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

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.

Study Overview

• Status: Terminated
• Conditions: PIK3CA Mutated Advanced Solid Tumors; PIK3CA Amplified Advanced Solid Tumors
• Intervention / Treatment: Drug: BYL719; Drug: AMG 479

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.

• Study Type: Interventional
• Enrollment (Actual): 47
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Belgium
  • Leuven, Belgium, 3000
    • Novartis Investigative Site
• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 1Z6
      • Novartis Investigative Site
• Spain
  • Madrid, Spain, 28041
    • Novartis Investigative Site
  • Madrid, Spain, 28033
    • Novartis Investigative Site
  • Andalucia
    • Sevilla, Andalucia, Spain, 41013
      • Novartis Investigative Site
  • Catalunya
    • Barcelona, Catalunya, Spain, 08035
      • Novartis Investigative Site
• United States
  • California
    • Los Angeles, California, United States, 90095
      • Novartis Investigative Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Novartis Investigative Site
  • New York
    • New York, New York, United States, 10017
      • Novartis Investigative Site
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: BYL719 + 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.

Drug: BYL719; BYL719 is a small molecule inhibiting PI3-Kinase.; Other Names: ALPELISIB; Drug: AMG 479; AMG 479 is a monoclonal antibody directed against IGF1-R.; Other Names: ganitumab

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Collaborators: NantCell, Inc.

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 27, 2012
• Primary Completion (ACTUAL): December 26, 2014
• Study Completion (ACTUAL): June 1, 2017

Study Registration Dates

• First Submitted: September 19, 2012
• First Submitted That Met QC Criteria: October 15, 2012
• First Posted (ESTIMATE): October 16, 2012

Study Record Updates

• Last Update Posted (ACTUAL): September 13, 2018
• Last Update Submitted That Met QC Criteria: August 15, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Keywords: breast cancer; ovarian cancer; advanced cancer; advanced solid tumor; PIK3CA mutation; advanced solid malignancies; nodule; cancers with a mass; bulky tumor; lump
• Additional Relevant MeSH Terms: Neoplasms
• Other Study ID Numbers: CBYL719X2105J; 2012-001962-13 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No