to said human for one week immediately thereafter, and then to repeat this cycle for one to several cycles.

Detailed Description of the Invention

For purpose of the present invention, the period of three weeks that the compound of formula (I) is administered to the human in need thereof may be referred to as the "treatment period". The period of one week that the compound of formula (I) is not administered to the human in need thereof may be referred to as the "interruption period". Each "cycle" of the dosage regimen of the present invention comprises one treatment period and one interruption period. The first day that the first dose of the compound of formula (I) or any pharmaceutically acceptable salt thereof is administered to the patient is considered to be the first day of the treatment period. The first day that the first dose of the compound of formula (I) is not administered to the patient after such treatment period is considered to be the first day of the interruption period.

The general terms used herein are defined with the following meanings, unless explicitly stated otherwise:

The terms "comprising" and "including" are used herein in their open-ended and non- limiting sense unless otherwise noted.

The terms "a" and "an" and "the" and similar references in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Where the plural form is used for compounds, salts, and the like, this is taken to mean also a single compound, salt, or the like.

The term "a phosphatidylinositol 3-kinase inhibitor" or "PI3K inhibitor" is defined herein to refer to a compound which targets, decreases or inhibits activity of the phosphatidylinositol 3- kinase.

The term "pharmaceutically acceptable" is defined herein to refer to those compounds, materials, compositions and/or dosage forms, which are, within the scope of sound medical judgment, suitable for contact with the tissues of a patient without excessive toxicity, irritation allergic response and other problem complications commensurate with a reasonable benefit / risk ratio.

The term "treat", "treating" or "treatment" as used herein comprises a treatment or therapeutic regimen relieving, reducing or alleviating at least one symptom in a patient or effecting a delay of progression of a proliferative disorder. For example, treatment can be the diminishment of one or several symptoms of a disorder or complete eradication of a proliferative disease, such as cancer. Within the meaning of the present invention, the term "treat" also denotes to arrest, delay the onset (i.e., the period prior to clinical manifestation of a disorder) and/or reduce the risk of developing or worsening a proliferative disease. The term "prevent", "preventing" or "prevention" as used herein comprises the prevention of at least one symptom associated with or caused by the state, disease or disorder being prevented.

The term "daily dose" refers to the total dosage amount of the therapeutic agent administered to a specific patient in any single day.

The terms "therapeutically effective" is an observable improvement over the baseline clinically observable signs and symptoms of the state, disease or disorder treated with the therapeutic agent.

The term "therapeutically effective amount" is an amount sufficient to provide an observable improvement over the baseline clinically observable signs and symptoms of the state, disease or disorder treated with the therapeutic agent.

The term "pharmaceutical composition" refers to a mixture or solution containing at least one therapeutic agent to be administered to a patient, in order to prevent or treat a particular disease or condition affecting the patient.

The term "day" refers to either one calendar day or one 24-hour period.

The term "week" refers to either seven consecutive calendar days or seven consecutive 24-hour periods. The phrase "three weeks" refers to either twenty-one consecutive calendar days or twenty-one consecutive 24-hour periods starting on any day of the calendar week.

The term "combination" refers to either a fixed combination in one dosage unit form, a non-fixed combination or a kit of parts for the combined administration where the compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent may be administered simultaneously, independently at the same time or separately within time intervals that allow that the combination partners show a cooperative, e.g., synergistic, effect. The term "fixed combination" means that the therapeutic agents, e.g. the compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one additional therapeutic agent, are both administered to a patient simultaneously in the form of a single entity or dosage unit. The term "non-fixed combination" or "kit of parts" means that the therapeutic agents, e.g. the compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one additional therapeutic agent, are both administered to a patient as separate entities or dosage units either simultaneously, concurrently or sequentially within time intervals, especially where these time intervals allow that the therapeutic agents show cooperative, e.g., synergistic, effect. The latter also applies to cocktail therapy, e.g. the administration of three or more therapeutic agents.

The term "combined administration" is defined to encompass the administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the therapeutic agents are not necessarily administered by the same route of administration or at the same time.

The term "patient" or "subject" is intended to include warm-blooded-animals. Examples of subjects include mammals, e.g., humans, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals. Particularly preferred, the patient is human, e.g., a human suffering from, at risk of suffering from, or potentially capable of suffering from a cancer.

The terms "about" or "approximately" usually mean within 10%, more preferably within 5%, of a given value or range.

WO2010/029082 describes specific 2-carboxamide cycloamino urea derivatives, which have been found to have highly selective inhibitory activity for the alpha-isoform of

phosphatidylinositol 3-kinase (PI3K). The alpha-isoform selective PI3K inhibitor suitable for the present invention is a compound having the following formula (I):

(hereinafter "compound of formula (I)" or "Compound A" or "Alpelisib") or pharmaceutically acceptable salts thereof. The compound of formula (I) is also known as the chemical compound (S)-Pyrrolidine-I , 2-dicarboxylic acid 2-amide 1 -({4-methyl-5-[2-(2,2,2-trifluoro-1 ,1 - dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl}-amide), and it is also known as Alpelisib. The compound of formula (I), its pharmaceutically acceptable salts and suitable formulations are described in PCT Application No. WO2010/029082, which is hereby incorporated by reference in its entirety, and methods of its preparation have been described, for example, in Example 15 therein.

As used herein, the term "salt" or "salts", can be present alone or in mixture with free base form of the compound of formula (I) and are preferably pharmaceutically acceptable salts. Such salts are formed, for example, as acid addition salts, preferably with organic or inorganic acids, from the compound of formula (I) with a basic nitrogen atom. Suitable in-organic acids are, for example, halogen acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid. Suitable organic acids are, e.g., carboxylic acids or sulfonic acids, such as fumaric acid or methansulfonic acid. For isolation or purification purposes it is also possible to use

pharmaceutically unacceptable salts, for example picrates or perchlorates. For therapeutic use, only pharmaceutically acceptable salts or free base form of the compound are employed (where applicable in the form of pharmaceutical preparations), and these are therefore preferred. In view of the close relationship between the compound of formula (I) in free form and those in the form of its salts, any reference to the free base form of the compound hereinbefore and hereinafter is to be understood as referring also to the corresponding salts, as appropriate. The salts of compound of the formula (I) are preferably pharmaceutically acceptable salts; suitable counter-ions forming pharmaceutically acceptable salts are known in the field.

Preferably, the compound of formula (I) is used in the free base form.

The compound of formula (I) or its pharmaceutically acceptable salts may be orally administered at a daily dose of about 100 mg to about 450 mg per day to a human in need thereof, preferably an adult human in need thereof. In further embodiments, the compound of formula (I) may be administered to a human at a daily dose of about 200 mg to about 400 mg per day, or about 240 mg to about 400 mg per day, or about 300 mg to about 400 mg per day, or about 350 mg to about 400 mg per day. In a preferred embodiment, the compound of formula (I) is administered to a human at a daily dose of about 350 mg to about 400 mg per day.

The effective dosage of the compound of formula (I) or pharmaceutically acceptable salt thereof may vary depending on the pharmaceutical composition employed, the mode of administration, the condition being treated, and the severity of the condition being treated.

Thus, the specific dosage selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; and the renal and hepatic function of the patient. With the teachings of the present invention, a physician or clinician of ordinary skill can readily determine and prescribe the effective daily dosage amount of the therapeutic agent required to alleviate, counter or arrest the proliferative disease when using the dosage regimen of the present invention. The optimum dosage of the compound of formula (I) or pharmaceutically acceptable salt thereof that yield efficacy without toxicity are based on the kinetics of the compound.

The daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered to the human in a single dose (once per day, q.d.) or divided doses (more than once per day, e.g., twice per day, b.i.d.). In one embodiment of the present invention, the daily dose is administered in a once per day (q.d.). In a further embodiment of the present invention, the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice per day (b.i.d.)

The daily dose may be administered to the human in a single dosage unit or amounts of multiple dosage units to make up the daily dose.

The present invention further relates to the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing a proliferative disease, wherein said medicament is orally administered to a human in need thereof in a daily dose of about 100 mg to about 450 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof each day for a period of three weeks and then not administered to said human for one week immediately thereafter, and wherein this cycle is repeated for from one to several cycles. The present invention further relates to the compound of formula (I) or a

In one embodiment, the present invention further relates to a method of treating or preventing a proliferative disease in a human in need thereof comprising orally administering to said human a daily dose of about 100 mg to about 450 mg, or about 200 mg to about 400 mg, of the compound of formula (I) or a pharmaceutically acceptable salt thereof once per day (q.d.) each day for a period of three weeks and then not administering said compound of formula (I) or a pharmaceutically salt thereof to said human for one week immediately thereafter and then repeating this cycle for one cycle to several cycles. In a further embodiment, the present invention relates to the above method of treatment except the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice per day (b.i.d.).

In one embodiment, the present invention relates to the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing a proliferative disease, wherein said medicament is orally administered to a human in need thereof in a daily dose of about 100 mg to about 450 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof thereof once per day (q.d.) each day for a period of three weeks and then not administered to said human for one week immediately thereafter, and wherein this cycle is repeated for from one to several cycles. In a further embodiment, the present invention relates to the above use except the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice per day (b.i.d.).

The dosage regimen of the present invention comprises a cycle comprising (a) a treatment period wherein said compound of formula (I) or a pharmaceutically salt thereof is administered to a human in need thereof in a daily dose of about 100 mg to about 450 mg each day for a period of three weeks, and (b) an interruption period wherein said compound of formula (I) or a pharmaceutically acceptable salt thereof is not administered to said human for one week immediately thereafter (together one treatment period and one interruption period are "a cycle"), wherein this cycle is repeated for one to several cycles. This shall be referred to as the "dosage regimen of the present invention".

In the dosage regimen of the present invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a human in need thereof for a period of three consecutive weeks in each cycle.

The defined cycle of the dosage regimen of the present invention is repeated for 1 cycle to several cycles, for example, for an additional 1 cycle to 10 or more cycles. In specific embodiments of the dosage regimen of the present invention, the cycle is repeated for 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, or more cycles. In a further embodiment, the cycle is repeated for 1 to 10 cycles. In a further embodiment, the cycles may be repeated for one cycle to several cycles until the proliferative disease is treated, or until the disease progresses, or until at least one side effect is relieved, reduced, or alleviated in severity, occurrence rate, or frequency in the human patient. In a preferred embodiment, the cycle is repeated for one cycle or several cycles until at least one side effect, particularly hepatic dysfunction or hepatobiliary toxicity, is relieved, reduced, or alleviated in severity, occurrence rate, or frequency in the human patient.

In one embodiment, the present invention relates to a method of treating or preventing a proliferative disease in a human in need thereof comprising orally administering to said human a daily dose of about 100 mg to about 450 mg of the compound of formula (I) or a

pharmaceutically acceptable salt thereof each day for a period of three weeks and then not administering said compound of formula (I) or a pharmaceutically salt thereof to said human for one week immediately thereafter and then repeating this cycle for 1 cycle to 10 cycles.

In one embodiment, the present invention relates to the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing a proliferative disease, wherein said medicament is orally administered to a human in need thereof in a daily dose of about 100 mg to about 450 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof thereof each day for a period of three weeks and then not administered to said human for one week immediately thereafter, and wherein this cycle is repeated for 1 cycle to 10 cycles. It is understood that the dosage regimen of the present invention is particularly suitable for the treatment of a human suffering from a proliferative disease, especially a cancer.

Proliferative diseases that may be treated or prevented by the administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof in accordance with the dosage regimen of the present invention are particularly those mediated by the alpha-isoform of the PI3K. It is understood that one embodiment of the present invention includes the treatment of the proliferative disease, and that a further embodiment of the present invention includes the prevention of the proliferative disease.

Preferably, the proliferative disease is a cancer. The term "cancer" refers to tumors and/or cancerous cell growth preferably mediated by the alpha-isoform of the

phosphatidylinositol 3-kinase. In particular, the compounds are useful in the treatment of cancers including, for example, sarcoma, lung cancer, bronchial cancer, prostate cancer, breast cancer (including hormone-receptor-positive, HER2-negative breast cancer, sporadic breast cancers and sufferers of Cowden disease), a mammary carcinoma, pancreatic cancer, gastrointestinal cancer, colon cancer, rectal cancer, thyroid cancer, liver cancer, intrahepatic bile duct cancer, hepatocellular cancer, adrenal gland cancer, gastric cancer, esophageal cancer, glioma, glioblastoma, melanoma, kidney cancer, renal pelvic cancer, urinary bladder cancer, cancer of the uterine corpus, cancer of the uterine cervix, vaginal cancer, ovarian cancer, multiple myeloma, a leukemia (including acute myelogenous leukemia, chronic myelogenous leukemia, lymphocytic leukemia, and myeloid leukemia), brain cancer, head and neck cancer, cancer of the oral cavity and pharynx, larynx, a lymphoma (including non-Hodgkin lymphoma), a neoplasia, basal cell carcinoma, and squamous cell carcinoma.

In one embodiment, the proliferative disease is a solid tumor.

In one embodiment, the proliferative disease is a cancer selected from lung cancer, breast cancer (including hormone-receptor-positive, HER2-negative breast cancer, sporadic breast cancers and sufferers of Cowden disease), head and neck cancer, prostate cancer, colon cancer, rectal cancer, and squamous cell carcinoma.

In one embodiment, the proliferative disease is a breast cancer, particularly hormone- receptor-positive, HER2-negative breast cancer.

Proliferative diseases may include those proliferative diseases (particularly cancers) mediated by the alpha-subunit of PI3K, e.g., characterized by or dependent on overexpression or amplification of PI3K alpha, somatic mutation of PIK3CA or germline mutations or somatic mutation of PTEN or mutations and translocation of p85a that serve to up-regulate the p85-p1 10 complex. In a preferred embodiment, the cancer is a tumor and/or cancerous growth mediated by the alpha isoform of PI3K.

In one embodiment, the present invention relates to the treatment of a cancer by the administration of the compound of formula (I) or a pharmaceutically acceptable in accordance with the dosage regimen of the present invention.

It is believed that reducing the dosing of this potent alpha-isoform selective PI3K inhibitor compound of formula (I) or a pharmaceutically acceptable salt thereof from oral administration at (a) a daily dose of about 100 mg to about 450 mg daily on a continuous daily schedule to (b) a daily dose of about 100 mg to about 450 mg each day for a period of three weeks and then not administering said compound of formula (I) or a pharmaceutically salt thereof to said human for one week immediately thereafter and then repeating this cycle for one to several cycles, may be effective to treat or prevent a cancer while relieving, reducing, or alleviating the severity, occurrence rate and/or frequency of side effects. This is particularly applicable to treatment of a cancer.

Examples of such side effects which may relieved, reduced, or alleviated by the dosage regimen of the present invention include, but are not limited to, neutropenia, elevated bilirubin, cardiac toxicity, unstable angina, myocardial infarction, persistent hypertension, peripheral sensory or motor neuropathy/ pain, hepatic dysfunction or hepatobiliary toxicity (e.g., liver injury or liver disease, aspartate transaminase level elevation, alanine aminotransferase level elevation, etc.), reduced red and/or white blood cell count, hyperglycemia, nausea, decreased appetite, diarrhea, rash (e.g, maculopapular, acneiform, etc.) and hypersensitivity (e.g., increased sensitivity to bruise), photosensitivity, asthenia/ fatigue, vomiting, stomatitis, oral mucositis, pancreatitis, dysgeusia, and dyspepsia. It is understood by one of ordinary skill in the art how to assess such side effects in a human suffering from proliferative diseases using one's experience or prior knowledge and/or by referencing standard side effect grading criteria, for example, by assessing such human using the NCI Common Terminology Criteria for Adverse Events, version 4.03 (website located at: http://evs.nci.nih.gov/ftp1/CTCAE/About.html), which is hereby incorporated by reference in its entirety. Preferably, the side effect relieved, reduced, or alleviated by the dosage regimen of the present invention is a condition selected from hepatic dysfunction or hepatobiliary toxicity (e.g., liver injury or liver disease, aspartate transaminase level elevation, alanine aminotransferase level elevation, etc.), hyperglycemia, nausea, decreased appetite, diarrhea, rash (e.g, maculopapular, acneiform, etc.) and hypersensitivity (e.g., increased sensitivity to bruise), photosensitivity, asthenia/ fatigue, vomiting, stomatitis, oral mucositis, dysgeusia, and dyspepsia.

More preferably, the side effect relieved, reduced, or alleviated by the dosage regimen of the present invention is hepatic dysfunction or hepatobiliary toxicity (e.g., liver injury or liver disease, aspartate transaminase level elevation, alanine aminotransferase level elevation, etc.).

pharmaceutically acceptable salt thereof each day for a period of three weeks and then not administering said compound of formula (I) or a pharmaceutically salt thereof to said human for one week immediately thereafter and then repeating this cycle for one to several cycles until the proliferative disease is treated, or until the disease progresses, or until at least one side effect is relieved, reduced, or alleviated in severity, occurrence rate, or frequency in the human.

Preferably, the cycles are repeated for one to several cycles until the side effect of hepatic dysfunction or hepatobiliary toxicity is relieved, reduced, or alleviated in severity, occurrence rate, or frequency in the human.

In a further embodiment, the present invention relates to a method of treating or preventing a proliferative disease in accordance with the dosage regimen herein, wherein the cycle is repeated for one to several cycles until at least one side effect is relieved, reduced, or alleviated in severity, occurrence rate, or frequency in the human. Preferably, the side effect relieved, reduced, or alleviated in severity, occurrence rate, or frequency is hepatic dysfunction or hepatobiliary toxicity.

In a further embodiment, the present invention relates to a method of treating or preventing a proliferative disease in accordance with the dosage regimen herein, wherein the cycle is repeated for one to several cycles until the proliferative disease is treated. In a further embodiment, the present invention relates to a method of treating or preventing a proliferative disease in accordance with the dosage regimen herein, wherein the cycle is repeated for one to several cycles until the disease progresses.

In a further embodiment, the present invention relates to a method of treating or preventing a proliferative disease comprising: first, orally administering to a human in need thereof a compound of formula (I) or a pharmaceutically acceptable salt thereof in a daily dose of about 100 mg to about 450 mg each day on a continuous schedule; second, determining said human has a side effect selected from hepatic dysfunction or hepatobiliary toxicity (e.g., liver injury or liver disease, aspartate transaminase level elevation, alanine aminotransferase level elevation, etc.), hyperglycemia, nausea, decreased appetite, diarrhea, rash (e.g, maculopapular, acneiform, etc.) and hypersensitivity (e.g., increased sensitivity to bruise), photosensitivity, asthenia/ fatigue, vomiting, stomatitis, oral mucositis, dysgeusia, and dyspepsia after administration of said compound of formula (I) or a pharmaceutically acceptable salt thereof to said human; and third, reducing the oral administration of said compound of formula (I) or a pharmaceutically acceptable salt thereof to a daily dose of about 100 mg to about 450 mg each day for a period of three weeks and then not administering said compound of formula (I) or a pharmaceutically salt thereof to said human for one week immediately thereafter and then repeating this cycle for one to several cycles.

In a further embodiment, the present invention relates to a method of reducing at least one side effect selected from hepatic dysfunction or hepatobiliary toxicity (e.g., liver injury or liver disease, aspartate transaminase level elevation, alanine aminotransferase level elevation, etc.), hyperglycemia, nausea, decreased appetite, diarrhea, rash (e.g, maculopapular, acneiform, etc.) and hypersensitivity (e.g., increased sensitivity to bruise), photosensitivity, asthenia/ fatigue, vomiting, stomatitis, oral mucositis, dysgeusia, and dyspepsia from prior treatment with the compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising orally administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to a daily dose of about 100 mg to about 450 mg each day for a period of three weeks and then not administering said compound of formula (I) or a pharmaceutically salt thereof to said human for one week immediately thereafter and then repeating this cycle for one to several cycles. In one embodiment, the present invention relates to the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing a proliferative disease, wherein said medicament is orally administered in accordance with the dosage regimen herein and the cycle is repeated for one cycle to several cycles until the proliferative disease is treated, or until the disease progresses, or until at least one side effect is relieved, reduced, or alleviated in severity, occurrence rate, or frequency in the human. Preferably, the cycles are repeated until the side effect of hepatic dysfunction or hepatobiliary toxicity is relieved, reduced, or alleviated in severity, occurrence rate, or frequency in the human.

In a further embodiment, the present invention relates to the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing a proliferative disease, wherein said medicament is orally administered in accordance with the dosage regimen herein and the cycle is repeated for one cycle to several cycles until the proliferative disease is treated.

In a further embodiment, the present invention relates to the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing a proliferative disease, wherein said medicament is orally administered in accordance with the dosage regimen herein and the cycle is repeated for one cycle to several cycles until the disease progresses.

In a further embodiment, the present invention relates to the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing a proliferative disease, wherein: first, the medicament comprising compound of formula (I) or a pharmaceutically acceptable salt thereof is orally administered to a human in need thereof in a daily dose of about 100 mg to about 450 mg each day on a continuous schedule; second, said human is determined to have a side effect selected from hepatic dysfunction or hepatobiliary toxicity (e.g., liver injury or liver disease, aspartate transaminase level elevation, alanine aminotransferase level elevation, etc.), hyperglycemia, nausea, decreased appetite, diarrhea, rash (e.g, maculopapular, acneiform, etc.) and hypersensitivity (e.g., increased sensitivity to bruise), photosensitivity, asthenia/ fatigue, vomiting, stomatitis, oral mucositis, dysgeusia, and dyspepsia after administration of said medicament to said human; and third, the medicament comprising compound of formula (I) or a pharmaceutically acceptable salt thereof is orally administered to a human in need thereof in a daily dose of about 100 mg to about 450 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof each day for a period of three weeks and then not administered to said human for one week immediately thereafter, and wherein this cycle is repeated for from one to several cycles.

In a further embodiment, the present invention relates to the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for reducing at least one side effect selected from hepatic dysfunction or hepatobiliary toxicity (e.g., liver injury or liver disease, aspartate transaminase level elevation, alanine

aminotransferase level elevation, etc.), hyperglycemia, nausea, decreased appetite, diarrhea, rash (e.g, maculopapular, acneiform, etc.) and hypersensitivity (e.g., increased sensitivity to bruise), photosensitivity, asthenia/ fatigue, vomiting, stomatitis, oral mucositis, dysgeusia, and dyspepsia from prior treatment with the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the medicament comprising compound of formula (I) or a pharmaceutically acceptable salt thereof is orally administered to a human in need thereof in a daily dose of about 100 mg to about 450 mg of the compound of formula (I) or a

pharmaceutically acceptable salt thereof each day for a period of three weeks and then not administered to said human for one week immediately thereafter, and wherein this cycle is repeated for from one to several cycles.

In one embodiment, the present invention relates to the compound of formula (I) or a pharmaceutically acceptable salt thereof is for use in the treatment or prevention of a proliferative disease, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is orally administered to a human in need thereof in a daily dose of about 100 mg to about 450 mg each day for a period of three weeks and then not administered to said human for one week immediately thereafter, and wherein this cycle is repeated for one to several cycles until the proliferative disease is treated, or until the disease progresses, or until at least one side effect is relieved, reduced, or alleviated in severity, occurrence rate, or frequency in the human. Preferably, the cycles are repeated until the side effect of hepatic dysfunction or hepatobiliary toxicity is relieved, reduced, or alleviated in severity, occurrence rate, or frequency in the human.

In a further embodiment, the present invention relates to the compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a proliferative disease, wherein said medicament is orally administered in accordance with the dosage regimen herein and the cycle is repeated for one cycle to several cycles until the proliferative disease is treated.

In a further embodiment, the present invention relates to the compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a proliferative disease, wherein said medicament is orally administered in accordance with the dosage regimen herein and the cycle is repeated for one cycle to several cycles until the disease progresses.

In a further embodiment, the present invention relates to the compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a proliferative disease, wherein: first, said compound is orally administered to a human in need thereof in a daily dose of about 100 mg to about 450 mg each day on a continuous schedule; second, said human is determined to have a side effect selected from hepatic dysfunction or hepatobiliary toxicity (e.g., liver injury or liver disease, aspartate transaminase level elevation, alanine aminotransferase level elevation, etc.), hyperglycemia, nausea, decreased appetite, diarrhea, rash (e.g, maculopapular, acneiform, etc.) and hypersensitivity (e.g., increased sensitivity to bruise), photosensitivity, asthenia/ fatigue, vomiting, stomatitis, oral mucositis, dysgeusia, and dyspepsia after administration of said medicament to said human; and third, said compound is orally administered to a human in need thereof in a daily dose of about 100 mg to about 450 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof each day for a period of three weeks and then not administered to said human for one week immediately thereafter, and wherein this cycle is repeated for from one to several cycles.

In a further embodiment, the present invention relates to the compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the reduction of at least one side effect selected from hepatic dysfunction or hepatobiliary toxicity (e.g., liver injury or liver disease, aspartate transaminase level elevation, alanine aminotransferase level elevation, etc.), hyperglycemia, nausea, decreased appetite, diarrhea, rash (e.g, maculopapular, acneiform, etc.) and hypersensitivity (e.g., increased sensitivity to bruise), photosensitivity, asthenia/ fatigue, vomiting, stomatitis, oral mucositis, dysgeusia, and dyspepsia from prior treatment with the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the medicament comprising compound of formula (I) or a pharmaceutically acceptable salt thereof is orally administered to a human in need thereof in a daily dose of about 100 mg to about 450 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof each day for a period of three weeks and then not administered to said human for one week immediately thereafter, and wherein this cycle is repeated for from one to several cycles.

It can be shown by established test models that the dosage regimen of the present invention results in the beneficial effects described herein before. The person skilled in the art is fully enabled to select a relevant test model to prove such beneficial effects. The

pharmacological activity of the compound of formula (I) or its pharmaceutically acceptable salt may, for example, be demonstrated in a clinical study, an animal study or in a test procedure as essentially described herein.

Suitable clinical studies are in particular, for example, open-label, dose escalation and/or dose expansion studies in patients with a proliferative disease, including for example a cancer, e.g., breast cancer, wherein said patients are orally administered the compound of formula (I) in accordance with the dosage regimen of the present invention. Preferably, patients are assigned to different groups wherein at least one group is administered the compound of formula (I) on a continuous daily schedule and at least one group is administered the compound of formula (I) in accordance with the dosage regimen of the present invention. Such studies prove in particular the efficacy of the therapeutic agent and its impact on existing or potential side effects. The beneficial effects on a proliferative disease may be determined directly through the results of these studies which are known as such to a person skilled in the art. Such studies may be, in particular, suitable to compare the efficacy or side effects of a continuous daily schedule using the therapeutic agents and the dosing regimen of the present invention. Each patient may receive doses of the compound of formula (I) or its pharmaceutically acceptable salt either once per day or more than once (e.g., twice) per day. The efficacy of the treatment may be determined in such studies, e.g., after 8, 16, 24, 32, 40 and/or 48 weeks by evaluation of symptom scores and/or tumor size measurements every 6 or 12 weeks.

In accordance with the present invention, the compound of formula (I) or a

pharmaceutically acceptable salt thereof is preferably administered in the form of

pharmaceutically compositions or medicament that contain a therapeutically effective amount of the compound of formula (I) or pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable excipients suitable for oral administration. The pharmaceutical composition may comprise an amount of about 100 mg to about 450 mg of a compound of formula (I) or pharmaceutically acceptable salt thereof to be administered in single dosage unit or a single dosage unit subdivided into multiple dosage units.

The pharmaceutical compositions or medicaments used according to the dosage regimen of present invention can be prepared in a manner known per se to be suitable for oral administration to humans. Pharmaceutical compositions or medicaments for oral administration may include, for example, those in dosage unit forms, such as sugar-coated tablets, tablets, capsules, sachets and furthermore ampoules. If not indicated otherwise, these are prepared in a manner known per se, for example by means of conventional mixing, granulating, sugar- coating, dissolving or lyophilizing processes. It will be appreciated that the amount of the active ingredient contained in an individual dose or dosage unit need not in itself constitute a therapeutically effective amount since the necessary effective amount can be reached by administration of a plurality of dosage units.

The pharmaceutical composition or medicament may contain, for example, from about 10 % to about 100 %, preferably from about 20 % to about 60 %, of the active ingredient.

In preparing the pharmaceutical compositions or medicaments for oral dosage unit form, any of the usual pharmaceutically acceptable excipients may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents; or excipients such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, capsules and tablets, with the solid oral preparations being preferred over the liquid preparations. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical excipients are obviously employed.

One of ordinary skill in the art may select one or more of the aforementioned excipients with respect to the particular desired properties of the dosage unit form by routine

experimentation and without any undue burden. The amount of each excipient used may vary within ranges conventional in the art. The following references which are all hereby

incorporated by reference disclose techniques and excipients used to formulate oral dosage forms. (See The Handbook of Pharmaceutical Excipients, 4th edition, Rowe et al., Eds., American Pharmaceuticals Association (2003); and Remington: the Science and Practice of Pharmacy, 20th edition, Gennaro, Ed., Lippincott Williams & Wilkins (2003).)

Examples of pharmaceutically acceptable disintegrants include, but are not limited to, starches; clays; celluloses; alginates; gums; cross-linked polymers, e.g., cross-linked polyvinyl pyrrolidone or crospovidone, e.g., POLYPLASDONE XL from International Specialty Products (Wayne, NJ); cross-linked sodium carboxymethylcellulose or croscarmellose sodium, e.g., AC- DI-SOL from FMC; and cross-linked calcium carboxymethylcellulose; soy polysaccharides; and guar gum. The disintegrant may be present in an amount from about 0% to about 10% by weight of the composition. In one embodiment, the disintegrant is present in an amount from about 0.1 % to about 5% by weight of composition.

Examples of pharmaceutically acceptable binders include, but are not limited to, starches; celluloses and derivatives thereof, for example, microcrystalline cellulose, e.g., AVICEL PH from FMC (Philadelphia, PA), hydroxypropyl cellulose hydroxylethyl cellulose and hydroxylpropylmethyl cellulose METHOCEL from Dow Chemical Corp. (Midland, Ml); sucrose; dextrose; corn syrup; polysaccharides; and gelatin. The binder may be present in an amount from about 0% to about 50%, e.g., 2-20% by weight of the composition.

Examples of pharmaceutically acceptable lubricants and pharmaceutically acceptable glidants include, but are not limited to, colloidal silica, magnesium trisilicate, starches, talc, tribasic calcium phosphate, magnesium stearate, aluminum stearate, calcium stearate, magnesium carbonate, magnesium oxide, polyethylene glycol, powdered cellulose and microcrystalline cellulose. The lubricant may be present in an amount from about 0% to about 10% by weight of the composition. In one embodiment, the lubricant may be present in an amount from about 0.1 % to about 1 .5% by weight of composition. The glidant may be present in an amount from about 0.1 % to about 10% by weight.

Examples of pharmaceutically acceptable fillers and pharmaceutically acceptable diluents include, but are not limited to, confectioner's sugar, compressible sugar, dextrates, dextrin, dextrose, lactose, mannitol, microcrystalline cellulose, powdered cellulose, sorbitol, sucrose and talc. The filler and/or diluent, e.g., may be present in an amount from about 0% to about 80% by weight of the composition.

In one embodiment, the present invention relates to a pharmaceutical composition or medicament comprising an amount of about 100 mg to about 450 mg of a compound of formula (I) or pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable excipients for use in the treatment or prevention of a proliferative disease in a human in need thereof, wherein the pharmaceutical composition is orally administered to a human each day for a period of three weeks and then not administered to said human for one week immediately thereafter and then this cycle is repeated for one to several cycles.

Further, the present invention includes a method of treating or preventing a proliferative disorder in accordance with any other embodiment disclosed above for the present invention.

Further, the present invention includes any use of the compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing a proliferative disease in accordance with the methods of treatment or any other embodiment disclosed above for the present invention.

Further, the present invention includes the compound of formula (I) or a

pharmaceutically acceptable salt thereof for use in the treatment or prevention of a proliferative disease in accordance with the methods of treatment, uses for the manufacture of a medicament, or any other embodiment disclosed above for the present invention.

The present invention further relates to a method of treating or preventing a proliferative disease in a human in need thereof comprising orally administering to said human a daily dose of about 100 mg to about 450 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof each day for a period of three weeks and then not administering said compound of formula (I) or a pharmaceutically salt thereof to said human for one week immediately thereafter and then repeating this cycle for one to several cycles, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with at least one additional therapeutic agent.

Suitable additional therapeutic agents for use in accordance with the present invention include, but are not limited to, kinase inhibitors, anti-estrogens, anti androgens, other inhibitors, cancer chemotherapeutic drugs, alkylating agents, chelating agents , biological response modifiers, cancer vaccines, agents for antisense therapy. Examples are set forth below: A. Kinase Inhibitors including inhibitors of Epidermal Growth Factor Receptor (EGFR) kinases such as gefitinib (US 5457105, US 5616582, and US 5770599), ZD-6474 (WO

01/32651), erlotinib (Tarceva®, US 5,747,498 and WO 96/30347), T-DM1 (Kadcyla®,

WO2001/000244), lapatinib (US 6,727,256 and WO 02/02552), and cetuximab; Vascular Endothelial Growth Factor Receptor (VEGFR) kinase inhibitors, including SU-1 1248 (WO 01/60814), SU 5416 (US 5,883, 1 13 and WO 99/61422), SU 6668 (US 5,883,1 13 and WO 99/61422), CHIR-258 (US 6,605,617 and US 6,774,237), vatalanib or PTK-787 (US 6,258,812), VEGF-Trap (WO 02/57423), B43-Genistein (WO-096061 16), fenretinide (retinoic acid p- hydroxyphenylamine) (US 4,323,581 ), IM-862 (WO 02/62826), bevacizumab or Avastin® (WO 94/10202), KRN-951 , 3-[5-(methylsulfonylpiperadine methyl)-indolyl]-quinolone, AG-13736 and AG-13925, pyrrolo[2,1 -f][1 ,2,4]triazines, ZK-304709, Veglin®, VMDA-3601 , EG-004, CEP-701 (US 5,621 , 100), Cand5 (WO 04/09769); Erb2 tyrosine kinase inhibitors such as pertuzumab (WO 01/00245), trastuzumab, and rituximab; Akt protein kinase inhibitors, such as RX-0201 ; Protein Kinase C (PKC) inhibitors, such as LY-317615 (WO 95/17182), and perifosine (US 2003171303); Raf/Map/MEK/Ras kinase inhibitors including sorafenib (BAY 43-9006), ARQ- 350RP, LErafAON, BMS-354825, AMG-548, and others disclosed in WO 03/82272; Fibroblast Growth Factor Receptor (FGFR) kinase inhibitors; Cell Dependent Kinase (CDK) inhibitors, including CYC-202, roscovitine (WO 97/20842 and WO 99/02162), and 7-Cyclopentyl-2-(5- piperazin-1 -yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (WO 2010/020675); Platelet-Derived Growth Factor Receptor (PDGFR) kinase inhibitors such as CHIR-258, 3G3 mAb, AG-13736, SU-1 1248 and SU6668; and Bcr-Abl kinase inhibitors and fusion proteins such as STI-571 or Gleevec® (imatinib).

B. Anti-Estrogens: Estrogen-targeting agents include Selective Estrogen Receptor Modulators (SERMs) including tamoxifen, toremifene, raloxifene; aromatase inhibitors including Arimidex® or anastrozole; Estrogen Receptor Downregulators (ERDs) including Faslodex® or fulvestrant.

C. Anti-Androgens: Androgen-targeting agents including flutamide, bicalutamide, finasteride, aminoglutethamide, ketoconazole, and corticosteroids.

D. Other Inhibitors including protein farnesyl transferase inhibitors including tipifarnib or R-1 15777 (US 2003134846 and WO 97/21701 ), BMS-214662, AZD-3409, and FTI-277;

topoisomerase inhibitors including merbarone and diflomotecan (BN-80915); mitotic kinesin spindle protein (KSP) inhibitors including SB-743921 and MKI-833; proteasome modulators such as bortezomib or Velcade® (US 5,780,454), XL-784; cyclooxygenase 2 (COX-2) inhibitors including non-steroidal antiinflammatory drugs I (NSAIDs); letrozole; exemestane; and eribulin.

E. Cancer Chemotherapeutic Drugs including anastrozole (Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxane®), busulfan (Myleran®), busulfan injection

(Busulfex®), capecitabine (Xeloda®), N4-pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (Paraplatin®), carmustine (BiCNU®), chlorambucil (Leukeran®), cisplatin (Platinol®), cladribine (Leustatin®), cyclophosphamide (Cytoxan® or Neosar®), cytarabine, cytosine arabinoside (Cytosar-U®), cytarabine liposome injection (DepoCyt®), dacarbazine (DTIC-Dome®), dactinomycin (Actinomycin D, Cosmegan), daunorubicin hydrochloride (Cerubidine®), daunorubicin citrate liposome injection (DaunoXome®), dexamethasone, docetaxel

(Taxotere®), doxorubicin hydrochloride (Adriamycin®, Rubex®), etoposide (Vepesid®), fludarabine phosphate (Fludara®), 5-fluorouracil (Adrucil®, Efudex®), flutamide (Eulexin®), tezacitibine, Gemcitabine (difluorodeoxycitidine), hydroxyurea (Hydrea®), Idarubicin

(Idamycin®), ifosfamide (IFEX®), irinotecan (Camptosar®), L-asparaginase (ELSPAR®), leucovorin calcium, melphalan (Alkeran®), 6-mercaptopurine (Purinethol®), methotrexate (Folex®), mitoxantrone (Novantrone®), mylotarg, paclitaxel (Taxol®), phoenix (Yttrium90/MX- DTPA), pentostatin, polifeprosan 20 with carmustine implant (Gliadel®), tamoxifen citrate (Nolvadex®), teniposide (Vumon®), 6-thioguanine, thiotepa, tirapazamine (Tirazone®), topotecan hydrochloride for injection (Hycamptin®), vinblastine (Velban®), vincristine

(Oncovin®), and vinorelbine (Navelbine®).

F. Alkylating Agents including VNP-40101 M or cloretizine, oxaliplatin (US 4,169,846, WO 03/24978 and WO 03/04505), glufosfamide, mafosfamide, etopophos (US 5,041 ,424), prednimustine; treosulfan; busulfan; irofluven (acylfulvene); penclomedine; pyrazoloacridine (PD-1 15934); 06-benzylguanine; decitabine (5-aza-2-deoxycytidine); brostallicin; mitomycin C (MitoExtra); TLK-286 (Telcyta®); temozolomide; trabectedin (US 5,478,932); AP-5280 (Platinate formulation of Cisplatin); porfiromycin; and clearazide (meclorethamine).

G. Chelating Agents including tetrathiomolybdate (WO 01/60814); RP-697; Chimeric T84.66 (cT84.66); gadofosveset (Vasovist®); deferoxamine; and bleomycin optionally in combination with electorporation (EPT).

H. Biological Response Modifiers, such as immune modulators, including staurosprine and macrocyclic analogs thereof, including UCN-01 , CEP-701 and midostaurin (see WO 02/30941 , WO 97/07081 , WO 89/07105, US 5,621 , 100, WO 93/07153, WO 01/04125, WO 02/30941 , WO 93/08809, WO 94/06799, WO 00/27422, WO 96/13506 and WO 88/07045); squalamine (WO 01/79255); DA-9601 (WO 98/04541 and US 6,025,387); alemtuzumab;

interferons (e.g. IFN-a, IFN-b etc.); interleukins, specifically IL-2 or aldesleukin as well as IL-1 , IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-1 1 , IL-12, and active biological variants thereof having amino acid sequences greater than 70% of the native human sequence; altretamine (Hexalen®); SU 101 or leflunomide (WO 04/06834 and US 6,331 ,555); imidazoquinolines such as resiquimod and imiquimod (US 4,689,338, 5,389,640, 5,268,376, 4,929,624, 5,266,575, 5,352,784, 5,494,916, 5,482,936, 5,346,905, 5,395,937, 5,238,944, and 5,525,612); and SMIPs, including benzazoles, anthraquinones, thiosemicarbazones, and tryptanthrins (WO 04/87153, WO 04/64759, and WO 04/60308).

I. Cancer Vaccines: Anticancer vaccines including Avicine® (Tetrahedron Lett. 26:2269- 70 (1974)); oregovomab (OvaRex®); Theratope® (STn-KLH); Melanoma Vaccines; GI-4000 series (GI-4014, GI-4015, and GI-4016), which are directed to five mutations in the Ras protein; GlioVax-1 ; MelaVax; Advexin® or INGN-201 (WO 95/12660); Sig/E7/LAMP-1 , encoding HPV-16 E7; MAGE-3 Vaccine or M3TK (WO 94/05304); HER-2VAX; ACTIVE, which stimulates T-cells specific for tumors; GM-CSF cancer vaccine; and Listeria monocytogenes-based vaccines.

J. Antisense Therapy: Anticancer agents including antisense compositions, such as AEG-35156 (GEM-640); AP-12009 and AP-1 1014 (TGF-beta2-specific antisense

oligonucleotides); AVI-4126; AVI-4557; AVI-4472; oblimersen (Genasense®); JFS2;

aprinocarsen (WO 97/29780); GTI-2040 (R2 ribonucleotide reductase mRNA antisense oligo) (WO 98/05769); GTI-2501 (WO 98/05769); liposome-encapsulated c-Raf antisense

oligodeoxynucleotides (LErafAON) (WO 98/43095); and Sirna-027 (RNAi-based therapeutic targeting VEGFR-1 mRNA).

The structure of the drug substances identified by code numbers, generic or trade names may be taken from the Internet, actual edition of the standard compendium "The Merck Index" or from databases, e.g., Patents International, e.g., IMS World Publications, or the publications mentioned above and below. The corresponding content thereof is hereby incorporated by reference.

In one embodiment, the additional therapeutic agent is the CDK 4/6 inhibitor 7- Cyclopentyl-2-(5-piperazin-1 -yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide and referred to herein as the compound having the structure of formula (II):

The compound having the structure of Formula (II) is also known in the art as Ribociclib, and is referred to herein as "Compound of formula (II)", "Compound (II)," or "LEE01 1 ".

Compound of formula (II) is described in PCT Application No. WO 2010/020675, which is hereby incorporated by reference in its entirety, as Example 74.

Compound of formula (II), in general, is administered in a dose in the range from 10 mg to 2000 mg per day in human. In one embodiment, Compound of formula (II) is administered 600mg once daily on a continuous or intermittent schedule (e.g., three week treatment followed by one week interruption on a repeated 28 day cycle). In another embodiment, Compound of formula (II) is administered 300mg once daily on a continuous or intermittent schedule (e.g., three week treatment followed by one week interruption on a repeated 28 day cycle). In another embodiment, Compound of formula (II) is administered in 900mg once daily on a continuous or intermittent schedule (e.g., three week treatment followed by one week interruption on a repeated 28 day cycle). .

In one embodiment, the additional therapeutic agent is selected from gefinitib, erlotinib, T-DM1 , pertuzumab, trastuzumab, tamoxifen, fulvestrant, capecitabine, cisplatin, carboplatin, cetuximab, paclitaxel, temozolamide, letrozole, exemestane, eribulin, and Compound of formula (II) and any pharmaceutically acceptable salt thereof.

In one embodiment, the additional therapeutic agent is selected from T-DM1 , fulvestrant, cetuximab, letrozole, and Compound of formula (II) and any pharmaceutically acceptable salt thereof.

In one embodiment, the additional therapeutic agent is fulvestrant. In one embodiment, the additional therapeutic agent is T-DM1 . In one embodiment, the additional therapeutic agent is letrozole. In one embodiment, the additional therapeutic agent is the Compound of formula (II) or any pharmaceutically acceptable salt thereof. In one embodiment, the additional therapeutic agent is letrozole and Compound of formula (II) or any pharmaceutically acceptable salt thereof.

The compound of formula (I) and the additional therapeutic agent may be administered together in a single pharmaceutical composition, separately in two or more separate unit dosage forms, or sequentially. The pharmaceutical composition or dosage unit form comprising the additional therapeutic agent may be prepared in a manner known per se and are those suitable for enteral, such as oral or rectal, topical, and parenteral administration to humans.

In particular, a therapeutically effective amount of each of the therapeutic agents may be administered simultaneously or sequentially and in any order, and the components may be administered separately or as a fixed combination, preferably in synergistically effective amounts. The individual therapeutic agents of the combination may be administered separately at different times during the course of therapy or concurrently in divided or single combination forms.

"Synergy" or "synergistic" refers to the action of two therapeutic agents such as, for example, (a) a compound of formula (I) or a pharmaceutically acceptable salt thereof and (b) an additional therapeutic agent, producing an effect, for example, slowing the symptomatic progression of a proliferative disease or disorder, particularly cancer, or symptoms thereof, which is greater than the simple addition of the effects of each therapeutic agent administered by themselves. A synergistic effect can be calculated, for example, using suitable methods such as the Sigmoid-Emax equation (Holford, N. H. G. and Scheiner, L. B., Clin.

Pharmacokinet. 6: 429-453 (1981 )), the equation of Loewe additivity (Loewe, S. and Muischnek, H., Arch. Exp. Pathol Pharmacol. 1 14: 313-326 (1926)) and the median-effect equation (Chou, T. C. and Talalay, P., Adv. Enzyme Regul. 22: 27-55 (1984)). Each equation referred to above can be applied to experimental data to generate a corresponding graph to aid in assessing the effects of the therapeutic agent combination. The corresponding graphs associated with the equations referred to above are the concentration-effect curve, isobologram curve and combination index curve, respectively. Synergy may be further shown by calculating the synergy score of the combination according to methods known by one of ordinary skill.

Examples of proliferative diseases that may be treated with a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one additional therapeutic agent include, but not limited to, those set forth above. As set forth above, it can be shown by established test models that the combination of the present invention results in the beneficial effects described herein before. The person skilled in the art is fully enabled to select a relevant test model to prove such beneficial effects. The pharmacological activity of a combination of the present invention may, for example, be demonstrated in a clinical study or in a test procedure as essentially described herein.

In a further embodiment, the present invention relates to the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing a proliferative disease in accordance with the dosage regimen of the present invention, wherein said compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with at least one additional therapeutic agent.

In a further embodiment, the present invention relates to the compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a proliferative disease in accordance with the dosage regimen of the present invention, wherein said compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with at least one additional therapeutic agent.

The present invention further relates to a therapeutic regimen comprising orally administering to a human suffering from a proliferative disease a daily dose of about 100 mg to about 450 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof each day for a period of three weeks and then not administering said compound of formula (I) or a pharmaceutically acceptable salt thereof to said human for one week immediately thereafter, and then repeating this cycle for one to several cycles.

The present invention further relates to a package comprising a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients together with instructions to orally administer said pharmaceutical composition at a daily dose of about 100 mg to about 450 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof each day for a period of three weeks and then to not administer said pharmaceutical composition to said human for one week immediately thereafter, and then to repeat this cycle for one to several cycles. Utility of the dosage regimen of the compounds of formula (I) of the present invention may be demonstrated in vitro, in animal test methods as well as in clinic studies. For example in the utility of the compounds of formula (I) in accordance with the present invention may be demonstrated in accordance with the methods hereinafter described:

Example 1 :

List of abbreviations

AE Adverse Event

ALT Alanine Aminotransferase/Glutamic Pyruvic Transaminase/GPT

AST Aspartate Aminotransferase/Glutamic Oxaloacetic Transaminase/GOT

b.i.d. bis in d/^'em/twice a day

BLRM Bayesian Logistic Regression Model

CBR Clinical Benefit Rate

CDK Cyclin-Dependent Kinase

CR Complete Response

DLT Dose Limiting Toxicity

ECG Electrocardiogram

ECHO Echocardiogram

EOT End of Treatment

ER Estrogen Receptor

EWOC Escalation with Overdose Control

FSH Follicle Stimulating Hormone

HR Hormone Receptor

LFT Liver Function Test

MTD Maximum Tolerated Dose

O.d. Omnia die/once a day

OS Overall Survival

PD Progression of Disease

PET Positron Emission Tomography

P.O . Per so/ by mouth/ orally

PFS Progression-Free Survival

PgR Progesterone Receptor

PI3K Phosphatidylinositol 3-Kinase

PIK3CA Phosphatidylinositol 3-Kinase Catalytic Subunit Alpha

PK Pharmacokinetics

PR Partial Response

PR+ Progesterone Receptor Positive

Qd Quaque diem/once daily

QHS Quaque Hora Somni/ every bedtime

RP2D Recommended Phase Two Dose

SAE Serious Adverse Event

SD Stable Disease

A phase Ib/ll , multi-center, open-label, five-arm, dose finding clinical study is conducted to assess the MTD and/or RP2D and the safety and tolerability of the following combination treatments in adult patients with advanced hormone-receptor-positive (HR+), HER2-negative breast cancer: 1. Ribociclib and standard dose letrozole (ARM 1 ),

2. Alpelisib and standard dose letrozole (ARM 2),

Cohort 1 (Dose escalation and expansion): both Alpelisib and letrozole administered in the morning,

Cohort 2 (Dose expansion only): Alpelisib administered in the evening and letrozole administered in the morning

3. Ribociclib administered for a 28-day repeating cycle comprising 3 weeks daily treatment followed by a 1 week interruption period in combination with Alpelisib (once- daily continuous schedule) and standard dose letrozole (once daily continuous schedule) (ARM 3),

4. Ribociclib administered once daily continuous schedule in combination with Alpelisib (once-daily continuous schedule) and standard dose letrozole (once daily continuous schedule) (ARM 4), and

5. Ribociclib administered for a 28-day repeating cycle comprising 3 weeks daily treatment followed by a 1 week interruption period in combination with Alpelisib

(administered for a 28-day repeating cycle comprising 3 weeks continuous daily followed by a 1 week interruption period) and standard dose letrozole (once daily continuous schedule) (ARM 5).

This trial aims to establish one or more of the following objectives: (1 ) Primary Objectives:

(a) Dose escalation: To estimate the MTD and/or RP2D of the five combinations ARM 1 , Cohort 1 of ARM 2, ARM 3, ARM 4 and ARM 5 in patients with hormone-receptor-positive (HR-positive), HER2-negative advanced breast cancer.

(b) Dose expansion: To characterize the safety and tolerability of Ribociclib in combination with letrozole (ARM 1 ); Alpelisib in combination with letrozole (ARM 2), including Alpelisib daily continuous morning dosing regimen (ARM 2, Cohort 1 expansion) and Alpelisib daily continuous evening dosing regimen (ARM 2, Cohort 2 expansion); and the triple combinations of Ribociclib, Alpelisib and letrozole (ARMS 3, 4 and 5).

(2) Secondary

(a) To characterize the pharmacokinetics profiles of Ribociclib, Alpelisib (morning and evening dosing regimens for doublet ARM 2 and morning dosing regimen for triplet ARMS 3, 4 and 5), and letrozole when used in combination as well as to evaluate any other clinically significant metabolites that may be identified.

(b) To assess preliminary antitumor activity of Ribociclib in combination with letrozole, Alpelisib in combination with letrozole and the triple combination of Ribociclib, Alpelisib and letrozole.

(c) To assess the preliminary clinical antitumor activity of Ribociclib in combination with letrozole and Alpelisib in patients who previously progressed on treatment with either doublet and then continued on the optional crossover group.

(d) To evaluate the incidence of grade 3/4 hyperglycemia of Alpelisib morning dosing regimen in ARM 2 cohort 1 and Alpelisib evening dosing regimen in ARM 2 cohort 2.

(e) To evaluate the incidence of grade 3/4 AST/ALT elevations in each of ARMS 3, 4 and 5.

(3) Exploratory

(a) To evaluate the relationship between anti-tumor activity of the combination (Alpelisib +letrozole and Ribociclib + Alpelisib +letrozole) and PIK3CA status (defined as PIK3CA mutation) in tissue and blood.

(b) To characterize the relationship between pharmacodynamic (PD) marker assessments or safety data and exposure to Ribociclib and/or relevant metabolites in each of the five combinations (c) To evaluate the relationship between anti-tumor activity and molecular aberrations in the D-cyclin-CDK4/6 and PI3K pathways, and other cancer-related genes in archival tumor samples.

(d) To evaluate potential mechanisms of hepatotoxicity through comparison of select liver markers in patients exhibiting signs of liver toxicity compared to matched unaffected controls

The study is conducted in adult post-menopausal women with locally advanced or metastatic Hormone Receptor-positive /HER2-negative breast cancer. In the dose escalation part of the study, patients may have any number of prior lines of endocrine therapy with up to one prior cytotoxic regimen in the metastatic or locally advanced setting. In the dose expansion of ARMS 1 , 2 and 3, patients must not have received prior systemic treatment with the exception of more than one month of systemic therapy with letrozole in the advanced

(metastatic or locally advanced) setting. In the dose expansion of ARMS 4 and 5, patients with any number of prior endocrine therapies for metastatic or locally advanced setting are allowed and must have at least 1 measurable visceral lesion as defined by RECIST 1 .1 .

As of May 22, 2016, a total of 170 patients were enrolled in the initial clinical study evaluating ARM 1 , ARM 2 (morning dosing only, Cohort 1), and ARM 3. Enrollment in the dose expansion phase of ARM 1 and ARM 3 is completed. This clinical study will be amended to further investigate safety and tolerability of ARM 2 (evening dosing only, Cohort 2), ARM 4 and ARM 5.

Patients enrolled in this study are not permitted to participate in parallel investigational drug or device studies.

Patients eligible for inclusion in this study have to meet all of the following criteria:

1. Written informed consent must be obtained prior to any screening procedures

2. Adult women (age≥18 years) with advanced (metastatic or locally advanced) breast cancer not amenable to curative treatment by surgery or radiotherapy.

3. Histologic and/or cytologic confirmation of estrogen-receptor positive (ER+) and/ or

progesterone receptor positive (PR+) breast cancer by local laboratory. Postmenopausal women. Postmenopausal status is defined either by:

• Age≥ 18 with prior bilateral oophorectomy

• Age≥ 60 years

• Age <60 years with amenorrhea for at least 12 months (in the absence of

chemotherapy, tamoxifen, toremifen, or ovarian suppression) and both follicle- stimulating hormone (FSH) and estradiol levels are in postmenopausal range (according to the local laboratory)

Note: For women with therapy-induced amenorrhea, serial measurements of FSH

and/or estradiol are needed to ensure postmenopausal status (NCCN Guidelines Version 2.2014). Ovarian radiation or treatment with a luteinizing hormone- releasing hormone (LH-RHa) (goserelin acetate or leuprolide acetate) is not permitted for induction for ovarian suppression in this trial.

World Health Organization (WHO) performance status of 0 - 1.

Dose escalation: Any number of prior lines of endocrine therapy is allowed with the exception of cytotoxic therapy which is limited to one prior line administered in the advanced (metastatic or locally advanced) setting.

Dose expansion :

• ARMS 1 , 2 and 3

• No prior systemic treatment in the advanced (metastatic or locally advanced) setting with the exception of treatment with letrozole or anastrozole for a maximum duration of one month prior to starting study treatment.

• Patients who received (neo) adjuvant therapy for breast cancer are eligible. Prior therapy with letrozole or anastrozole in the (neo) adjuvant setting is permitted if the disease free interval is greater than 12 months from the completion of treatment.

• ARMS 4 and 5 • Any number of prior lines of endocrine therapy for advanced (metastatic or locally advanced) setting is allowed Phase lb dose escalation only: Presence of measurable or non-measurable disease (as per RECIST 1 .1 criteria). Isolated bone lesions (lytic or mixed lesions) are acceptable in the absence of other measurable or non-measurable disease. Phase lb dose expansion only:

ARMS 1 , 2 and 3: At least one measurable lesion (as per RECIST 1 .1 criteria) Isolated bone lesions (lytic or mixed lesions) are acceptable in the absence of other measurable or non-measurable disease.

ARMS 4 and 5: At least one measurable (as per RECIST 1.1 criteria) visceral (lung or liver) lesion. A representative tumor specimen (archival or newly obtained) is requested for molecular testing, for all patients. For dose expansion ARMS 2 to 5 and dose escalation ARMS 4 and 5, patient must have adequate formalin-fixed paraffin embedded (FFPE) tumor tissue for the analysis of PIK3CA mutation status by PCR conducted at a Novartis-designated central laboratory. One tumor block (preferred) or a minimum of 5 slides need to be shipped to the central laboratory for the determination of PIK3CA status. Time since the last prior therapy to treat underlying malignancy:

• Cytotoxic chemotherapy: greater than the duration of the most recent cycle of the previous regimen (with a minimum of two weeks for all, except six weeks for nitrosoureas and mitomycin-C)

• Biologic therapy (e.g., antibodies):≥ two weeks

• Endocrine therapies: Fulvestrant four weeks or Tamoxifen two weeks; other

aromatase inhibitors two weeks. Patients taking letrozole prior to screening do not have to stop letrozole.

• ≥ 5 x t1/2 of a small molecule therapeutic, not otherwise defined above, with a

minimum of 2 weeks Recovery from all adverse events of prior cancer therapies including surgery and radiotherapy, to baseline or CTCAE Grade≤1 , except for alopecia.

Patients eligible for this study must not meet any of the following criteria:

1. HER2-overexpression in the patient's tumor tissue by local laboratory testing (IHC 3+ or in situ hybridization positive).

2. Current symptomatic brain metastases. Patients with brain or CNS metastases that have been adequately treated and are asymptomatic and do not require corticosteroid and /or enzyme inducing anti -epileptic medication for brain metastases treatment are eligible.

3. Diffuse lymphangitic carcinomatosis

4. Patient who have received systemic corticosteroids≤ 2 weeks prior to starting study treatment, or who have not fully recovered from side effects of such treatment. (Local administration methods, e.g. topical, otic, optic and single systemic doses i.e. for prophylaxis are not considered systemic administration for the purpose of this protocol).

5. Patients who have undergone major surgery within the last 2 weeks prior to starting study treatment or who would not have fully recovered from previous surgery

6. Patients with acute or chronic pancreatitis

7. Any patient who meets the following criteria:

• Fasting plasma glucose≥ 140 mg/dL (7.7 mmol/L) and HbA1 c > 6.5% (both criteria have to be met). History of gestational diabetes mellitus or documented steroid- induced diabetes mellitus

8. Any patient with the following laboratory values during screening and prior to dosing on Cycle 1 Day 1 :

Hematologic

• Absolute Neutrophil Count (ANC) ≤1 .5x10⁹/L,

• Hemoglobin (Hgb)≤9.0 g/dL, • Platelets (pit)≤100x10⁹/L Biochemistry

• Total bilirubin > ULN except for patients with Gilbert's syndrome who may only be included if the total bilirubin is≤ 3.0 ^χ ULN or direct bilirubin≤ 1 .5 ^χ ULN

• Serum creatinine >1.5 mg /dL

• AST/SGOT or ALT/SGPT > 2.5 x Upper Limit of Normal (ULN) or > 5.0 x ULN if liver metastases are present

• Fasting plasma glucose (FPG)≥ 140 mg/dL (7.7 mmol/L) and Glycosylated

Hemoglobin (HbA1 c)≥6.5% (both criteria have to be met).

• Patient that do not have the following laboratory values within normal limits or correct to within normal limits with supplements before the first dose of study medication:

• Sodium

• Potassium

• Magnesium

• Total Calcium (corrected for serum albumin)

• Phosphorous Another malignancy within three years prior to starting study treatment, with the exception of adequately treated in situ carcinoma of the uterine cervix, basal or squamous cell carcinoma of the skin, or other indolent malignancies that have not required therapy within the past 3 years. Patients who have been treated with radiotherapy within four weeks prior to starting study treatment except in case of localized radiotherapy for analgesic purpose or for lytic lesions at risk of fracture, which can then be completed within two weeks prior to starting study treatment. Patients must have recovered from radiotherapy toxicities prior to starting study treatment. Patients who are currently receiving treatment with therapeutic doses of warfarin sodium (Coumadin^®) or any other coumarin-derivative anticoagulants. Dose escalation : Prior treatment with CDK4/6, AKT, mTOR or PI3K inhibitor and failure to benefit. Enrollment of patients previously treated with such agents requires approval by Novartis. Enrollment of patients with prior treatment with Ribociclib (Dose escalation ARM 1 and ARM 3) and Alpelisib (Dose escalation ARM 2 and ARM 3) is not allowed. Dose expansion only: Any prior treatment with CDK4/6, AKT, mTOR or PI3K inhibitor. Patients currently receiving hormone replacement therapy, unless discontinued 5 half- lives prior to starting study treatment Severe and /or uncontrolled medical conditions such as:

• Severe and/ or uncontrolled medical condition that would in the investigator's

judgment, cause unacceptable safety risks, contraindicate patient participation in the clinical study or compromise compliance with the protocol : ( e.g. chronic pancreatitis, chronic active hepatitis, active untreated or uncontrolled fungal, bacterial or viral infections, etc.)

• Patient has currently documented pneumonitis (the chest CT scan performed at baseline for the purpose of tumor assessment should be reviewed to confirm that there are no relevant pulmonary complications present).

• Impairment of gastrointestinal function or who have gastrointestinal disease that may significantly alter the absorption of study drugs (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).

• Active skin, mucosa, pulmonary, ocular or Gl disorders of Grade > 1 Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality, including any of the following:

• History of angina pectoris, symptomatic pericarditis, or myocardial infarction or coronary artery bybass graft (CABG) within 6 months prior to study entry

• Documented cardiomyopathy • Left ventricular ejection fraction (LVEF) < 50% as determined by multiple gated acquisition scan (MUGA) or echocardiogram (ECHO)

• Clinically significant arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high grade AV block (e.g. bifascicular block, Mobitz type II and third degree AV block).

• Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome, or any of the following;

• Risk factors for Torsades de Pointe (TdP) including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically

significant/symptomatic bradycardia

• Concomitant Medication(s) with known risk to prolong QT interval and/or known to cause Torsades de Pointe that cannot be discontinued or replaced by safe alternative medication (e.g. within 5 half-lives or 7 days prior to starting study drug)

• Systolic Blood Pressure (SBP) >160 or <90 mmHg

• Bradycardia (heart rate < 50 at rest), by ECG or pulse

• On screening, inability to determine the QT corrected with Fredericia's (QTcF) interval on the ECG (ie: unreadable or not interpretable) or QTcF >450 msec. All as determined by screening ECG (mean of triplicate ECGs).

• Sinus tachycardia (heart rate >90 bpm) Patient is currently receiving any of the following medications and cannot be discontinued 7 days prior to the start of the treatment:

• That are known strong inducers or inhibitors of CYP3A4/5, including grapefruit, grapefruit hybrids, pummelos, start fruit and Seville oranges

• That have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5.

• Herbal preparations/medications, dietary supplements. 18. Patients with known hypersensitivity to letrozole or to any components of the drug, or known hypersensitivity to Alpelisib or Ribociclib or excipients of either.

19. Not able to understand and to comply with study instructions and requirements.

All Arms of the Dose Escalation phase are performed in postmenopausal patients with Hormone Receptor-positive (ER+ and/or PR+) and HER2-negative breast cancer with any number of prior lines of endocrine therapy with up to one prior cytotoxic regimen in the advanced (metastatic or local advanced setting). No dose escalation is planned for Cohort 2 of ARM 1 .

The Dose Expansion phase in ARMS 1 and 2 (Cohorts 1 and 2) commence enrollment once the RP2D for the corresponding double combination is identified in the dose escalation cohorts. Dose expansion in ARMS 3 to 5 commence once the RP2D for the triple combinations is identified. Patients in all Arms (except the dose escalation of ARMS 1 to 3 and dose expansion of ARM 1 ) are screened to assess mutational status of PIK3CA. Patients whose disease has progressed while enrolled in either of the doublet combinations (ARM 1 or 2) may be eligible to receive treatment with the triplet combination if and when the RP2D has been identified, in the optional crossover group. Patients who have experienced dose reduction for any reason including Grade 3 or higher related adverse events during the dose escalation or dose expansion ARMS 1 or 2 are not eligible to enroll in the optional triplet crossover group. For the optional crossover triplet group, patients must have progressed on the double combination. Patients are not re-screened, and they must have recovered from all adverse events of prior cancer therapies to baseline or CTCAEv4.03 Grade≤1 -except for alopecia. The window between the crossover from the doublet to the triplet crossover group must be no longer than 30 days.

Screening

Upon signing the study Informed Consent Form, patients are evaluated against study inclusion and exclusion criteria. Eligible patients are enrolled in the study within 28 days prior to the screening assessments and evaluations.

In order to be preliminarily eligible for dose expansion ARMS 2 to 5 and for dose escalation ARMS 4 and 5, patients must have their tumor tissue available for PIK3CA mutation analysis. Dosing

The following Table 1 -1 summarizes the dose and treatment schedule for all patients in the study:

Pharmaceutical form Frequency and/or

Study and route of Regimen

treatments administration Strength (28 day cycles)

Ribociclib capsule for oral use 50 mg, 200 mg Daily (21 days or

continuous)

Letrozole tablet for oral use 2.5 mg Daily (continuous)

Alpelisib tablet for oral use 50 mg, 200 mg Daily (21 days or

continuous)

Letrozole is administered orally at a dose of 2.5 mg oral QD. Ribociclib is administered orally, once daily for 21 consecutive days followed by a 7-day planned break (28-day cycle) in all applicable Arms, except for ARM 4 in which Ribociclib is administered once daily on a continuous dosing schedule (28 day-cycle). Alpelisib is administered orally, once daily on a continuous dosing schedule (28-day cycle) in all applicable arms with the exception of ARM 5 in which Alpelisib is administered once daily for 21 consecutive days followed by a 7-day planned break (28-day cycle). All drugs are administered in the morning with the exception of ARM 2, Cohort 2 in which Alpelisib is administered in the evening and letrozole isadministered in the morning.

For all Arms (except Cohort 2 of ARM 2), Ribociclib, Letrozole and Alpelisib are taken by the patient as follows:

• Patients must take the study treatment of one or more tablets of Alpelisib,

Ribociclib and letrozole together with a large glass of water (about 250 mL) daily in the morning preferably within 1 hour of meal. The preferred time of dosing of ribocicilib and Alpelisib is in the morning one hour after breakfast. Ribociclib and letrozole can be taken without regard to meals. Alpelisib must be taken within 1 hour of a meal.

• Fasting glucose testing will be assessed in all patients for safety purposes (Cycle 1 Days 1 , 8, 15 and 22, Cycle 2 Days 1 and 15 and Day 1 on Cycle 3 and subsequent cycles, and EOT visit). Patients should be instructed to fast overnight at least 8 hours before the collection of the blood sample for fasting glucose testing. Note: If a non-fasting glucose sample is abnormally elevated, then the patient should also have a fasting glucose test within 24 hours for confirmation. o Patients may then have a light breakfast, followed 1 hour later by the study treatment administration. o Patient should continue to fast for 1 hour after the study treatment

administration. o On days of pre-dose PK blood collection, the pre-dose PK sample should be collected just prior to study treatment administration.

• If vomiting occurs during the course of treatment, no re-dosing of the patient is allowed before the next scheduled dose.

• Any doses that are missed (not taken within 6 hours of the intended time) should be skipped and should not be replaced or made up on a subsequent day.

• Patients must avoid consumption of grapefruit, Seville oranges, grapefruit

hybrids, pummelos, star fruit or products containing the juice of each during the entire study and preferably 7 days before the first dose of study medications, due to potential CYP3A4 interaction with the study medications. Orange juice is allowed. Cohort 2 of ARM 2, Letrozole and Alpelisib are taken by the patient as follows:

• Patients should be instructed to take letrozole in the morning with a large glass of water (about 250 mL) with or without a meal.

• For the evening dosing of Alpelisib, Alpelisib should be taken within 1 hour after a meal (e.g. dinner or late snack).

• PK sampling will be performed in on all patients treated. On Day 1 and 21 of Cycle 1 , pre-dose PK sample will be collected in the evening before

administration of the Alpelisib dose and 1-2 hour, 3-4 hour, 6-10 hour, and 12-14 hours post dose. On Cycle 1 Day 8 and Day 15 of Cycles 1 , 2, 4 and 6, pre-dose PK sample will be collected at anytime after noon (approximately 16 hours after the last Alpelisib evening dose).

• Pre-dinner glucose evaluation will also be conducted on C1 D15 and C2D1 .

Patients must be fasting for at least 6h prior to pre-dinner glucose evaluation.

• Fasting glucose testing will also be assessed in all patients for safety purposes (Cycle 1 Days 1 , 2, 8, 15 and 22, Cycle 2 Days 1 and 15 and Day 1 on Cycle 3 and subsequent cycles, and EOT visit). Patients should be instructed to fast overnight at least 8 hours before the collection of the blood sample for fasting glucose testing. Note: If a non-fasting glucose sample is abnormally elevated, then the patient should also have a fasting glucose test within 24 hours for confirmation.

In all treatment ARMS, patients may continue study treatment until disease progression, unacceptable toxicity occurs that precludes any further treatment and/or treatment is discontinued at the discretion of the investigator or the patient, as well as in the event of patient's death.

Dose Escalation Phase

The dose escalation process is implemented stepwise. Initially, cohorts of patients are enrolled and treated with the dual combinations. ARM 1 (Ribociclib and letrozole) is completing enrollment of the first dose cohort before enrollment into a cohort in ARM 2 (Alpelisib and letrozole). After the MTD/RP2D of both the dual combinations has been determined, cohorts of patients are enrolled into ARM 3 to 5 (Ribociclib, Alpelisib and letrozole).

For the purposes of dose escalation decisions, each cohort consists of 3 to 6 newly enrolled patients who are treated at the specified combination dose levels. The first cohort is treated with the starting combination doses of Ribociclib 600 mg QD and letrozole 2.5 mg QD. The second cohort is treated with the starting combination doses of Alpelisib 300 mg QD and letrozole 2.5 mg QD.

Patients must complete a minimum of 1 cycle of treatment with the minimum safety evaluation and drug exposure or have had a DLT within the first cycle of treatment to be considered evaluable for dose escalation decisions. Dose escalation decisions for a given combination occur when the cohort of patients in the corresponding arm has met these criteria. ARM 1 :

The starting dose for the study drug combination is 600 mg QD for Ribociclib and 2.5 mg daily for letrozole. The following Table 1 -2 sets forth the starting dose and the dose levels that may be evaluated:

Dose escalation is continued until MTD/RP2D is reached. In the case that any Ribociclib dose in combination with letrozole 2.5 mg QD is considered to be too toxic by the BLRM after any cohort, no MTD/RP2D can be defined for this treatment. Ribociclib and letrozole are administered as a flat-fixed dose, and not by body weight or body surface area.

ARM 2:

The starting dose for the study drug combination is 300 mg QD for Alpelisib and 2.5 mg daily for letrozole. The following Table 1 -3 sets forth the starting dose and the dose levels that may be evaluated:

*Dose level Alpelisib mg/day Letrozole mg/day

250 2.5

1 (starting dose) 300 2.5

2 350 2.5

3 400 2.5

^*lt is possible for additional and/or intermediate dose levels to be added during the course of the study. Cohorts may be added at any dose level below the MTD/RP2D in order to better understand safety, PK or PD.

^** Dose level -1 is the dose level for patients requiring dose reduction. A dose lower than the dose indicated may be explored. Dose escalation is continued until MTD/RP2D is reached. In the case that any Alpelisib dose in combination with letrozole 2.5 mg QD is considered to be too toxic by the BLRM after any cohort, no MTD/RP2D can be defined for this treatment. Alpelisib and letrozole will be administered as a flat-fixed dose, and not by body weight or body surface area.

ARM 3:

The starting doses of Ribociclib, Alpelisib, and letrozole of the triple combination are 400 mg QD for Ribociclib, 100 mg QD for Alpelisib, and 2.5 mg QD for letrozole. The following Table 1-4 sets forth the starting dose and the dose levels that may be evaluated:

Dose escalation is continued until MTD/RP2D is reached. In the case that any Ribociclib and Alpelisib dose in combination with letrozole 2.5 mg QD is considered to be too toxic by the BLRM after any cohort, no MTD/RP2D can be defined for this treatment. Ribociclib, Alpelisib and letrozole will be administered as a flat-fixed dose, and not by body weight or body surface area. Multiple dose levels may be explored in parallel during ARM 3 if recommended by the BLRM.

ARM 4: The following Table 1 -5 sets forth the starting dose and the dose levels that may be evaluated:

Dose escalation is continued until MTD/RP2D is reached. In the case that any Ribociclib continuous dosing and Alpelisib continuous dosing in combination with letrozole 2.5 mg QD is considered to be too toxic by the BLRM after any cohort, no MTD/RP2D can be defined for this treatment. Multiple dose levels may be explored in parallel during ARM 4 if recommended by the BLRM .

ARM 5:

The following Table 1 -6 sets forth the starting dose and the dose levels that may be evaluated:

*Dose level Ribociclib mg/day Alpelisib mg/day Letrozole mg/day

-1 a** 250 200 2.5

-1 b** 300 150 2.5

1 (starting dose) 300 200 2.5

2a 300 250 2.5

2b 400 200 2.5

3 300 300 2.5

4 400 300 2.5

*lt is possible for additional and/or intermediate dose levels to be added during the course of the study. Cohorts may be added at any dose level below the MTD/RP2D in order to better understand safety, PK or PD.

** A dose lower than the dose indicated may be explored. Dose escalation is continued until MTD/RP2D is reached. In the case that any Ribociclib 3 weeks on 1 week off dosing and Alpelisib 3 weeks on 1 week off dosing in combination with letrozole 2.5 mg QD is considered to be too toxic by the BLRM after any cohort, no MTD/RP2D can be defined for this treatment. Multiple dose levels may be explored in parallel during ARM 5 if recommended by the BLRM.

Criteria for Dose Escalation and Determination of MTD and RP2D

The MTD is defined as the highest combination drug dosage not causing medically unacceptable, dose-limiting toxicity (DLT) in 35% or more of the treated patients in the first cycle of treatment. AEs and laboratory abnormalities considered to be DLTs are defined in the following Table 1 -7:

TOXICITY DLT CRITERIA

Hematology ≥ CTCAE grade 4 neutropenia lasting more than 4 consecutive

days

CTCAE grade 3 thrombocytopenia with clinically significant bleeding

CTCAE grade 4 thrombocytopenia

Febrile neutropenia (decrease in neutrophils associated with fever, ANC < 1 .0 x 10⁹/L, fever > 38.5°C)

CTCAE grade 4 lymphopenia lasting more than 7 consecutive days

Skin and CTCAE grade 3 Rash > 7 days despite optimal management and subcutaneous tissue does not resolve to Grade 0 or 1

disorders CTCAE grade 4 Rash

≥ CTCAE grade 3 photosensitivity

Metabolism Grade 2 hyperglycemia (Fasting glucose 200 - 249 mg/dL)

(confirmed with a repeat Fasting glucose within 24 hours) that does not resolve to Fasting glucose <200 mg/dL within 14 consecutive days (despite optimal oral anti-diabetic therapy, i.e. glimepiride, glibenclamide and/or metformin)

Grade 3 hyperglycemia (Fasting glucose 250-499 mg/dL)

(confirmed with a repeat Fasting glucose within 24 hours) for > 14 consecutive days despite optimal oral anti-diabetic treatment

Grade 4 hyperglycemia (Fasting glucose >499 mg/dL)

Hyperglycemia leading to diabetic keto-acidosis, hospitalization for IV insulin infusion, or non-ketotic coma

CTCAE grade 3 amylase and/or lipase, not reversible to≤ CTCAE grade 2 for > 7 consecutive days CTCAE grade 4 amylase and/or lipase

Gastro-intestinal ≥ CTCAE grade 3 vomiting≥ 48 hrs despite optimal anti-emetic

therapy

≥ CTCAE grade 3 diarrhea≥ 48 hrs despite optimal anti-diarrhea treatment

Hepato-biliary ≥ CTCAE grade 3 total bilirubin

≥ CTCAE grade 3 ALT lasting >4 days (isolated increases in AST without concomitant increases in ALT will not be considered dose- limiting, because of the non-specific nature of AST)

≥ CTCAE grade 2 ALT with a≥ Grade 2 bilirubin elevation of any duration

≥ CTCAE grade 4 ALT of any duration

ECG QT Interval QTcF interval≥ 501 ms on at least two separate ECGs

Renal ≥ CTCAE grade 3 serum creatinine

Events not described ≥ CTCAE grade 3, except for the exclusions noted below

above

Exceptions to DLT Grade 3 alopecia

criteria CTCAE grade 3 fatigue < 5 days

CTCAE Grade 3 laboratory abnormalities that are responsive to oral supplementation or deemed by the investigator to be clinically insignificant

CTCAE grade 3 edema <48 hours

CTCAE version 4.03 will be used for all grading.

Optimal therapy for vomiting or diarrhea will be based in institutional guidelines, with

consideration of the prohibited medications listed in this protocol.

Typically the MTD is a tested dose with maximum probability of targeted toxicity (DLT rate in the interval [16%-35%)).

Patients must complete a minimum of 1 cycle of treatment with the minimum safety evaluation and drug exposure or have had a DLT within the first cycle of treatment to be considered evaluable for dose escalation decisions. Dose escalation decisions for a given combination occur when the cohort of patients in the corresponding arm has met these criteria.

The recommended doses for the next cohort of subjects are guided by the Bayesian logistic regression model (BLRM) with EWOC principle. If the first two patients in a previously untested dose level experience a DLT, enrollment to that cohort stops, and the next cohort is opened at the next lower dose level or an intermediate dose that satisfies the EWOC criteria. However, if the first two patients in a new cohort at a previously tested dose level experience a DLT (e.g., a total of eight patients are treated on this dose level with two DLTs observed), further enrollment to that cohort stops. By incorporating information gained at the preceding dose cohorts, additional patients may be enrolled into the current dose cohort only if the combination still meets the EWOC criteria and as agreed by Investigators and Study Sponsor. Alternatively, if recruitment to the same cohort may not resume, a new cohort of patients may be recruited to a lower dose combination as agreed by Investigators and Study Sponsor and if the BLRM predicts that the risk for this lower dose combination to exceed the MTD remains below 25% (EWOC). Re-escalation may then occur if data in subsequent cohorts supports this (EWOC criteria are satisfied) and Investigators and Study Sponsor agree.

Dose escalation for each arm (double and triple combinations) is continued until identification of the MTD or a suitable lower dose for dose expansion and/or Phase II (RP2D) for each treatment, respectively. This will occur when the following conditions are met:

1. At least 6 patients have been treated at this dose

2. This dose satisfies one of the following conditions:

a. The posterior probability of targeted toxicity (in the interval [16%, 35%) ) at this dose exceeds 50% and is highest among potential doses, or

b. For each of the two dual combination arms a minimum of 12 patients and for the triple combination arms a minimum of 12 patients have already been treated on the study.

3. It is the dose recommended for patients, either per the model or by review of all clinical data by Study Sponsor and Investigators at a dose escalation meeting.

The RP2D for each Arm is selected based on available safety, tolerability, PK, PD and efficacy data, as well as the recommendations from the BLRM using EWOC and the

Investigators.

After the RP2D is determined, additional patients may be enrolled in a dose expansion at the RP2D for each double combination with approximately 30 patients for the Ribociclib + letrozole combination and approximately 45 patients in Cohort 1 and approximately 20 patients in Cohort 2 for the Alpelisib + letrozole combination each.

In parallel, after the RP2D are determined for both ARMS 1 and 2, enrollment commences in ARM 3 to 5 beginning with the dose escalation of the triple combination at the specified starting doses. For ARM 3 after the RP2D is determined, enrollment of approximately 45 patients commences for ARM 3 dose expansion. Following RP2D determination in ARMS 4 and 5, either ARM 4 or ARM 5 (or both if safety profiles are comparable) enrolls approximately 25 patients in the dose expansion.

Intra-patient dose escalation prior to declaration of MTD/RP2D is not permitted at any time during this study. However once the MTD/RP2D is declared, for a given combination regimen (i.e. either doublet or the triplet regimen), individual patients may be considered for escalation to treatment at the RP2D of the combination.

Dose Limiting Toxicities (DLTs)

Assessment of DLTs are performed in the dose escalation part only. A DLT is defined as an adverse event or abnormal laboratory value assessed as having a reasonable possibility related to the study medication, unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurs within the first 28 days of treatment (cycle 1 ) with Ribociclib, Alpelisib and letrozole and meets any of the criteria included in Table 1-7. National Cancer Institute Common Terminology Criteria for Adverse events (NCI CTCAE) version 4.03 are used for all grading.

Whenever a patient experiences toxicity that fulfills the criteria for a DLT, treatment with the study drug combination is interrupted and the toxicity is followed up.

Dose Modification

Up to two dose reductions are permitted per patient per study drug. If a patient requires a dose interruption of >28 days from the intended day of the next scheduled dose, then the patient must discontinue the study drug that was interrupted. No specific dose modifications are recommended for letrozole.

A. Dose modification and dose delay during Cycle 1 in dose escalation part

If a patient experiences a DLT, then treatment with all investigational drugs (Ribociclib and/or Alpelisib) are interrupted. For all toxicity grades, if the toxicity resolves to grade 1 or baseline within 1 week of onset, treatment may be resumed at the same or a lower dose level at the Investigator's discretion.

For toxicities related to study medications that result in treatment delays of more than 7 but not more than 21 days, treatment may be resumed at a lower dose level. The dose during Cycle 1 should not be reduced unless the patient has experienced a DLT. All patients in all arms are routinely asked about and observed for the occurrence of adverse events including new or changed pulmonary symptoms (consistent with lung abnormalities). Patients receiving Alpelisib who are suspected to have developed pneumonitis should stop Alpelisib and Ribociclib immediately and undergo appropriate imaging (high resolution CT scan requiring slice thickness of 5mm or less) and bronchoalveolar lavage for biopsy should be considered. Treatment with letrozole may continue. Investigators should follow institutional practice for management of pneumonitis

B. Dose modification after Cycle 1 in dose escalation and for all cycles in dose expansion

For ARMS 4 and 5 upon the determination of the recommended dose for dose expansion, up to 2 dose reductions are permitted per patient per study drug (Ribociclib or Alpelisib). If a patient requires more than 2 dose reductions for a given study drug (Ribociclib or Alpelisib), then this study drug must be discontinued.

Recommendations for dose reduction of ARM 2 and ARM 3 are provided in Table 1 -8 and 1 -9:

Table 1 -8 Dose modification guidelines ARM 2

Alpelisib Dose

Starting dose 300 mg

First dose reduction 250 mg

Second dose reduction 200 mg

Table 1 -9 Dose modification guidelines ARM 3

Ribociclib Dose Alpelisib Dose

Starting dose 300 mg 200 mg

First dose reduction 250 mg 150 mg Second dose reduction 200 mg 100 mg

For ARMS 4 and 5 upon the determination of the recommended dose for dose expansion, up to two dose reductions are permitted per patient per study drug. If a patient requires more than two dose reductions for a given study drug (Ribociclib or Alpelisib), then this study drug must be discontinued.

Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment. However, for events requiring a

discontinuation in Table 1 -10, treatment must be discontinued:

Adverse drug Severity^* Do se adji JSttTK int a nd

reaction Recommendation

Hematology Grade 3 febrile neutropenia Hold Ribociclib until improvement of ANC

ANC <1.0 x 109/L with a ≥ 1.0 x 10⁹/L and no fever. Restart at the single temperature of next lower dose level.

>38.3 °C (101 °F) or a If febrile neutropenia recurs, discontinue sustained temperature of Ribociclib.

≥38 °C (100.4 °F) for more

than one hour Hold Alpelisib dose until resolved, then reduce 1 dose level.

Grade 4 febrile neutropenia Discontinue Ribociclib.

Life-threatening

consequences; Hold Alpelisib dose until resolved, then urgent intervention reduce 1 dose level.

indicated

Grade 3 Anemia Hold Ribociclib until recovery to grade≤ (<8.0 g/dL) 2.

Re-initiate Ribociclib at the same dose.

Grade 4 Anemia Discontinue Ribociclib. and Alpelisib Life-threatening

consequences;

urgent intervention

indicated

QTcF prolongation Grade 3 Hold Ribociclib

QTc≥ 501 ms on at least Transmit ECG immediately and confirm two separate ECGs prolongation/abnormalities with central assessment.

Perform repeat triplicate ECGs one hour after the first QTcF of≥ 501 ms.

If QTcF remains≥ 501 ms, consult with a cardiologist (or qualified specialist) and repeat cardiac monitoring as clinically indicated until the QTcF returns to < 481 ms.

If QTcF returns to < 481 ms, Ribociclib will be reduced by 1 dose level.

Repeat ECGs 7 days and 14 days after dose resumption ( then as clinically indicated) for any patients who hadtherapy interrupted due to QTcF≥ 501 ms

If QTcF of≥ 501 ms recurs, discontinue Ribociclib.

First Occurrence:

• Hold Alpelisib

• Perform an analysis of serum potassium and magnesium, and if below lower limit of normal, correct with supplements to within normal limits. Concomitant medication usage must be reviewed.

• Perform a repeat ECG within one hour of the first QTcF of > 500 ms or >60ms from baseline

• If QTcF remains > 500 ms or >60ms from baseline, repeat ECG as clinically indicated, but at least once a day until the QTcF returns to < 480 ms. Seek cardiologist input.

» Once QTcF prolongation has returned to < 480 msec, consider re-introducing treatment at reduced dose, and increase ECG monitoring.

Second Occurrence:

Permanently discontinue patient from

Alpelisib.

Grade 4 Discontinue Ribociclib and Alpelisib.

[QT/QTc≥ 501 or > 60 ms Transmit ECG immediately and confirm change from baseline] prolongation/abnormalities with central and assessment.

[Torsades de pointes or Obtain local cardiologist consultation. polymorphic ventricular

Perform repeat triplicate ECGs one hour tachycardia, or

after the first QTcF of≥ 501 ms, repeat signs/symptoms

cardiac monitoring as indicated until the of serious arrhythmia]

QTcF returns to <481 ms.

If QTcF remains≥ 501 ms, repeat ECG as clinically indicated, but at least once a day until the QTcF returns to < 501 ms.,

Cardiac - Left Refractory or poorly Permanently discontinue patient from Ventricular Systolic controlled, Alpelisib.

ejection fraction < 20%

Dysfunction

Other Cardiac Event Grade 4 Discontinue the patient from Alpelisib (other than QTc and Ribociclib treatment .

prolongation)

Hyperglycemia Grade 4 (> 500 mg/dL) [≥ Omit Alpelisib, confirm fasting status of

27.8 mmol/L] the assessment. If non-fasting, re-check within 24 hours. Exclude confounding factors like e.g. urinary tract infection. Consider cooperation with diabetologist, initiate or intensify medication with appropriate anti-diabetic treatment (see Grade 3), re-check within 24 hours. If grade improves then follow specific grade recommendations. If FPG is confirmed at Grade 4 and confounding factors could be excluded, discontinue patient from Alpelisib.

Hepatobiliary Total bilirubin without ALT/AST increase above baseline value

Grade 2 Hold Ribociclib

(> 1.5 - 3.0 x ULN) If resolved to≤ grade 1 in≤ 21 days, then maintain dose level

If resolved to≤ grade 1 in > 21 days or toxicity recurs, then reduce 1 dose level

Repeat liver enzyme and bilirubin tests twice weekly for 2 weeks after dose resumption

If toxicity recurs after two dose reductions, discontinue Ribociclib

Hold Alpelisib .Monitor LFTs weekly or more frequently if clinically indicated, dose until resolved to≤ Grade 1 , then:

• If resolved in≤ 14 days, then maintain dose level

• If resolved in > 14 days, then reduce 1 dose level

If toxicity recurs after two dose reductions, discontinue Ribociclib and Alpelisib treatment Grade 3 Hold Ribociclib

(> 3.0 - 10.0 x ULN) If resolved to≤ grade 1 in≤ 21 days, lower 1 dose level of Ribociclib

If resolved to≤ grade 1 in > 21 days or toxicity recurs, discontinue Ribociclib treatment.

Hold Alpelisib Monitor LFTs weekly or more frequently if clinically indicated, Omit dose until resolved to≤ Grade 1 , then:

• If resolved in≤ 14 days, reduce 1 dose level

• If resolved in > 14 days discontinue patient from Alpelisib

If toxicity recurs after two dose reductions, discontinue Ribociclib and Alpelisib treatment

The patient should be monitored weekly (including LFTs), or more frequently if clinically indicated, until total bilirubin have resolved to baseline or stabilization over 4 weeks

Grade 4 (> 10.0 x ULN) Discontinue Ribociclib and Alpelisib treatment.

AST or ALT without bilirubin elevation >2 x ULN

Increase from baseline Hold Ribociclib

grade 0 or 1 to grade 2 (> If resolved to≤ baseline grade in≤ 21 3.0 - 5.0 x ULN) days, then maintain dose level

If resolved to≤ baseline grade in > 21 days or toxicity recurs, then reduce 1 dose level

If toxicity recurs after two dose reductions or recovery to≤ baseline grade is > 28 days, discontinue

Ribociclib treatment Hold Alpelisib

Omit dose until resolved to≤ baseline grade

If treatment delay is≤ 7 days, restart at same dose

If resolved in > 7 days, reduce 1 dose level

[For patients with grade 2 at screening Maintain dose level with LFTs monitored per protocol]

Increase from baseline Hold Ribociclib until resolved to≤ grade 2 to grade 3 (> 5.0 - baseline grade, then lower 1 dose level 20.0 x ULN) of Ribociclib

If recovery to≤ baseline grade is > 28 days, discontinue Ribociclib

If toxicity recurs, discontinue Ribociclib treatment.

Hold Alpelisib

until resolved to≤ Baseline grade, then If treatment delay is≤ 7 days, restart at same dose

If resolved in > 7 days, reduce 1 dose level.

Increase from baseline Hold Ribociclib until resolved to≤ grade 0 or 1 to grade 3 (> baseline grade, then lower 1 dose level 5.0 - 20.0 x ULN) of Ribociclib

If recovery to≤ baseline grade is > 28 days, discontinue Ribociclib

If toxicity recurs, discontinue Ribociclib treatment.

Hold Alpelisib until resolved to≤ baseline grade, then

if treatment delay is≤ 7 days, restart at same dose.

If resolved in > 7 days, reduce 1 dose level.

Grade 4 (> 20.0 x ULN) Discontinue Ribociclib treatment. Hold Alpelisib until resolved to≤ grade 1 , then reduce dose of Alpelisib by 1 dose level.

AST or ALT and Bilirubin

For patients with normal Permanently discontinue Ribociclib ALT or AST or total bilirubin treatment.

at baseline : AST or ALT≥ Permanently discontinue Alpelisib.

grade 2 combined with total

bilirubin > 2 x ULN without

evidence of cholestasis^**

OR

For patient with elevated

AST or ALT or total bilirubin

at baseline : [AST or ALT

>2 x baseline AND >3.0x

ULN] OR [AST or ALT 8.0x

ULN]- whichever is lower- combined with [total

bilirubin 2xbaseline AND

>2.0 x ULN]

Stomatitis/Oral Grade 4 Permanently discontinue patient from mucositis Alpelisib and Ribociclib.

Rash Grade 4 Permanently discontinue patient from

(any % BSA associated with Alpelisib and consider a dermatology extensive superinfection, consult.

with IV antibiotics indicated; Treatment of rash should follow lifethreatening guidelines for Grade 3/intolerable consequences) Grade 2 rash above with the exception of rechallenge and with any additional measures needed.

-Consider exploratory skin biopsy.

Serum creatinine Grade≥3 (>3 xULN) Discontinue Alpelisib.

Grade≥2 non acute renal Discontinue Ribociclib.

impairment

Pancreatitis Grade≥ 3 Hold Alpelisib and Ribociclib. If the

pancreatitis resolves to Grade 0 within 21 days, then treatment may be restarted.

If the pancreatitis is not resolved to Grade 0 within 21 days, then Alpelisib treatment should be discontinued.

Continuation of Ribociclib in triplet arms may be discussed with the Medical Monitor.

Pneumonitis Any Grade Omit Ribociclib and Alpelisib for any case of suspected pneumonitis. Obtain appropriate imaging (high

resolution CT scan requiring 5 mm slice thickness or less) and consider bronchoalveolar lavage for biopsy.

Concurrent corticosteroid and antibiotic therapy is recommended if infectious causes have not been ruled out.

Alpelisib should be permanently discontinued in all patients with confirmed pneumonitis related to study drugs.

Upon resolution of the pneumonitis, reinitiation of treatment with Ribociclib may be considered at the same or a lower dose following consultation with Novartis.

All other toxicities Grade 3 Determine attribution of toxicity. Hold assigned therapy until resolved to≤ Grade 1 or baseline. If toxicity cannot be attributed to one study drug, hold both Ribociclib and Alpelisib. Initiate appropriate medical therapy and monitor. Re-initiate Ribociclib and/or Alpelisib at the next lower dose level.

If toxicity recurs at grade 2: temporary dose interruption until recovery to grade ≤1 and reduce Ribociclib If toxicity recurs at grade 3, discontinue Ribociclib Omit dose until resolved to≤ grade 1 , thenj, 1 dose level

Grade 4 Determine attribution of toxicity.

Discontinue assigned therapy. If toxicity cannot be attributed to one study drug, discontinue both Ribociclib and Alpelisib. Initiate appropriate medical therapy and monitor.

a Severity grade description (per CTCAE v4.03): 1 = mild symptoms; 2 = moderate symptoms; 3 = severe symptoms; 4 = life-threatening symptoms.

For the triplet arms, it is left to the investigator's clinical judgement in the best interest of the patient, as to what adjustments should be made to what compound.

No specific dose modifications are recommended for letrozole. Toxicities attributed to letrozole should be managed consistent with the investigator's usual practice and the package insert for letrozole. Patient Assessment Types

Patients are assessed for efficacy, safety and tolerability, physical signs and symptoms (including laboratory evaluations (e.g., hematology, clinical chemistry, urinalysis, glucose safety monitoring, hepatic safety markers, and electrocardiogram), and pharmacokinetics during the study.

Efficacy assessments

Tumor response are evaluated locally by the investigator according to the Sponsor's guideline (Version 3.1) based on RECIST version 1.1 1. The following assessments are required at screening/baseline (within 28 days prior to the start of treatment):

• Chest, abdomen and pelvis CT or MRI.

• Documented review of high-resolution chest CT scan must be obtained for all new patients at screening/baseline

• Brain MRI or CT if clinically indicated.

• Whole body bone assessment per institutional standard of care [e.g. Tc-99 bone scan, MRI, FDG-PET or sodium fluoride positron emission tomography (NaF PET)] must be obtained at baseline. Localized imaging should be acquired for all skeletal lesions identified on the screening bone scan that are not visible on the chest, abdomen and pelvis CT/MRI, using a method consistent with institutional practice.

• Color photographs for any skin lesions present (including a ruler/scale).

• CT or MRI of other areas of disease if clinically indicated.

Subsequent tumor evaluations are performed every 8 weeks through cycle 6. After cycle 6 tumor evaluations will be performed every 12 weeks (C2D28+/- 7, C4D28+/- 7, C6D28+/- 7, C9D28+/- 7, C12D28+/- 7, etc.), or sooner if there is clinical evidence of disease progression. Tumor evaluations will also be performed at End of Treatment. All efficacy evaluations have a +/- 7 day window. If the last prior tumor evaluation was within 28 days of End of Treatment or objective evidence of progressive disease has already been documented, then tumor evaluations do not need to be repeated at End of Treatment. Tumor evaluations after the screening assessment include evaluation of all sites of disease identified at baseline. Chest, abdomen, pelvis scans need to be repeated at each tumor assessment visit (including if negative at baseline).

Any potentially measurable lesion that has been previously treated with radiotherapy should be considered as a non-measurable lesion. However, if a lesion previously treated with radiotherapy has clearly progressed since the radiotherapy, it can be considered as a measurable lesion.

Individual lesion measurements are listed along with the overall lesion response. Overall response rate (ORR) and Disease control rate (DCR) are summarized by treatment group and dose expansion arm with accompanying 95% confidence intervals.

Clinical Benefit is defined as CR or PR or SD for 24 weeks or longer. CR, PR and SD are defined according to RECIST 1 .1 .

Safety and tolerability assessments

Safety is monitored by assessing the procedures as well as collecting of the adverse events at every visit. An adverse event is defined as the appearance of (o worsening of any pre-existing) undesirable sign(s), symptom(s), or medical conditions that occur after patient's signed informed consent is obtained. Adverse events are assessed according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.03. All adverse events should be treated appropriately. All safety assessments are performed pre-dose unless otherwise specified. Serious adverse event (SAE) is defined as one of the following:

Is fatal or life-threatening

Results in persistent or significant disability/incapacity Constitutes a congenital anomaly/birth defect

Is medically significant, i.e., defined as an event that jeopardizes the patient or may require medical or surgical intervention to prevent one of the outcomes listed above

Requires inpatient hospitalization or prolongation of existing hospitalization,

Note that hospitalizations for the following reasons should not be reported as serious adverse events: Routine treatment or monitoring of the studied indication, not associated with any deterioration in condition

Elective or pre-planned treatment for a pre-existing condition that is unrelated to the indication under study and has not worsened since signing the informed consent

Social reasons and respite care in the absence of any deterioration in the patient's general condition

Discontinuation of study treatment

Study treatment may be discontinued under the following circumstances:

• Adverse event

• Patient withdrew consent

• Lost to follow-up

• Physician decision

• Disease progression

• Protocol deviation

• Study termination by sponsor

• Technical problems

Patient must be withdrawn from the study treatment if any of the following occur:

• Pregnancy

• Death

• Subject/Guardian decision

At a minimum, all patients who discontinue study treatment, including those who refuse to return for a final visit, will be contacted for safety evaluations during the 30 days following the last dose of study treatment.

If a patient discontinues study treatment, but continues study assessments, the patient remains on study until such time as she completes protocol criteria for ending study assessments.

Patients who are enrolled in the optional crossover triplet group will have two end of treatment study visits. The first end of treatment study visit will occur when the patient reaches progressive disease while on the doublet in dose escalation or dose expansion. Tumor imaging does not need to be repeated prior to the crossover. Blood tests are only repeated if outside the screening (14 day) window from first triplet dose. The second end of treatment study visit will occur when the patient reaches progressive disease while on the crossover triplet.

End of treatment visit is not considered as the end of the study.

30-day safety follow-up assessments

The End of Treatment visit occurs within 14 days after the last administration of study treatment, or within 14 days of the decision to discontinue treatment due to an AE, in the case that treatment was already on hold due to an AE. Safety follow-up assessments should be completed 30 days after the last dose of the study treatment.

Disease progression follow-up assessments

Patients enrolled who discontinue study treatment for any reason other than disease progression will be followed every two months for progression of disease.

End of Study

End of Study is achieved when the treatment period, safety follow-up and disease follow- up have ended for all patients, or when the study is terminated early.

Claims

What is Claimed is:

1. A method of treating or preventing a proliferative disease in a human in need thereof comprising orally administering to said human a daily dose of about 100 mg to about 450 mg of the compound of formula (I)

2. Use of the compound of formula (I)

or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing a proliferative disease, wherein said medicament is orally administered to a human in need thereof in a daily dose of about 100 mg to about 450 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof each day for a period of three weeks and then not administered to said human for one week immediately thereafter, and wherein this cycle is repeated for from one to several cycles.

3. The method according to claim 1 or the use according to claim 2, wherein the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is about 200 mg to about 400 mg.

4. The method according to claim 1 or the use according to claim 2, wherein the proliferative disease is a cancer.

5. The method or the use according to any one of claims 1 to 4 , wherein the proliferative disease is a cancer selected from lung cancer, breast cancer (including sporadic breast cancers and sufferers of Cowden disease), head and neck cancer, prostate cancer, colon cancer, rectal cancer, and squamous cell carcinoma.

6. The method or the use according to any one of claims 1 to 5, wherein the proliferative disease is characterized by or dependent on overexpression or amplification of PI3K alpha, somatic mutation of PIK3CA or germline mutations or somatic mutation of PTEN or mutations and translocation of p85a that serve to up-regulate the p85-p1 10 complex.

7. The method according to claim 1 or the use according to claim 2, wherein the compound of formula (I) or a pharmaceutically acceptable salt is orally administered once per day or twice per day in a daily dose of about 200 mg to about 400 mg.

8. The method according to claim 1 or the use according to claim 2, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with at least one additional therapeutic agent.

9. The method or the use according to claim 8, wherein the at least one additional therapeutic agent is fulvestrant or letrozole.

10. The method or the use according to claim 8, wherein the at least one additional therapeutic agent is letrozole and Compound of formula (II)

and any pharmaceutically acceptable salt thereof.

1 1 . The compound of formula (I)

or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a proliferative disease, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is orally administered in a daily dose of about 100 mg to about 450 mg each day for a period of three weeks and then not administered for one week immediately thereafter, and wherein this cycle is repeated for one to several cycles.

12. The compound according to claim 1 1 , wherein the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is about 200 mg to about 400 mg.

13. The compound according to claim 1 1 , wherein the proliferative disease is a cancer.

14. The compound according to any one of claims 1 1 to 13, wherein the proliferative disease is a cancer selected from lung cancer, breast cancer (including sporadic breast cancers and sufferers of Cowden disease), head and neck cancer, prostate cancer, colon cancer, rectal cancer, and squamous cell carcinoma.

15. The compound according to any one of claims 1 1 to 14, wherein the proliferative disease is characterized by or dependent on overexpression or amplification of PI3K alpha, somatic mutation of PIK3CA or germline mutations or somatic mutation of PTEN or mutations and translocation of p85a that serve to up-regulate the p85-p1 10 complex.

16. The compound according to claim 1 1 , wherein the compound of formula (I) or a pharmaceutically acceptable salt is orally administered once per day or twice per day in a daily dose of about 200 mg to about 400 mg.

17. The compound according to any one of claims 1 1 to 16, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with at least one additional therapeutic agent.

18. A method of treating or preventing a proliferative disease comprising: first, orally administering to a human in need thereof a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof in a daily dose of about 100 mg to about 450 mg each day on a continuous schedule; second, determining said human has a side effect of hepatic dysfunction or hepatobiliary toxicity after administration of said compound of formula (I) or a pharmaceutically acceptable salt thereof to said human; and third, reducing the oral administration of said compound of formula (I) or a pharmaceutically acceptable salt thereof to a daily dose of about 100 mg to about 450 mg each day for a period of three weeks and then not administering said compound of formula (I) or a pharmaceutically salt thereof to said human for one week immediately thereafter and then repeating this cycle for one to several cycles.