Study of Safety and Efficacy of Alpelisib With Everolimus or Alpelisib With Everolimus and Exemestane in Advanced Breast Cancer Patients, Renal Cell Cancer and Pancreatic Tumors

A Phase Ib Dose-finding Study of BYL719 Plus Everolimus and BYL719 Plus Everolimus Plus Exemestane in Patients With Advanced Solid Tumors, With Dose-expansion Cohorts in Renal Cell Cancer (RCC), Pancreatic Neuroendocrine Tumors (pNETs), and Advanced Breast Cancer (BC) Patients.

Dose escalation part: to determine the highest dose of alpelisib administered on a daily basis when given in combination with daily everolimus or in combination with daily everolimus and exemestane.

Dose expansion part: To describe safety and tolerability of the alpelisib and everolimus or alpelisib, everolimus and exemestane combinations.

The main purpose of the study was to determine the maximum tolerated dose/recommended dose for expansion (MTD/RDE) of alpelisib in combination with everolimus, and of alpelisib in combination with everolimus and exemestane, and additionally to describe safety, preliminary efficacy and the magnitude of the alpelisib-everolimus interaction. The study was conducted in patients with metastatic and/or recurrent solid tumors including renal cell carcinoma (RCC), pancreatic neuroendocrine tumor (pNET), and advanced solid tumors previously treated with an mTOR inhibitor, to evaluate everolimus and alpelisib, and in postmenopausal females with HR-positive HER2-negative advanced breast cancer to evaluate everolimus, alpelisib and exemestane.

This was a Phase Ib, open-label, multi-center, dose-finding study. The initial dose level of alpelisib was 300 mg every day (qd) and everolimus was initially administered at 2.5 mg qd. The dose-finding study (escalation phase) was followed by an expansion phase where safety and preliminary efficacy of the doublet (alpelisib and everolimus) as well as of the triplet (alpelisib, everolimus and exemestane) were assessed in selected subject populations.

Alpelisib, everolimus and exemestane were administered orally once daily on a continuous dosing schedule and dosed on a flat-fixed dose and not by body weight or body surface area, starting on Day 1 in a 28-day cycle.

In the doublet escalation phase, alpelisib was administered at 300 mg or 250 mg in combination with 2.5 mg everolimus. In the triplet escalation phase, alpelisib was administered at 200 mg in combination with 2.5 mg everolimus and 25 mg exemestane.

In the doublet expansion phase, alpelisib was administered at 250 mg in combination with 2.5 mg everolimus. In the breast cancer expansion phase, alpelisib was administered at 200 mg in combination with 2.5 mg everolimus and 25 mg exemestane or alpelisib was administered at 250 mg in combination with 25 mg exemestane.

No fixed treatment duration was specified. Patients in the study were planned to receive the treatment until disease progression (assessed by Response Evaluation Criteria in Solid Tumors (RECIST v1.1)), unacceptable toxicity, death, or discontinuation from study treatment for any other reason.

Inclusion Criteria For entire trial:

• Adult > or = 18 years old
• has signed the Informed Consent Form
• has tumor tissue available for the analysis as described in the protocol
• has an Eastern Cooperative Oncology Group performance status ≤2
• has adequate bone marrow and organ function as defined in the protocol
• is able to swallow and retain oral medication
• has either measurable or non-measurable disease as per RECIST 1.1.

Inclusion Criteria for the BYL719+ Everolimus combination - escalation phase - all above plus has a histologically/cytologically confirmed metastatic and/or recurrent solid tumors for whom no standard therapy exists.

Inclusion Criteria for the BYL719+ Everolimus combination - expansion phase, renal cell carcinoma cohort - all of above first 7 criteria plus has an histologically/cytologically confirmed Renal Cell Cancer as detailed in the protocol

Inclusion Criteria for the BYL719+ Everolimus combination - expansion phase, pancreatic NeuroEndocrine Tumor cohort

- all of above first 7 criteria plus has an histologically/cytologically confirmed pancreatic NeuroEndocrine Tumor as detailed in the protocol

Inclusion Criteria for the BYL719+ Everolimus combination - expansion phase, mTOR inhibitor-pretreated patients' cohort - all of above first 7 criteria plus has a histologically and/or cytologically confirmed solid malignancy as described in the protocol

Inclusion Criteria for the breast cancer cohorts in escalation and expansion phases, - all of above first 7 criteria plus is post-menopausal and has a histologically and/or cytologically confirmed diagnosis of breast cancer as described in the protocol

Specific Inclusion Criteria at the time of cross-over (breast cancer, expansion phase),

- Patient randomized to the alpelisib and exemestane combination who has a radiologically documented progressive disease as detailed in the protocol

Exclusion Criteria:

• Patient has received previous treatment with a PI3K and/or AKT and/or mTOR inhibitor (mTOR inhibitor is allowed in expansion cohorts where patients should have areceived a prior mTOR inhibitor)
• Known intolerance or hypersensitivity to Everolimus or other rapamycin analogs
• Patient with primary central nervous system (CNS) tumor or CNS tumor involvement as detailed in the protocol
• Patient with diabetes mellitus, or documented steroid-induced diabetes mellitus
• Patient has a history of another malignancy within 2 years prior to starting study treatment as described in the protocol
• Patient who has not recovered to grade 1 or better (except alopecia) from related side effects of any prior antineoplastic therapy as detailed in the protocol
• Patient who has had systemic therapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to starting study treatment
• Patient who has received radiotherapy ≤ 4 weeks prior to starting study drugs, with exception of palliative radiotherapy (≤ 2 weeks prior to starting study drugs), who has not recovered from side effects of such therapy to baseline or Grade ≤ 1 and/or from whom ≥ 30% of the bone marrow was irradiated
• Patient who has undergone major surgery ≤ 4 weeks prior to starting study treatment or who has not recovered from side effects of such procedure
• Patient has a clinically significant cardiac disease or impaired cardiac function or any severe and/or uncontrolled medical conditions as detailed in the protocol
• Patient who is currently receiving medication with a known risk of prolonging the QT interval or inducing Torsades de Pointes (TdP) and the treatment cannot either be discontinued or switched to a different medication prior to starting study drug treatment
• Patient who has participated in a prior investigational study within 30 days prior to enrollment as described in the protocol
• Patient who is currently receiving treatment with drugs known to be moderate or strong inhibitors or inducers of isoenzymes CYP34A or CYP2C8 as described in the protocol. Switching to a different medication prior to start of treatment is allowed
• Patient with impaired gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral alpelisib, everolimus, exemestane
• Patient with known positive serology for human immunodeficiency virus
• Patients who have received live attenuated vaccines within 1 week of start of study drug and during the study as specified in the protocol.
• Pregnant or nursing (lactating) woman as detailed in the protocol.
• Patient who does not apply highly effective contraception during the study and through the duration as defined in the protocol
• Patients in the mTOR inhibitor-pretreated cohorts: all of above first 19 criteria plus have discontinued prior mTOR inhibitor therapy due to non-tolerable toxicity