A Study to Investigate Safety, Pharmacokinetics (PK) and Pharmacodynamics (PD) of BKM120 Plus GSK1120212 in Selected Advanced Solid Tumor Patients

A Phase Ib, Open-label, Multi-center, Dose-escalation Study of Oral BKM120 in Combination With Oral GSK1120212 in Adult Patients With Selected Advanced Solid Tumors.

This is an open label, dose finding, phase Ib clinical trial to determine the maximum tolerated dose (MTD) and /or recommended phase II dose (RP2D) and schedule for the PI3K (Phosphatidylinositol 3-Kinase) inhibitor BKM120 given in combination with the MEK inhibitor GSK1120212 in patients with selected, advanced solid tumors. The focus will be on tumors with RAS/RAF mutations and on triple negative breast cancer.

Both study drugs will be administered once daily orally on a continuous schedule, a treatment cycle is defined as 28 days.

Cohorts of at least 3 and up to a maximum of 6 patients eligible for the dose-determining set will be enrolled per dose combination below the MTD. The MTD is defined as the highest drug dosage not causing in the first cycle of treatment medically unacceptable, dose-limiting toxicity (DLT) in more than 33% of the treated patients.. At least 12 patients will be required at MTD and 6 patients at RP2D level to allow the evaluation of the combination's safety and pharmacokinetics or pharmacodynamics.

Upon declaration of MTD and/or RP2D, patients will be enrolled to an expansion part of the study, to further assess safety, as well as to learn more about the efficacy of the study drug combination.

• Expansion Arm 1 will consist of approximately 15 patients with RAS or BRAF mutant advanced NSCLC
• Expansion Arm 2 will consist of approximately 15 patients with RAS or BRAF-mutant ovarian cancer
• Expansion Arm 3 will consist of approximately 15 patients with RAS or BRAF-mutant pancreatic cancer

Study Overview

• Status: Completed
• Conditions: Advanced and Selected Solid Tumors
• Intervention / Treatment: Drug: BKM120; Drug: GSK1120212

• Study Type: Interventional
• Enrollment (Actual): 113
• Phase: Phase 1

Contacts and Locations

Study Locations

• Belgium
  • Leuven, Belgium, 3000
    • Novartis Investigative Site
• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • Novartis Investigative Site
• Spain
  • Andalucia
    • Sevilla, Andalucia, Spain, 41013
      • Novartis Investigative Site
  • Catalunya
    • Barcelona, Catalunya, Spain, 08035
      • Novartis Investigative Site
• Switzerland
  • Bellinzona, Switzerland, 6500
    • Novartis Investigative Site
• United States
  • California
    • Los Angeles, California, United States, 90095
      • University of California at Los Angeles Div. of Hematology/Oncology
  • Texas
    • Houston, Texas, United States, 77030-4009
      • University of Texas/MD Anderson Cancer Center Dept of MD Anderson (8)

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

Inclusion Criteria:

• histologically/ cytologically confirmed, advanced non resectable solid tumors
• Measurable or non-measurable, but evaluable disease as determined by RECIST 1.0

Exclusion Criteria:

• Patients with primary Central Nervous System (CNS) tumor or CNS tumor involvement.
• Clinically manifested diabetes mellitus - Unacceptable ocular/retinal conditions

Other protocol-defined inclusion/exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: BKM120 + GSK1120212 DE; Dose Escalation	Drug: BKM120; Drug: GSK1120212
EXPERIMENTAL: BKM120 + GSK1120212 NSCLC patients; Advanced RAS or BRAF mutant NSCLC patients	Drug: BKM120; Drug: GSK1120212
EXPERIMENTAL: BKM120 + GSK1120212 ovarian cancer patients; Advanced RAS or BRAF mutant ovarian cancer patients	Drug: BKM120; Drug: GSK1120212
EXPERIMENTAL: BKM120 + GSK1120212 pancreatic cancer patients; Advanced RAS or BRAF mutant pancreatic cancer patients	Drug: BKM120; Drug: GSK1120212

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Maximum Tolerated Dose (MTD) and/or recommended phase II dose (RP2D) and schedule of BKM120+GSK1120212	in average 1 year

Secondary Outcome Measures

Outcome Measure	Time Frame
Measure the number of Adverse Event and laboratory values that fall outside of pre-determined ranges as a measure of Safety and tolerability of the oral combination of BKM120 and GSK1120212	in average 1 year
Determine the single and multiple dose pharmacokinetics of BKM120 and GSK1120212 in measurement of the plasma concentration profiles of BKM120 and GSK1120212	Assessed during the first Cycle (28 days) of treatment
Preliminary anti-tumor activity of the combination	Assessed every 8 weeks of treatment
Treatment-induced PI3K and MEK/ERK(Mitogen-activated protein kinase /extracellular-signal-regulated kinases) pathway signaling inhibition and evidence of biological activity in tumor and skin	Assessed every 2 weeks during the first cycle, then every 4 weeks
Molecular status (genetic alterations, protein expression and/or activation) of markers related to PI3K and ERK signaling in tumor tissue and blood and investigate their potential relationship to clinical responses	Assessed at baseline (pre-treatment)

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

Helpful Links

• Results for CBKM120B2101 on the Novartis Clinical Trial website

Study record dates

Study Major Dates

• Study Start: April 1, 2010
• Primary Completion (ACTUAL): November 1, 2014
• Study Completion (ACTUAL): November 1, 2014

Study Registration Dates

• First Submitted: June 17, 2010
• First Submitted That Met QC Criteria: June 30, 2010
• First Posted (ESTIMATE): July 1, 2010

Study Record Updates

• Last Update Posted (ACTUAL): December 9, 2020
• Last Update Submitted That Met QC Criteria: December 6, 2020
• Last Verified: June 1, 2016

More Information

Terms related to this study

• Keywords: MEK inhibitor; BKM120; PI3K inhibitor,; RAS RAF mutations,; triple negative breast cancer,; pancreatic cancer,
• Additional Relevant MeSH Terms: Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Trametinib
• Other Study ID Numbers: CBKM120B2101; 2009-017157-35 (EUDRACT_NUMBER)