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

Study Description

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Brief Summary:

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. 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.

Condition or disease	Intervention/treatment	Phase
PIK3CA Mutated Advanced Solid Tumors; PIK3CA Amplified Advanced Solid Tumors	Drug: BYL719; Drug: AMG 479	Phase 1; Phase 2

Detailed Description:

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	47 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A Phase Ib/II Study of the Combination of BYL719 Plus AMG 479 in Adult Patients With Selected Solid Tumors
Actual Study Start Date :	November 27, 2012
Actual Primary Completion Date :	June 1, 2017
Actual Study Completion Date :	June 1, 2017

Arms and Interventions

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Arm

Intervention/treatment

Experimental: BYL719 + AMG 479; For: Dose escalation phase/Phase II Expansion Phase. Cohorts of 3-6 patients will be enrolled sequentially until an MTD or a recommended Phase II dose could be defined. All patients will receive the combination treatment. Sequential cohorts may receive different doses of the combination. In the Phase II expansion, all patients will receive the same combination treatment.

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

Outcome Measures

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Primary Outcome Measures :

1. Incidence of dose limiting toxicities (DLTs) [ Time Frame: Cycle 1 (initial 28 days of treatment) ]
   Phase lb only
2. Objective response rate (ORR) [ Time Frame: Baseline, Every 8 weeks during the 6 months immediately following start of treatment ]
   Phase II only, Cycle 1 Day 1 through Cycle 6 Day 28; assessed at baseline and every 8 weeks thereafter

Secondary Outcome Measures :

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

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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

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.

Other protocol-defined inclusion/exclusion criteria may apply.

Contacts and Locations

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Locations

United States, California
University of California at Los Angeles TORI
Los Angeles, California, United States, 90095
United States, Massachusetts
Massachusetts General Hospital Mass General 2
Boston, Massachusetts, United States, 02114
United States, New York
Memorial Sloan Kettering Cancer Center MSKCC 5
New York, New York, United States, 10065
United States, Tennessee
Sarah Cannon Research Institute SCRI 3
Nashville, Tennessee, United States, 37203
Belgium
Novartis Investigative Site
Leuven, Belgium, 3000
Canada, Ontario
Novartis Investigative Site
Toronto, Ontario, Canada, M5G 1Z6
Spain
Novartis Investigative Site
Sevilla, Andalucia, Spain, 41013
Novartis Investigative Site
Barcelona, Catalunya, Spain, 08035
Novartis Investigative Site
Madrid, Spain, 28033
Novartis Investigative Site
Madrid, Spain, 28041

Sponsors and Collaborators

Novartis Pharmaceuticals

NantCell, Inc.

Investigators

Study Director:	Novartis Pharmaceuticals	Novartis Pharmaceuticals

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	Novartis Pharmaceuticals
ClinicalTrials.gov Identifier:	NCT01708161 History of Changes
Other Study ID Numbers:	CBYL719X2105J; 2012-001962-13 ( EudraCT Number )
First Posted:	October 16, 2012
Last Update Posted:	July 21, 2017
Last Verified:	July 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	Undecided
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

Studies a U.S. FDA-regulated Drug Product:		Yes
Studies a U.S. FDA-regulated Device Product:		No

Keywords provided by Novartis ( Novartis Pharmaceuticals ):

PIK3CA mutation; advanced solid tumor; breast cancer; ovarian cancer

Additional relevant MeSH terms:

Neoplasms; Antibodies, Monoclonal; Immunologic Factors; Physiological Effects of Drugs