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A Study of the Safety, Tolerability, and Effects of Cobimetinib and GDC-0994 in Patients With Locally Advanced or Metastatic Solid Tumors

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02457793
Recruitment Status : Completed
First Posted : May 29, 2015
Results First Posted : August 24, 2018
Last Update Posted : November 20, 2018
Sponsor:
Information provided by (Responsible Party):
Genentech, Inc.

Tracking Information
First Submitted Date  ICMJE May 27, 2015
First Posted Date  ICMJE May 29, 2015
Results First Submitted Date  ICMJE November 28, 2017
Results First Posted Date  ICMJE August 24, 2018
Last Update Posted Date November 20, 2018
Actual Study Start Date  ICMJE June 16, 2015
Actual Primary Completion Date December 5, 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 13, 2018)
  • Number of Participants With Dose-Limiting Toxicities (DLTs) [ Time Frame: 28 days (Cycle 1) ]
    DLTs include symptoms considered by the investigator to be possibly related to study drug.
  • Percentage of Participants With at Least One Adverse Event [ Time Frame: Up to 15 months ]
    An adverse event is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution.
  • Percentage of Participants With at Least One Adverse Event of Special Interest [ Time Frame: Up to 15 months ]
    AESIs were graded per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), v4.0. AESIs included the following: Grade ≥ 1 retinal vein occlusion; Grade ≥ 2 visual disturbances (including events suggestive of serous retinopathy); Grade ≥ 3 rash for > 7 days; Grade ≥ 3 diarrhea for > 3 days; Grade ≥ 2 left ventricular ejection fraction (LVEF) decrease; Grade 3 hepatotoxicity; any dose-limiting toxicity (DLT); cases of potential drug-induced liver injury that include an elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) (AST > 3 × baseline value [and above the upper limit of normal, ULN]) in combination with either an elevated bilirubin ( > 2 × ULN) or clinical jaundice; or suspected transmission of an infectious agent by either study drug.
  • Percentage of Participants With at Least One Serious Adverse Event (SAE) [ Time Frame: Up to 15 months ]
    A SAE is any experience that: results in death, is life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is medically significant.
  • Percentage of Participants With Laboratory Abnormalities [ Time Frame: Up to 15 months ]
    Laboratory abnormalities were graded per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), v4.0. SGPT/ALT - serum glutamic-pyruvic transaminase/alanine aminotransferase; SGOT/AST - serum glutamic oxaloacetic transaminase/aspartate aminotransferase
  • Mean Change From Baseline in Diastolic Blood Pressure [ Time Frame: Baseline, up to 15 months ]
  • Mean Change From Baseline in Lean Body Mass [ Time Frame: Baseline, Day 15 ]
  • Mean Change From Baseline in Pulse Rate [ Time Frame: Baseline, up to 15 months ]
  • Mean Change From Baseline in Respiratory Rate [ Time Frame: Baseline, up to 15 months ]
  • Mean Change From Baseline in Systolic Blood Pressure [ Time Frame: Baseline, up to 15 months ]
  • Mean Change From Baseline in Temperature [ Time Frame: Baseline, up to 15 months ]
  • Mean Change From Baseline in Weight [ Time Frame: Baseline, up to 15 months ]
Original Primary Outcome Measures  ICMJE
 (submitted: May 28, 2015)
  • Percentage of patients with dose limiting toxicity (DLTs) [ Time Frame: Up to 3 years ]
  • Percentage of patients experiencing at least one adverse event [ Time Frame: Up to 3 years ]
  • Mean change from baseline in vital signs [ Time Frame: Up to 3 years ]
  • Percentage of patients with at least one adverse event of special interest [ Time Frame: Up to 3 years ]
  • Percentage of patients experiencing at least one serious adverse event [ Time Frame: Up to 3 years ]
  • Percentage of patients experiencing laboratory abnormalities [ Time Frame: Up to 3 years ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 13, 2018)
  • Maximum Serum Concentration (Cmax) for GDC-0994 [ Time Frame: Up to Day 22 ]
  • Median Time to Maximum Serum Concentration (Tmax) for GDC-0994 [ Time Frame: Up to Day 22 ]
  • Maximum Serum Concentration (Cmax) for Cobimetinib [ Time Frame: Up to Day 22 ]
  • Median Time to Maximum Serum Concentration (Tmax) for Cobimetinib [ Time Frame: Up to Day 22 ]
  • Total Exposure (AUC From Time 0 to 24 Hour After Dose) for GDC-0994 [ Time Frame: 0 to 24 hours post-dose (Up to Day 22) ]
    Data are reported for evaluable participants.
  • Total Exposure (AUC From Time 0 to 24 Hour After Dose) for Cobimetinib [ Time Frame: 0 to 24 hours post-dose (Up to Day 22) ]
  • Mean Accumulation Ratio [ Time Frame: Pre-dose Day 1 Cycle 1, 2, 3, Day 18, 21 Cycle 1; post-dose 0.5, 1, 2, 3, 4, 6 hours Day 1, 18, 21 Cycle 1; Day 2, 15, 19, 22, Cycle 1 ]
  • Mean Terminal Half-life (t1/2) [ Time Frame: Up to day 22 of study ]
  • Change From Baseline in Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) [ Time Frame: Baseline, Day 15 ]
  • Change From Baseline in Tumor Tissue Biomarkers [ Time Frame: Up to 15 months ]
Original Secondary Outcome Measures  ICMJE
 (submitted: May 28, 2015)
  • Mean Accumulation Ratio [ Time Frame: Up to 3 years ]
  • Pharmacokinetic: Serum concentration (Cmax) [ Time Frame: Up to day 22 of study ]
  • Pharmacokinetic: Total exposure (AUC from time 0 to 24 hour after dose) [ Time Frame: Up to day 22 of study ]
  • Pharmacokinetic: Median time to maximum concentration (t-max) [ Time Frame: Up to day 22 of study ]
  • Pharmacokinetic: Mean terminal half-life (t1/2) [ Time Frame: Up to day 22 of study ]
  • Pharmacodynamic: Change from baseline in fluorodeoxyglucose positron emission tomography (FDG-PET) [ Time Frame: Day 15 of study ]
  • Pharmacodynamic: Change from baseline in tumor tissue biomarkers [ Time Frame: Up to 3 years ]
  • Objective Response (OR) for patients with measurable disease [ Time Frame: Up to 3 years ]
  • Progression-Free Survival (PFS) [ Time Frame: Up to 3 years ]
  • Duration of Response (DOR) [ Time Frame: Up to 3 years ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study of the Safety, Tolerability, and Effects of Cobimetinib and GDC-0994 in Patients With Locally Advanced or Metastatic Solid Tumors
Official Title  ICMJE A Phase Ib, Open-Label, Dose-Escalation Study Of The Safety, Tolerability, and Pharmacokinetics of Cobimetinib and GDC-0994 In Patients With Locally Advanced or Metastatic Solid Tumors
Brief Summary This is a two-stage dose-escalation study to assess the safety, tolerability and effects of oral dosing of cobimetinib and GDC-0994 administered in combination in patients with histologically confirmed, locally advanced, or metastatic solid tumors for which standard therapies either do not exist or have proven ineffective or intolerable.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Non-Small Cell Lung Cancer, Metastatic Colorectal Cancer, Metastatic Non Small Cell Lung Cancer, Metastatic Cancers, Melanoma
Intervention  ICMJE
  • Drug: Cobimetinib
    Cobimetinib given concurrently or intermittently with GDC-0994 for 21 consecutive days followed by 7 days off.
  • Drug: GDC-0994
    GDC-0994 given for 21 consecutive days followed by 7 days off, along with concurrent or intermittent dosing of cobimetinib.
Study Arms  ICMJE
  • Experimental: Not assigned
    One participant was assigned to receive intermittent cobimetinib 80 milligrams (mg) + GDC 0994 200 mg) and did receive study drug. However, the participant diary was not returned, and the site was unable to document study dose administration.
    Interventions:
    • Drug: Cobimetinib
    • Drug: GDC-0994
  • Experimental: COB 20 mg + GDC 200 mg
    Concurrent or intermittent dosing of cobimetinib 20 mg, concurrent with GDC-0994 200 mg for 21 consecutive days, followed by 7 days off.
    Interventions:
    • Drug: Cobimetinib
    • Drug: GDC-0994
  • Experimental: COB 40 mg + GDC 200 mg
    Concurrent or intermittent dosing of cobimetinib 40 mg, concurrent with GDC-0994 200 mg for 21 consecutive days, followed by 7 days off.
    Interventions:
    • Drug: Cobimetinib
    • Drug: GDC-0994
  • Experimental: COB 80 mg + GDC 200 mg
    Concurrent or intermittent dosing of cobimetinib 80 mg, concurrent with GDC-0994 200 mg for 21 consecutive days, followed by 7 days off.
    Interventions:
    • Drug: Cobimetinib
    • Drug: GDC-0994
  • Experimental: COB 80 mg + GDC 400 mg
    Concurrent or intermittent dosing of cobimetinib 80 mg, concurrent with GDC-0994 400 mg for 21 consecutive days, followed by 7 days off.
    Interventions:
    • Drug: Cobimetinib
    • Drug: GDC-0994
  • Experimental: COB 100 mg + GDC 200 mg
    Concurrent or intermittent dosing of cobimetinib 100 mg, concurrent with GDC-0994 200 mg for 21 consecutive days, followed by 7 days off.
    Interventions:
    • Drug: Cobimetinib
    • Drug: GDC-0994
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: November 13, 2018)
24
Original Estimated Enrollment  ICMJE
 (submitted: May 28, 2015)
142
Actual Study Completion Date  ICMJE December 5, 2016
Actual Primary Completion Date December 5, 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  • 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
  • Life expectancy > or = 12 weeks
  • Adequate hematologic and end organ function
  • For female patients of childbearing potential and male patients with partners of childbearing potential, use of an effective form of contraception with continued use for study duration and up to 3 months or more following discontinuation of treatment drug
  • Fluorodeoxyglucose positron emission tomography (FDG-PET) avid disease on baseline scan

For enrollment in part 2, patients must meet all of the following:

  • Measurable disease
  • No more than four prior systemic therapies for locally advanced or metastatic cancer

Exclusion Criteria:

  • History of prior significant toxicity from another MEK inhibitor or ERK inhibitor requiring discontinuation of treatment
  • Evidence of visible retinal pathology as assessed by ophthalmologic examination that is considered a risk factor for retinal vein thrombosis
  • History of glaucoma
  • Intraocular pressure > 21 mmHg as measured by tonometry
  • Predisposing factors to retinal vein occlusion (RVO)
  • History of RVO, neurosensory retinal detachment, or neovascular macular degeneration
  • Allergy or hypersensitivity to components of the cobimetinib or GDC-0994 formulation
  • 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 the first dose of study-drug treatment in Cycle 1, or anticipation of the need for major surgery during the course of study treatment
  • Anti-cancer therapy within 28 days prior to the first dose of study-drug treatment in Cycle 1
  • Current severe, uncontrolled systemic disease
  • History of clinically significant cardiac dysfunction
  • History of symptomatic congestive heart failure or serious cardiac arrhythmia requiring treatment
  • History of myocardial infarction within 6 months prior to the first dose of study-drug treatment in Cycle 1
  • History of congenital long QT syndrome or QTc > 470 msec
  • LVEF
  • History of malabsorption or other condition that would interfere with enteral absorption
  • Clinically significant history of liver disease, current alcohol abuse, or current known active infection with HIV, hepatitis B virus, or hepatitis C virus
  • Any condition requiring warfarin or thrombolytic anticoagulants
  • 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 (PD) or efficacy assays
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries France
 
Administrative Information
NCT Number  ICMJE NCT02457793
Other Study ID Numbers  ICMJE GO29653
2015-000092-27 ( EudraCT Number )
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Genentech, Inc.
Study Sponsor  ICMJE Genentech, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Clinical Trials Genentech, Inc.
PRS Account Genentech, Inc.
Verification Date November 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP