A Phase Ib/II Study of the Combination of BYL719 Plus AMG 479 in Adult Patients With Selected Solid Tumors

Study Overview
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Brief Summary
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This was a multi-center, open-label, phase Ib/II study. The aim of the phase Ib part was to estimate the MTD(s) and/or identify the recommended phase II dose(s) (RP2Ds) for the combination of BYL719 and AMG 479 (ganitumab), followed by the phase II part to assess the clinical efficacy and to further assess the safety of the combination in selected patient populations. Patients were to be treated until progression of disease, unacceptable toxicity develops, or withdrawal of informed consent, whichever occurred first. All patients were to be followed up. At a minimum, patients must have completed the safety follow-up assessments 30 days after the last dose of the study treatment.

Detailed Description
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This was a multi-center, open-label, phase Ib/II study. The aim of the phase Ib part was to estimate the MTD(s) and/or identify the recommended phase II dose(s) (RP2Ds) for the combination of BYL719 and AMG 479 (ganitumab), followed by the phase II part to assess the clinical efficacy and to further assess the safety of the combination in selected patient populations. The dose escalation part of the study were to be guided by a Bayesian Logistic Regression Model (BLRM). Once MTD/RP2D had been determined, patients were to be enrolled in two Phase II arms. Patients with PIK3CA mutated or amplified hormone receptor positive breast carcinoma were to be enrolled in Arm 1; patients with PIK3CA mutated or amplified ovarian carcinoma were to be enrolled in Arm 2. Patients were to be treated until progression of disease, unacceptable toxicity develops, or withdrawal of informed consent, whichever occurred first. All patients were to be followed up. At a minimum, patients must have completed the safety follow-up assessments 30 days after the last dose of the study treatment.

Official Title
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A Phase Ib/II Study of the Combination of BYL719 Plus AMG 479 in Adult Patients With Selected Solid Tumors

Conditions
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PIK3CA Mutated Advanced Solid Tumors, PIK3CA Amplified Advanced Solid Tumors

Intervention / Treatment
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* Drug: BYL719
* Drug: AMG 479


Participation Criteria
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Eligibility Criteria
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Key inclusion criteria: Written informed consent. Patients aged ≥ 18 years (male or female). Patients with the following histologically/cytologically-confirmed advanced solid tumors with documented somatic PIK3CA mutations or amplifications in tumor tissue: Hormone receptor positive breast carcinoma Ovarian carcinoma Other tumors upon agreement with sponsor Adequate organ function Negative serum pregnancy test Key exclusion criteria: Patients with known history of severe infusion reactions to monoclonal antibodies. Patients with primary CNS tumor or CNS tumor involvement. History of thromboembolic event requiring full-dose anti-coagulation therapy any time prior to enrollment. Clinically significant cardiac disease. History of another malignancy within last 2 years. Pregnant or nursing (lactating) women.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BYL719 + AMG 479<br>For: Dose escalation phase/Phase II Expansion Phase. Cohorts of 3-6 patients were to be enrolled sequentially until an MTD or a recommended Phase II dose were defined. All patients were to receive the combination treatment. Sequential cohorts may receive different doses of the combination. In the Phase II expansion, all patients were to receive the same combination treatment. | Drug: BYL719<br>* BYL719 is a small molecule inhibiting PI3-Kinase.<br>* Other names: ALPELISIB;Drug: AMG 479<br>* AMG 479 is a monoclonal antibody directed against IGF1-R.<br>* Other names: ganitumab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Limiting Toxicities (DLTs) - Phase Ib | Phase lb only | 28 days | 
| Percentage of Patients With Overall Response Rate (RECIST) Based on Investigator Radiology Assessment for HR Positive Breast and Ovarian Cancer - Phase II | The antitumor activity of alpelisib in combination with ganitumab in patients with PIK3CA mutated or amplified hormone receptor positive (HR+) breast (arm 1) or ovarian (arm 2) cancer. Overall response rate is defined as the proportion of patients who have a best overall response of complete response or partial response assessed per RECIST 1.1. | Approximately 1 year (since initiation of Phase II, Dec 2013, till Primary CSR cut off 06Jan2015) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Best Overall Response (RECIST) Based on Investigator Radiology Assessment - Phase Ib | The anti-tumor activity of alpelisib and ganitumab in combination as per RECIST 1.1 | Approximately 1 year (since FPFV 27Nov2012, till MTD declaration 26Nov2013) | 
| Percentage of Patients With Disease Control Rate (RECIST) Based on Investigator Radiology Assessment - Phase Ib | The anti-tumor activity of alpelisib and ganitumab in combination as per RECIST 1.1 | Approximately 1 year (since FPFV 27Nov2012, till MTD declaration 26Nov2013) | 
| Percentage of Patients With Disease Control Rate (RECIST) Based on Investigator Radiology Assessment for HR Positive Breast and Ovarian Cancer - Phase II | the antitumor activity of alpelisib in combination with ganitumab in patients with PIK3CA mutated or amplified hormone receptor positive (HR+) breast (arm 1) or ovarian (arm 2) cancer. Phase II only, Cycle 1 Day 1 through Cycle 6 Day 28; assessed at baseline and every 8 weeks thereafter | Approximately 1 year (since initiation of Phase II, Dec 2013, till Primary CSR cut off 06Jan2015) | 
| Cmax of BYL - Phase Ib | Serum concentration for BYL719 (alpelisib) 1 cycle - 28 days of treatment | Cycle 1 Day 1, Cycle 1 Day 15 | 
| Area Under Curve (AUC) 0-24 Hour of BYL - Phase Ib | Area under curve for BYL719 (alpelisib) 1 cycle - 28 days of treatment | Cycle 1 Day 1 (0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post-dose), Cycle 1 Day 15 (0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post-dose) | 
| Tmax and T Half of BYL - Phase Ib | Tmax and half life of BYL719 (Alpelisib) 1 cycle - 28 days of treatment | Cycle 1 Day 1, Cycle 1 Day 15 | 
| Cmax of AMG - Phase Ib | Serum concentration for AMG 479 (ganitumab) 1 cycle - 28 days of treatment | Cycle 1 Day 15 | 
| Area Under Curve (AUC) 0-336 Hour of AMG - Phase Ib | Area under curve for AMG 479 (ganitumab) 1 cycle - 28 days of treatment | Cycle 1 Day 15 (0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post-dose) | 
| Tmax and T Half of AMG - Phase Ib | Tmax and half life of AMG 479 (ganitumab) 1 cycle - 28 days of treatment | Cycle 1 Day 15 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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bulky tumor, nodule, PIK3CA mutation, advanced solid tumor, breast cancer, ovarian cancer, cancers with a mass, lump, advanced cancer, advanced solid malignancies