Overview

This trial is active, not recruiting.

Conditions neoplasms, breast neoplasms, kidney neoplasms, pancreatic neuroendocine neoplasms
Treatments alpelisib, everolimus, exemestane
Phase phase 1
Targets PI3K, mTOR, FKBP-12
Sponsor Novartis Pharmaceuticals
Start date May 2014
End date August 2017
Trial size 78 participants
Trial identifier NCT02077933, 2013-004829-86, CBYL719Z2102

Summary

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.

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Allocation non-randomized
Endpoint classification safety/efficacy study
Intervention model crossover assignment
Masking open label
Primary purpose treatment
Arm
(Experimental)
alpelisib and everolimus administered once a day
alpelisib
alpelisib is administered orally once a day on a continuous dosing schedule and dosed on a flat-fixed dose and not adjusted by body weight or body surface area, starting on Day 8 of Cycle 1 in the dose escalation and Day 1 of Cycle 1 in the dose expansion. In the doublet dose escalation, the alpelisib starting dose is 300 mg. The alpelisib dose may be escalated or de-escalated, as needed. In the triplet dose escalation part, the alpelisib starting dose is one dose level lower of the MTD as determined during the doublet escalation. The alpelisib dose may be escalated or de-escalated, as needed. In the doublet dose expansion and triplet dose expansion (patients assigned to alpelisib, everolimus and exemestane), alpelisib is administered at the recommended dose determined in the dose escalation. In the triplet dose expansion (patients assigned to alpelisib and exemestane), alpelisib is administered at a dose of 250 mg daily.
everolimus
everolimus is administered orally once a day on a continuous dosing schedule and dosed on a flat-fixed dose and not adjusted by body weight or body surface area, starting on Day 1 of cycle 1 in both the dose escalation and dose expansion parts. In the dose escalation part, the everolimus starting dose is 2,5 mg. In the dose expansion part, everolimus is administered at the recommended dose determined in the dose escalation.
(Experimental)
alpelisib, everolimus and exemestane administered once a day
alpelisib
alpelisib is administered orally once a day on a continuous dosing schedule and dosed on a flat-fixed dose and not adjusted by body weight or body surface area, starting on Day 8 of Cycle 1 in the dose escalation and Day 1 of Cycle 1 in the dose expansion. In the doublet dose escalation, the alpelisib starting dose is 300 mg. The alpelisib dose may be escalated or de-escalated, as needed. In the triplet dose escalation part, the alpelisib starting dose is one dose level lower of the MTD as determined during the doublet escalation. The alpelisib dose may be escalated or de-escalated, as needed. In the doublet dose expansion and triplet dose expansion (patients assigned to alpelisib, everolimus and exemestane), alpelisib is administered at the recommended dose determined in the dose escalation. In the triplet dose expansion (patients assigned to alpelisib and exemestane), alpelisib is administered at a dose of 250 mg daily.
everolimus
everolimus is administered orally once a day on a continuous dosing schedule and dosed on a flat-fixed dose and not adjusted by body weight or body surface area, starting on Day 1 of cycle 1 in both the dose escalation and dose expansion parts. In the dose escalation part, the everolimus starting dose is 2,5 mg. In the dose expansion part, everolimus is administered at the recommended dose determined in the dose escalation.
exemestane
exemestane is administered orally once a day on a continuous dose of 25 mg starting on Day 1 of Cycle 1 in both the dose escalation and dose expansion.
(Experimental)
alpelisib and exemestane administered once a day
alpelisib
alpelisib is administered orally once a day on a continuous dosing schedule and dosed on a flat-fixed dose and not adjusted by body weight or body surface area, starting on Day 8 of Cycle 1 in the dose escalation and Day 1 of Cycle 1 in the dose expansion. In the doublet dose escalation, the alpelisib starting dose is 300 mg. The alpelisib dose may be escalated or de-escalated, as needed. In the triplet dose escalation part, the alpelisib starting dose is one dose level lower of the MTD as determined during the doublet escalation. The alpelisib dose may be escalated or de-escalated, as needed. In the doublet dose expansion and triplet dose expansion (patients assigned to alpelisib, everolimus and exemestane), alpelisib is administered at the recommended dose determined in the dose escalation. In the triplet dose expansion (patients assigned to alpelisib and exemestane), alpelisib is administered at a dose of 250 mg daily.
exemestane
exemestane is administered orally once a day on a continuous dose of 25 mg starting on Day 1 of Cycle 1 in both the dose escalation and dose expansion.

Primary Outcomes

Measure
Dose escalation : Incidence of dose Limiting Toxicity (DLTs)
time frame: First 35 days of treatment
Dose expansion: Number of patients with adverse events as a measure of safety and tolerability
time frame: Screening, every 28 days until 30 days after last dose

Secondary Outcomes

Measure
Dose escalation: Number of patients with adverse events as a measure of safety and tolerability
time frame: Screening, every 28 days, until 30 days after last dose
Dose escalation : alpelisib, everolimus and exemestane (when applicable) Plasma concentrations
time frame: Cycle 1 Day 7, Cycle 1 Day 8, Cycle 1 Day 15, Cycle 1 Day 16, Cycle 1 Day 22, Cycle 2 Day 1, Cycle 2 Day 2, Cycle 2 Day 15, Day 1 of each subsequent cycle
Dose escalation : alpelisib, everolimus drug-drug interaction
time frame: Cycle 1 Day 7, Cycle 1 Day 8, Cycle 1 Day 15, Cycle 1 Day 16, Cycle 1 Day 22, Cycle 2 Day 1, Cycle 2 Day 2, Cycle 2 Day 15, Day 1 of each subsequent cycle
Dose expansion: Progression free survival (Doublet cohorts)
time frame: Baseline, every 8 weeks until first documented disease progression up to 2.5 years.
Dose expansion : Duration of Response (Doublet and breast cancer cohorts)
time frame: Baseline, every 8 weeks until first documented disease progressionup to 2.5 years.
Dose expansion: Clinical benefit Rate (Doublet and breast cancer cohorts)
time frame: Baseline, every 8 weeks until first documented disease progression up to 2.5 years.
Dose expansion: Overall response rate (Doublet and breast cancer cohorts)
time frame: Baseline, every 8 weeks until first documented disease progression up to 2.5 years.

Eligibility Criteria

Male or female participants at least 18 years old.

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

Additional Information

Official title 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.
Trial information was received from ClinicalTrials.gov and was last updated in November 2016.
Information provided to ClinicalTrials.gov by Novartis.