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

NCT00996892 | Terminated Phase 1 Results

• 2 other identifiers: MEK4752gGO01330
• Study Type: interventional
• Target: 178
• Locations: 1 country
• Sites: 6

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

Outcome Measures

Primary Outcomes (8)

• Number of Participants With Dose-Limiting Toxicities (DLTs) During Dose Escalation Stages 1, 1A and 1B

  DLT was defined as 1 of the following toxicities considered treatment related by Investigator: Grade ≥3 non-hematologic, non-hepatic organ toxicity, excluding the following: Grade 3 nausea, vomiting, or diarrhea that resolved to Grade ≤1 within 7 days, Grade 3 rash or Grade ≥3 fatigue that resolved to Grade ≤2 within 7 days, Grade ≥3 hyperglycemia or lipid profile results that occurred during non-fasting conditions, Grade 3 or 4 elevation of serum creatine phosphokinase levels or Grade 3 non clinically significant (as assessed by Investigator) laboratory abnormality that was asymptomatic; Grade ≥3 febrile neutropenia; Grade ≥4 neutropenia (absolute neutrophil count \<500/microliter) lasting \>5 days; Grade ≥4 thrombocytopenia lasting \>48 hours; Grade ≥4 anemia; Grade ≥3 total bilirubin, hepatic transaminase, alkaline phosphatase, lasting \>72 hours; Grade ≥2 diffusion capacity of the lung for carbon monoxide concomitant with an absolute decrease of ≥20 percentage points from baseline.

  Cohorts 1-3: Day 1 to Day 35, All other cohorts: Day 1 to Day 28

• Maximum Tolerated Combination Doses of Cobimetinib and Pictilisib During Dose-Escalation Stages 1, 1A and 1B

  MTD was determined (by Investigator) based on the DLTs, as well as adverse events (AEs) in dose-escalation Stages 1, 1A, and 1B that did not meet protocol-defined DLT criteria but indicated intolerability of a given dose combination. Separate combination MTDs were determined for each dose-escalation stage. DLT was defined as 1 of the following toxicities considered treatment related by Investigator: Grade ≥3 non-hematologic, non-hepatic organ toxicity; Grade ≥3 febrile neutropenia; Grade ≥4 neutropenia (absolute neutrophil count \<500/microliter) lasting \>5 days; Grade ≥4 thrombocytopenia lasting \>48 hours; Grade ≥4 anemia; Grade ≥3 total bilirubin, hepatic transaminase, alkaline phosphatase, lasting \>72 hours; Grade ≥2 diffusion capacity of the lung for carbon monoxide concomitant with an absolute decrease of ≥20 percentage points from baseline.

  Cohorts 1-3: Day 1 to Day 35, All other cohorts: Day 1 to Day 28

• Time of Maximum Concentration (Tmax) of Cobimetinib on Day 3 - Stage 1, Cohorts 1-3

  0-4 hours pre-cobimetinib (Pr-C) dose, 0.5, 2, 4, 6 hours post-cobimetinib (Po-C) dose on Day 3, Day 4

• Maximum Plasma Concentration (Cmax) of Cobimetinib on Day 3 - Stage 1, Cohorts 1-3

  0-4 hours Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Day 3, Day 4

• Area Under the Concentration-Time Curve From Time 0 to 24 Hours Post-Dose (AUC0-24) of Cobimetinib on Day 3 - Stage 1, Cohorts 1-3

  0-4 hours Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Day 3, Day 4

• Tmax of Pictilisib on Day 1 - Stage 1, Cohorts 1-3

  0-4 hours pre-pictilisib (Pr-P) dose, 0.5, 2, 4, 6 hours post-pictilisib (Po-P) dose on Day 1, Day 2, 0-4 hours Pr-C dose on Day 3

• Cmax of Pictilisib on Day 1 - Stage 1, Cohorts 1-3

  0-4 hours Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Day 1, Day 2, 0-4 hours Pr-C dose on Day 3

• AUC0-24 of Pictilisib on Day 1 - Stage 1, Cohorts 1-3

  0-4 hours Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Day 1, Day 2, 0-4 hours Pr-C dose on Day 3

Secondary Outcomes (91)

• Tmax of Cobimetinib on Cycle 1 Day 1 (Cycle 1 Day 8 for Cohorts 1-3) - Stage 1 All Cohorts

  Cohorts 1-3: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 8, Cycle 1 Days 9, 15, 21; Cohorts 4-6A: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 1, Cycle 1 Day 2, 8, 14

• Cmax of Cobimetinib on Cycle 1 Day 1 (Cycle 1 Day 8 for Cohorts 1-3) - Stage 1 All Cohorts

  Cohorts 1-3: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 8, Cycle 1 Days 9, 15, 21; Cohorts 4-6A: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 1, Cycle 1 Day 2, 8, 14

• AUC0-24 of Cobimetinib on Cycle 1 Day 1 (Cycle 1 Day 8 for Cohorts 1-3) - Stage 1 All Cohorts

  Cohorts 1-3: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 8, Cycle 1 Days 9; Cohorts 4-6A: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 1, Cycle 1 Day 2

• Tmax of Cobimetinib on Cycle 1 Day 21 (Cycle 1 Day 28 for Cohorts 1-3) - Stage 1 All Cohorts

  Cohorts 1-3: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 28, Cycle 1 Day 29, Cycle 2 Days 1, 15, 21; Cohorts 4-6A: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 21, Cycle 1 Day 22, Cycle 2 Days 1, 15, 21

• Cmax of Cobimetinib on Cycle 1 Day 21 (Cycle 1 Day 28 for Cohorts 1-3) - Stage 1 All Cohorts

  Cohorts 1-3: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 28, Cycle 1 Day 29, Cycle 2 Days 1, 15, 21; Cohorts 4-6A: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 21, Cycle 1 Day 22, Cycle 2 Days 1, 15, 21

Study Arms (6)

Dose Escalation Stage 1: Cobimetinib + Pictilisib

EXPERIMENTAL

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.

Drug: Cobimetinib; Drug: Pictilisib

Dose Escalation Stage 1A: Cobimetinib + Pictilisib

EXPERIMENTAL

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.

Drug: Cobimetinib; Drug: Pictilisib

Dose Escalation Stage 1B: Cobimetinib + Pictilisib

EXPERIMENTAL

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.

Drug: Cobimetinib; Drug: Pictilisib

Dose Expansion Stage 2: Cobimetinib + Pictilisib

EXPERIMENTAL

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).

Drug: Cobimetinib; Drug: Pictilisib

Dose Expansion Stage 2A: Cobimetinib + Pictilisib

EXPERIMENTAL

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.

Drug: Cobimetinib; Drug: Pictilisib

Dose Expansion Stage 2B: Cobimetinib + Pictilisib

EXPERIMENTAL

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.

Drug: Cobimetinib; Drug: Pictilisib

Interventions

Cobimetinib DRUG

Repeated oral dosing.

Also known as: GDC-0973, XL518

Dose Escalation Stage 1: Cobimetinib + Pictilisib; Dose Escalation Stage 1A: Cobimetinib + Pictilisib; Dose Escalation Stage 1B: Cobimetinib + Pictilisib; Dose Expansion Stage 2: Cobimetinib + Pictilisib; Dose Expansion Stage 2A: Cobimetinib + Pictilisib; Dose Expansion Stage 2B: Cobimetinib + Pictilisib

Pictilisib DRUG

Repeated oral dosing.

Also known as: GDC-0941

Dose Escalation Stage 1: Cobimetinib + Pictilisib; Dose Escalation Stage 1A: Cobimetinib + Pictilisib; Dose Escalation Stage 1B: Cobimetinib + Pictilisib; Dose Expansion Stage 2: Cobimetinib + Pictilisib; Dose Expansion Stage 2A: Cobimetinib + Pictilisib; Dose Expansion Stage 2B: Cobimetinib + Pictilisib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Genentech, Inc.: lead

Study Sites (6)

Unknown Facility

Baltimore, Maryland, 21231, United States

Location

Unknown Facility

Boston, Massachusetts, 02114, United States

Location

Unknown Facility

Boston, Massachusetts, 02215, United States

Location

Unknown Facility

Detroit, Michigan, 48201, United States

Location

Unknown Facility

Oklahoma City, Oklahoma, 73104, United States

Location

Unknown Facility

Nashville, Tennessee, 37203, United States

Location

MeSH Terms

Conditions

Hereditary Sensory and Autonomic Neuropathies

Interventions

cobimetinib; 2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine

Condition Hierarchy (Ancestors)

Nervous System Malformations; Nervous System Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Polyneuropathies; Peripheral Nervous System Diseases; Neuromuscular Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn

Limitations and Caveats

The study was terminated prior to the initiation of Stage 2B and as per changes in planned analysis the data for duration of objective response and PFS were not analyzed.

Results Point of Contact

• Title: Medical Communications
• Organization: Hoffman-La Roche

genentech@druginfo.com

800-821-8590

Study Officials

• Iris Chan, M.D., Ph.D.

  Genentech, Inc.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 12, 2009
• First Posted: October 16, 2009
• Study Start: November 1, 2009
• Primary Completion: March 1, 2014
• Study Completion: March 1, 2014
• Last Updated: December 30, 2016
• Results First Posted: December 30, 2016

Record last verified: 2016-11

Locations

US (6)