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

Study Overview

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

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.

Neoplasms
Breast Neoplasms
Kidney Neoplasms
Pancreatic Neuroendocine Neoplasms (pNETs)

DRUG: alpelisib
DRUG: everolimus
DRUG: exemestane

CBYL719Z2102
2013-004829-86 (EUDRACT_NUMBER Identifier) (EUDRACT_NUMBER: )

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates	Results Reporting Dates	Study Record Updates
First Submitted 2014-02-28	Results First Submitted N/A	Last Update Submitted that met QC Criteria 2020-12-04
First Submitted that Met QC Criteria 2014-02-28	Results First Submitted that Met QC Criteria N/A	Last Update Posted (ACTUAL) 2020-12-08
First Posted (ACTUAL) 2014-03-04	Results First Posted N/A	Last Verified 2020-12

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

Design Details

Primary Purpose:
Treatment

Allocation:
Non Randomized

Interventional Model:
Parallel

Masking:
None

Arms and Interventions

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: alpelisib and everolimus alpelisib and everolimus administered once a day	DRUG: 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 DRUG: 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 do
EXPERIMENTAL: alpelisib, everolimus and exemestane alpelisib, everolimus and exemestane administered once a day	DRUG: 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 DRUG: 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 do DRUG: 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 alpelisib and exemestane administered once a day	DRUG: 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 DRUG: 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.

Participant Group/Arm

Intervention/Treatment

EXPERIMENTAL: alpelisib and everolimus

alpelisib and everolimus administered once a day

DRUG: 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

DRUG: 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 do

EXPERIMENTAL: alpelisib, everolimus and exemestane

alpelisib, everolimus and exemestane administered once a day

DRUG: 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

DRUG: 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 do

DRUG: 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

alpelisib and exemestane administered once a day

DRUG: 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

DRUG: 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 Outcome Measures	Measure Description	Time Frame
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.	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	Screening, every 28 days until 30 days after last dose

Secondary Outcome Measures	Measure Description	Time Frame
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	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)	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)	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.	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.	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.	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.	Baseline, every 8 weeks until first documented disease progression up to 2.5 years.

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person’s general health condition or prior treatments.

Ages Eligible for Study:
ALL

Sexes Eligible for Study:
18 Years

Accepts Healthy Volunteers:

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.

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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

STUDY_DIRECTOR: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Publications

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Fankhauser M, Bechmann N, Lauseker M, Goncalves J, Favier J, Klink B, William D, Gieldon L, Maurer J, Spottl G, Rank P, Knosel T, Orth M, Ziegler CG, Aristizabal Prada ET, Rubinstein G, Fassnacht M, Spitzweg C, Grossman AB, Pacak K, Beuschlein F, Bornstein SR, Eisenhofer G, Auernhammer CJ, Reincke M, Nolting S. Synergistic Highly Potent Targeted Drug Combinations in Different Pheochromocytoma Models Including Human Tumor Cultures. Endocrinology. 2019 Nov 1;160(11):2600-2617. doi: 10.1210/en.2019-00410.

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