A Phase 1 interventional study of alpelisib and everolimus in Neoplasms, Breast Neoplasms and Kidney Neoplasms, sponsored by Novartis Pharmaceuticals. Completed at 22 sites in 9 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2020-12-08.
Sponsored by Novartis Pharmaceuticals · Phase 1, Interventional, and Treatment
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.
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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
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),
Exclusion Criteria:
alpelisib and everolimus administered once a day
Drug: alpelisib · Drug: everolimus
alpelisib, everolimus and exemestane administered once a day
Drug: alpelisib · Drug: everolimus · Drug: exemestane
alpelisib and exemestane administered once a day
Drug: alpelisib · Drug: exemestane
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 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 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.
Dose escalation : Incidence of dose Limiting Toxicity (DLTs)
To determine the MTD and/or RDE of alpelisib in combination with everolimus, and the MTD and/or RDE of alpelisib in combination with everolimus and exemestane. A dose-limiting toxicity (DLT) is an adverse event or abnormal laboratory value assessed as being unrelated to disease, disease progression, inter-current illness, or concomitant medications, and that occurs within the first 35 days of treatment with alpelisib plus everolimus or alpelisib plus everolimus plus exemestane and meets any of the pre-defined criteria.
Time frame: First 35 days of treatment
Dose expansion: Number of patients with adverse events as a measure of safety and tolerability
Type, intensity, severity and seriousness of adverse events according to the National Cancer Institute Common Terminology Criteria for Advers Events (NCI CTC AE) v4.03. Dose interruptions, reductions and dose intensity
Time frame: Screening, every 28 days until 30 days after last dose
Dose escalation: Number of patients with adverse events as a measure of safety and tolerability
type, intensity, severity and seriousness of adverse events according to the NCI CTC AE v4.03. Dose interruptions, reductions and dose intensity
Time frame: Screening, every 28 days, until 30 days after last dose
Dose escalation : alpelisib, everolimus and exemestane (when applicable) Plasma concentrations
Plasma concentration time profiles of alpelisib , BZG791, everolimus and exemestane (when applicable). Plasma PK parameters of everolimus, alpelisib, BZG791 and exemestane (when applicable)
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
Plasma PK parameters of everolimus including AUC ratio (single agent vs. combination)
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)
Progression-free survival is defined as the time from start date of study treatment until objective tumor progression or death from any cause.
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)
Duration of response is defined as the time of first occurrence of Complete Response or Partial Response until the date of the first documented disease progression or death due to the disease.
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)
Clinical benefit rate is defined as the proportion of patients with a best overall response of complete response (CR) or partial response (PR) or stable disease (SD) for more than 24 weeks.
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)
Overall response rate is defined as the proportion of patients with a best overall response of complete response (CR) or partial response (PR), based on RECIST 1.1 criteria and the investigator assessment.
Time frame: Baseline, every 8 weeks until first documented disease progression up to 2.5 years.
Plan to share: No
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Novartis Pharmaceuticals