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

• Incidence of dose limiting toxicities (DLTs) [ Time Frame: Cycle 1 (initial 28 days of treatment) ] [ Designated as safety issue: Yes ]
  Phase lb only
  
  
• Objective response rate (ORR) [ Time Frame: Baseline, Every 8 weeks during the 6 months immediately following start of treatment ] [ Designated as safety issue: No ]
  Phase II only, Cycle 1 Day 1 through Cycle 6 Day 28; assessed at baseline and every 8 weeks thereafter
  
  

• Disease control rate (DCR) [ Time Frame: Baseline, Every 8 weeks during the 6 months immediately following start of treatment ] [ Designated as safety issue: No ]
  As per RECIST 1.1 (phase lb & ll)
  
  
• Duration of response (DOR) [ Time Frame: Baseline, Every 8 weeks during the 6 months immediately following start of treatment ] [ Designated as safety issue: No ]
  As per RECIST 1.1 (Phase lb & ll)
  
  
• Progression free survival (PFS) [ Time Frame: Baseline, Every 8 weeks during the 6 months immediately following start of treatment ] [ Designated as safety issue: No ]
  As per RECIST 1.1 (phae lb & ll)
  
  
• Overall survival (OS) [ Time Frame: Baseline, Every 8 weeks during the 6 months immediately following start of treatment; 4-monthly thereafter for discontinued patients ] [ Designated as safety issue: No ]
  Phase ll only
  
  
• Number of patients with Adverse Events (AEs) [ Time Frame: baseline, up to 30 weeks ] [ Designated as safety issue: Yes ]
  phase lb & ll
  
  
• Number of patients with Serious Adverse Events (SAEs) [ Time Frame: Baseline, up to 30 weeks ] [ Designated as safety issue: Yes ]
  phase lb & ll
  
  
• Change in hematology and chemistry values [ Time Frame: baseline, up to 30 weeks ] [ Designated as safety issue: Yes ]
  phase lb & ll
  
  
• Change in vital signs [ Time Frame: baseline, up to 30 weeks ] [ Designated as safety issue: Yes ]
  phase lb & ll
  
  
• Change in electrocardiograms (ECGs) [ Time Frame: baseline, up to 30 weeks ] [ Designated as safety issue: Yes ]
  phase lb & ll
  
  
• Plasma/serum concentration versus time profiles [ Time Frame: Cycle 1 Day 1, Cycle 1 Day 15 ] [ Designated as safety issue: No ]
  Plasma concentration for BYL719; Serum concentration for AMG 479 (ganitumab); cycle 1 = initial 28 days of treatment
  
  
• Derived basic pharmacokinetics paramaeters of BYL719 and AMG479 [ Time Frame: Cycle 1 Day 1, Cycle 1 Day 15 ] [ Designated as safety issue: No ]
  Standard non-compartmental PK parameters e.g. AUC, Cmax, apparent terminal elimination half-life; cycle 1 = initial 28 days of treatment
  
  

This is a multi-center, open-label, phase Ib/II study. The aim of the phase Ib part is 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 will be guided by a Bayesian Logistic Regression Model (BLRM).

Once MTD/RP2D has been determined, patients will be enrolled in two Phase II arms. Patients with PIK3CA mutated or amplified hormone receptor positive breast carcinoma will be enrolled in Arm 1; patients with PIK3CA mutated or amplified ovarian carcinoma will be enrolled in Arm 2. Patients will be treated until progression of disease, unacceptable toxicity develops, or withdrawal of informed consent, whichever occurs first. All patients will be followed up. At a minimum, patients must complete the safety follow-up assessments 30 days after the last dose of the study treatment. In addition, patients who have not progressed at the time of discontinuation of study treatment should have radiological follow-up for the disease status and phase II patients will be followed for survival.