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

November 4, 2016 updated by: Genentech, Inc.

A Phase Ib, Open-Label, Dose-Escalation Study Evaluating the Safety, Tolerability and Pharmacokinetics of GDC-0973 in Combination With GDC-0941 When Administered in Patients With Locally Advanced or Metastatic Solid Tumors

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.

Study Overview

Status

Terminated

Conditions

Solid Tumors

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

178

Phase

Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

United States
- Maryland
  - Baltimore, Maryland, United States, 21231
- Massachusetts
  - Boston, Massachusetts, United States, 02215
  - Boston, Massachusetts, United States, 02114
- Michigan
  - Detroit, Michigan, United States, 48201
- Oklahoma
  - Oklahoma City, Oklahoma, United States, 73104
- Tennessee
  - Nashville, Tennessee, United States, 37203

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Interventional Model: Single Group Assignment
Masking: None (Open Label)

Number of Arms

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: Cobimetinib Repeated oral dosing. Other Names: GDC-0973 XL518 Drug: Pictilisib Repeated oral dosing. Other Names: GDC-0941
Experimental: 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.	Drug: Cobimetinib Repeated oral dosing. Other Names: GDC-0973 XL518 Drug: Pictilisib Repeated oral dosing. Other Names: GDC-0941
Experimental: 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.	Drug: Cobimetinib Repeated oral dosing. Other Names: GDC-0973 XL518 Drug: Pictilisib Repeated oral dosing. Other Names: GDC-0941
Experimental: 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).	Drug: Cobimetinib Repeated oral dosing. Other Names: GDC-0973 XL518 Drug: Pictilisib Repeated oral dosing. Other Names: GDC-0941
Experimental: 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.	Drug: Cobimetinib Repeated oral dosing. Other Names: GDC-0973 XL518 Drug: Pictilisib Repeated oral dosing. Other Names: GDC-0941
Experimental: 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.	Drug: Cobimetinib Repeated oral dosing. Other Names: GDC-0973 XL518 Drug: Pictilisib Repeated oral dosing. Other Names: GDC-0941

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Dose-Limiting Toxicities (DLTs) During Dose Escalation Stages 1, 1A and 1B Time Frame: Cohorts 1-3: Day 1 to Day 35, All other cohorts: Day 1 to Day 28	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 Time Frame: Cohorts 1-3: Day 1 to Day 35, All other cohorts: Day 1 to Day 28	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 Time Frame: 0-4 hours pre-cobimetinib (Pr-C) dose, 0.5, 2, 4, 6 hours post-cobimetinib (Po-C) dose on Day 3, Day 4		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 Time Frame: 0-4 hours Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Day 3, Day 4		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 Time Frame: 0-4 hours Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Day 3, Day 4		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 Time Frame: 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		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 Time Frame: 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		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 Time Frame: 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		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 Outcome Measures

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Genentech, Inc.

Investigators

Study Director: Iris Chan, M.D., Ph.D., Genentech, Inc.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

November 1, 2009

Primary Completion (Actual)

March 1, 2014

Study Completion (Actual)

March 1, 2014

Study Registration Dates

First Submitted

October 12, 2009

First Submitted That Met QC Criteria

October 15, 2009

First Posted (Estimate)

October 16, 2009

Study Record Updates

Last Update Posted (Estimate)

December 30, 2016

Last Update Submitted That Met QC Criteria

November 4, 2016

Last Verified

November 1, 2016

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Neoplasms

Other Study ID Numbers

MEK4752g
GO01330 (Other Identifier: Hoffmann-La Roche)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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

A Phase Ib, Open-Label, Dose-Escalation Study Evaluating the Safety, Tolerability and Pharmacokinetics of GDC-0973 in Combination With GDC-0941 When Administered in Patients With Locally Advanced or Metastatic Solid Tumors

Study Overview

Status

Conditions

Intervention / Treatment

Study Type

Enrollment (Actual)

Phase

Contacts and Locations

Study Locations

Participation Criteria

Eligibility Criteria

Ages Eligible for Study

Accepts Healthy Volunteers

Genders Eligible for Study

Description

Study Plan

How is the study designed?

Design Details

Number of Arms

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure

Measure Description

Time Frame

Secondary Outcome Measures

Outcome Measure

Measure Description

Time Frame

Collaborators and Investigators

Sponsor

Investigators

Study record dates

Study Major Dates

Study Start

Primary Completion (Actual)

Study Completion (Actual)

Study Registration Dates

First Submitted

First Submitted That Met QC Criteria

First Posted (Estimate)

Study Record Updates

Last Update Posted (Estimate)

Last Update Submitted That Met QC Criteria

Last Verified

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers