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

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2016 by Novartis
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT02077933
First received: February 28, 2014
Last updated: August 1, 2016
Last verified: August 2016

February 28, 2014
August 1, 2016
May 2014
April 2018   (final data collection date for primary outcome measure)
  • Dose escalation : Incidence of dose Limiting Toxicity (DLTs) [ Time Frame: First 35 days of treatment ] [ Designated as safety issue: Yes ]

    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.

  • 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 ] [ Designated as safety issue: Yes ]
    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
  • Dose escalation : Incidence of dose Limiting Toxicity (DLTs) [ Time Frame: First 35 days of treatment ] [ Designated as safety issue: Yes ]

    To determine the MTD and/or RDE of BYL719 in combination with everolimus, and the MTD and/or RDE of BYL719 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 BYL719 plus Everolimus or BYL719 plus Everolimus plus Exemestane and meets any of the pre-defined criteria.

  • 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 ] [ Designated as safety issue: Yes ]
    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
Complete list of historical versions of study NCT02077933 on ClinicalTrials.gov Archive Site
  • 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 ] [ Designated as safety issue: Yes ]
    type, intensity, severity and seriousness of adverse events according to the NCI CTC AE v4.03. Dose interruptions, reductions and dose intensity
  • 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 ] [ Designated as safety issue: No ]
    Plasma concentration time profiles of alpelisib , BZG791, everolimus and exemestane (when applicable). Plasma PK parameters of everolimus, alpelisib, BZG791 and exemestane (when applicable)
  • 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 ] [ Designated as safety issue: No ]
    Plasma PK parameters of everolimus including AUC ratio (single agent vs. combination)
  • Dose expansion: Progression free survival (Doublet and triplet cohorts) [ Time Frame: Baseline, every 8 weeks until first documented disease progression up to 2.5 years. ] [ Designated as safety issue: No ]
    Progression-free survival is defined as the time from start date of study treatment until objective tumor progression or death from any cause.
  • Dose expansion : Duration of Response (Doublet and triplet cohorts) [ Time Frame: Baseline, every 8 weeks until first documented disease progressionup to 2.5 years. ] [ Designated as safety issue: No ]
    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.
  • Dose expansion: Clinical benefit Rate (Doublet and triplet cohorts) [ Time Frame: Baseline, every 8 weeks until first documented disease progression up to 2.5 years. ] [ Designated as safety issue: No ]
    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.
  • Dose expansion: Overall response rate (Doublet and triplet cohorts) [ Time Frame: Baseline, every 8 weeks until first documented disease progression up to 2.5 years. ] [ Designated as safety issue: No ]
    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.
  • Dose expansion: Progression free survival rate at 16 weeks (Triplet) [ Time Frame: Baseline, up to 16 weeks. ] [ Designated as safety issue: No ]
    Progression-free survival rate at 16 weeks is defined as the proportion of patients who are progression free 16 weeks after the study start reference date
  • 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 ] [ Designated as safety issue: Yes ]
    type, intensity, severity and seriousness of adverse events according to the NCI CTC AE v4.03. Dose interruptions, reductions and dose intensity
  • Dose escalation : BYL719, 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 ] [ Designated as safety issue: No ]
    Plasma concentration time profiles of BYL719, Everolimus and Exemestane (when applicable). Plasma PK parameters of Everolimus, BYL719 and Exemestane (when applicable)
  • Dose escalation : BYL719, 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 ] [ Designated as safety issue: No ]
    Plasma PK parameters of everolimus including AUC ratio (single agent vs. combination)
  • Dose expansion: Progression free survival [ Time Frame: Baseline, every 8 weeks from start of treatment until first documented disease progression up to 2.5 years. ] [ Designated as safety issue: No ]
    Progression-free survival is defined as the time from start date of study treatment until objective tumor progression or death from any cause.
  • Dose expansion : Duration of Response [ Time Frame: Baseline, every 8 weeks from start of treatment until first documented disease progressionup to 2.5 years. ] [ Designated as safety issue: No ]
    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.
  • Dose expansion: Clinical benefit Rate [ Time Frame: Baseline, every 8 weeks from start of treatment until first documented disease progression up to 2.5 years. ] [ Designated as safety issue: No ]
    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 of duration of response.
  • Dose expansion: Overall response rate [ Time Frame: Baseline, every 8 weeks from start of treatment until first documented disease progression up to 2.5 years. ] [ Designated as safety issue: No ]
    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.
Not Provided
Not Provided
 
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.

Not Provided
Interventional
Phase 1
Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Neoplasms,
  • Breast Neoplasms,
  • Kidney Neoplasms,
  • Pancreatic Neuroendocine Neoplasms
  • 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.

    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.

  • 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 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.

  • 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 everolimus
    alpelisib and everolimus administered once a day
    Interventions:
    • Drug: alpelisib
    • Drug: everolimus
  • Experimental: alpelisib, everolimus and exemestane
    alpelisib, everolimus and exemestane administered once a day
    Interventions:
    • Drug: alpelisib
    • Drug: everolimus
    • Drug: exemestane
  • Experimental: alpelisib and exemestane
    alpelisib and exemestane administered once a day
    Interventions:
    • Drug: alpelisib
    • Drug: exemestane
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
166
April 2018
April 2018   (final data collection date for primary outcome measure)

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
Both
18 Years and older   (Adult, Senior)
No
Contact: Novartis Pharmaceuticals 1-888-669-6682
Contact: Novartis Pharmaceuticals +41613241111
United States,   France,   Germany,   Hong Kong,   Hungary,   Italy,   Netherlands,   Spain,   United Kingdom
 
NCT02077933
CBYL719Z2102
No
Not Provided
Not Provided
Novartis Pharmaceuticals
Novartis Pharmaceuticals
Not Provided
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
Novartis
August 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP