Safety, Tolerability and Pharmacokinetics of Cobimetinib in Combination With Pictilisib in Patients With Locally Advanced or Metastatic Solid Tumors

NCT ID: NCT00996892

Last Updated: 2016-12-30

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1
• Total Enrollment: 178 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-11-30
• Study Completion Date: 2014-03-31

Brief Summary

This is an open-label, multicenter, Phase Ib dose-escalation study designed to assess the safety, tolerability and pharmacokinetics of oral dosing of cobimetinib and pictilisib administered in combination in patients with locally advanced or metastatic solid tumors.

Conditions

Solid Tumors

Keywords

GDC0941; GDC0973; MEK; MEK Inhibitor; PI3K; PI3K Inhibitor; PI3 Kinase; PI3 Kinase Inhibitor

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Dose Escalation Stage 1: Cobimetinib + Pictilisib

Participants will receive cobimetinib capsules (at a starting dose of 20 milligrams \[mg\]) and pictilisib capsules (at a starting dose of 80 mg) from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Doses will be increased to identify maximum tolerated dose (MTD) or potential recommended Phase 2 dose (RP2D). Treatment will continue until disease progression, unacceptable toxicity, or any other discontinuation criterion meets.

Group Type: EXPERIMENTAL

Cobimetinib

Intervention Type: DRUG

Repeated oral dosing.

Pictilisib

Intervention Type: DRUG

Repeated oral dosing.

Dose Escalation Stage 1A: Cobimetinib + Pictilisib

Participants will receive cobimetinib capsules (at a starting dose of 100 mg) on Days 1, 4, 8, 11, 15, and 18 and pictilisib capsules (at a starting dose of 130 mg) from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Doses will be increased to identify MTD or potential RP2D.Treatment will continue until disease progression, unacceptable toxicity, or any other discontinuation criterion meets.

Group Type: EXPERIMENTAL

Cobimetinib

Intervention Type: DRUG

Repeated oral dosing.

Pictilisib

Intervention Type: DRUG

Repeated oral dosing.

Dose Escalation Stage 1B: Cobimetinib + Pictilisib

Participants will receive cobimetinib capsules (at a starting dose of 40 mg) and pictilisib capsules (at a starting dose of 130 mg) from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants will be off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment will continue until disease progression, unacceptable toxicity, or any other discontinuation criterion meets.

Group Type: EXPERIMENTAL

Cobimetinib

Intervention Type: DRUG

Repeated oral dosing.

Pictilisib

Intervention Type: DRUG

Repeated oral dosing.

Dose Expansion Stage 2: Cobimetinib + Pictilisib

Participants will received cobimetinib capsules and pictilisib capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles, at doses identified as MTD/potential RP2D from Stage 1. Treatment will continue until disease progression, unacceptable toxicity, or any other discontinuation criterion meets. This indication specific cohort will include participants with Kirsten rat sarcoma viral oncogene homolog (KRAS) mutant non-small cell lung cancer (NSCLC); epidermal growth factor receptor (EGFR) T790M mutant and EGFR inhibitor-progressing NSCLC; pancreatic adenocarcinoma; and KRAS mutant colorectal cancer (CRC).

Group Type: EXPERIMENTAL

Cobimetinib

Intervention Type: DRUG

Repeated oral dosing.

Pictilisib

Intervention Type: DRUG

Repeated oral dosing.

Dose Expansion Stage 2A: Cobimetinib + Pictilisib

Participants received cobimetinib capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles, at doses identified as MTD/potential RP2D from Stage 1A. Treatment will continue until disease progression, unacceptable toxicity, or any other discontinuation criterion meets. This indication specific cohort will include participants with KRAS mutant NSCLC; EGFR T790M mutant and EGFR inhibitor-progressing NSCLC; pancreatic adenocarcinoma; KRAS mutant CRC, and KRAS mutant endometrioid carcinoma.

Group Type: EXPERIMENTAL

Cobimetinib

Intervention Type: DRUG

Repeated oral dosing.

Pictilisib

Intervention Type: DRUG

Repeated oral dosing.

Dose Expansion Stage 2B: Cobimetinib + Pictilisib

Participants will receive cobimetinib capsules and pictilisib capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles, at doses identified as MTD/potential RP2D from Stage 1B. Participants will be off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment will continue until disease progression, unacceptable toxicity, or any other discontinuation criterion meets. This indication specific cohort will include participants with KRAS mutant endometrioid carcinoma.

Group Type: EXPERIMENTAL

Cobimetinib

Intervention Type: DRUG

Repeated oral dosing.

Pictilisib

Intervention Type: DRUG

Repeated oral dosing.

Interventions

Cobimetinib

Repeated oral dosing.

Intervention Type: DRUG

Pictilisib

Repeated oral dosing.

Intervention Type: DRUG

Other Intervention Names

GDC-0973; XL518; GDC-0941

Eligibility Criteria

Inclusion Criteria

• Histologically or cytologically documented, locally advanced or metastatic solid tumors for which standard therapy either does not exist or has proven ineffective or intolerable
• Evaluable disease or disease measurable per Response Evaluation Criteria in Solid Tumors (RECIST)
• Life expectancy greater than or equal to (>=) 12 weeks
• Adequate hematologic and end organ function
• Agreement to use an effective form of contraception for the duration of the study

Exclusion Criteria

• History of prior significant toxicity from another mitogen-activated protein kinase (MEK) pathway inhibitor requiring discontinuation of treatment
• History of prior significant toxicity from another phosphoinositide 3-kinase (PI3K) pathway inhibitor requiring discontinuation of treatment
• Allergy or hypersensitivity to components of the cobimetinib or pictilisib formulations
• Palliative radiotherapy within 2 weeks prior to first dose of study drug treatment in Cycle 1
• Experimental therapy within 4 weeks prior to first dose of study drug treatment in Cycle 1
• Major surgical procedure or significant traumatic injury within 4 weeks prior to first dose of study drug treatment in Cycle 1, or anticipation of the need for major surgery during the course of study treatment
• Prior anti-cancer therapy within 28 days before the first dose of study drug treatment in Cycle 1
• History of diabetes requiring daily medication, or history of Grade >= 3 fasting hyperglycemia
• Current severe, uncontrolled systemic disease
• History of clinically significant cardiac or pulmonary dysfunction
• History of malabsorption or other condition that would interfere with enteral absorption
• Clinically significant history of liver disease (including cirrhosis), current alcohol abuse, or current known active infection with human immunodeficiency virus (HIV), hepatitis B virus, or hepatitis C virus
• Any condition requiring anticoagulants, such as warfarin, heparin, or thrombolytics
• Active autoimmune disease
• Uncontrolled ascites requiring weekly large volume paracentesis for 3 consecutive weeks prior to enrollment
• Pregnancy, lactation, or breastfeeding
• Known brain metastases that are untreated, symptomatic, or require therapy to control symptoms
• No other history of or ongoing malignancy that would potentially interfere with the interpretation of the pharmacodynamic or efficacy assays

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Genentech, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Iris Chan, M.D., Ph.D.

Role: STUDY_DIRECTOR

Genentech, Inc.

Locations

Baltimore, Maryland, United States

Boston, Massachusetts, United States

Boston, Massachusetts, United States

Detroit, Michigan, United States

Oklahoma City, Oklahoma, United States

Nashville, Tennessee, United States

Countries

United States

Other Identifiers

GO01330

Identifier Type: OTHER

Identifier Source: secondary_id

MEK4752g

Identifier Type: -

Identifier Source: org_study_id