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

Phase 1

Terminated

Conditions: PIK3CA Mutated Advanced Solid Tumors
PIK3CA Amplified Advanced Solid Tumors

Interventions: Drug: BYL719
Drug: AMG 479

Registration Number: NCT01708161

Lead Sponsor: Novartis Pharmaceuticals

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 47

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
BYL719 + AMG 479	BYL719	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.
BYL719 + AMG 479	AMG 479	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.

Primary Outcome Measures

Name	Time	Method
Dose Limiting Toxicities (DLTs) - Phase Ib	28 days	Phase lb only
Percentage of Patients With Overall Response Rate (RECIST) Based on Investigator Radiology Assessment for HR Positive Breast and Ovarian Cancer - Phase II	Approximately 1 year (since initiation of Phase II, Dec 2013, till Primary CSR cut off 06Jan2015)	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.

Secondary Outcome Measures

Name	Time	Method
Number of Patients With Best Overall Response (RECIST) Based on Investigator Radiology Assessment - Phase Ib	Approximately 1 year (since FPFV 27Nov2012, till MTD declaration 26Nov2013)	The anti-tumor activity of alpelisib and ganitumab in combination as per RECIST 1.1
Percentage of Patients With Disease Control Rate (RECIST) Based on Investigator Radiology Assessment - Phase Ib	Approximately 1 year (since FPFV 27Nov2012, till MTD declaration 26Nov2013)	The anti-tumor activity of alpelisib and ganitumab in combination as per RECIST 1.1
Tmax and T Half of BYL - Phase Ib	Cycle 1 Day 1, Cycle 1 Day 15	Tmax and half life of BYL719 (Alpelisib) 1 cycle - 28 days of treatment
Percentage of Patients With Disease Control Rate (RECIST) Based on Investigator Radiology Assessment for HR Positive Breast and Ovarian Cancer - Phase II	Approximately 1 year (since initiation of Phase II, Dec 2013, till Primary CSR cut off 06Jan2015)	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
Cmax of BYL - Phase Ib	Cycle 1 Day 1, Cycle 1 Day 15	Serum concentration for BYL719 (alpelisib) 1 cycle - 28 days of treatment
Area Under Curve (AUC) 0-336 Hour of AMG - Phase Ib	Cycle 1 Day 15 (0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post-dose)	Area under curve for AMG 479 (ganitumab) 1 cycle - 28 days of treatment
Area Under Curve (AUC) 0-24 Hour of BYL - Phase Ib	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)	Area under curve for BYL719 (alpelisib) 1 cycle - 28 days of treatment
Cmax of AMG - Phase Ib	Cycle 1 Day 15	Serum concentration for AMG 479 (ganitumab) 1 cycle - 28 days of treatment
Tmax and T Half of AMG - Phase Ib	Cycle 1 Day 15	Tmax and half life of AMG 479 (ganitumab) 1 cycle - 28 days of treatment