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

Genentech

Status and phase: Terminated; Phase 1

Conditions: Solid Tumors

Treatments: Drug: Pictilisib; Drug: Cobimetinib

Study type: Interventional

Funder types: Industry

Identifiers

NCT00996892

GO01330 (Other Identifier)

MEK4752g

Details and patient eligibility

About

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.

Enrollment: 178 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Single Group Assignment

Masking: None (Open label)

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178 participants in 6 patient groups

Dose Escalation Stage 1: Cobimetinib + Pictilisib

Experimental group

Description:

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.

Treatment:

Drug: Cobimetinib

Drug: Pictilisib

Dose Escalation Stage 1A: Cobimetinib + Pictilisib

Experimental group

Description:

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.

Treatment:

Drug: Cobimetinib

Drug: Pictilisib

Dose Escalation Stage 1B: Cobimetinib + Pictilisib

Experimental group

Description:

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.

Treatment:

Drug: Cobimetinib

Drug: Pictilisib

Dose Expansion Stage 2: Cobimetinib + Pictilisib

Experimental group

Description:

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).

Treatment:

Drug: Cobimetinib

Drug: Pictilisib

Dose Expansion Stage 2A: Cobimetinib + Pictilisib

Experimental group

Description:

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.

Treatment:

Drug: Cobimetinib

Drug: Pictilisib

Dose Expansion Stage 2B: Cobimetinib + Pictilisib

Experimental group

Description:

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.

Treatment:

Drug: Cobimetinib

Drug: Pictilisib