Clinical trial NCT02457793: A Study of the Safety, Tolerability, and Effects of Cobimetinib and GDC-0994 in Patients With Locally Advanced or Metastatic Solid Tumors
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Non-Small Cell Lung Cancer, Metastatic Colorectal Cancer, Metastatic Non Small Cell Lung Cancer, Metastatic Cancers, Melanoma
Lead sponsor: Genentech, Inc.
Sponsor class: INDUSTRY
First posted: 2015-05-29
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Number of Participants With Dose-Limiting Toxicities (DLTs)
timeFrame: 28 days (Cycle 1)
measure: Percentage of Participants With at Least One Adverse Event
timeFrame: Up to 15 months
measure: Percentage of Participants With at Least One Adverse Event of Special Interest
timeFrame: Up to 15 months
measure: Percentage of Participants With at Least One Serious Adverse Event (SAE)
timeFrame: Up to 15 months
measure: Percentage of Participants With Laboratory Abnormalities
timeFrame: Up to 15 months
measure: Mean Change From Baseline in Diastolic Blood Pressure
timeFrame: Baseline, up to 15 months
measure: Mean Change From Baseline in Lean Body Mass
timeFrame: Baseline, Day 15
measure: Mean Change From Baseline in Pulse Rate
timeFrame: Baseline, up to 15 months
measure: Mean Change From Baseline in Respiratory Rate
timeFrame: Baseline, up to 15 months
measure: Mean Change From Baseline in Systolic Blood Pressure
timeFrame: Baseline, up to 15 months
measure: Mean Change From Baseline in Temperature
timeFrame: Baseline, up to 15 months
measure: Mean Change From Baseline in Weight
timeFrame: Baseline, up to 15 months
Secondary outcomes:
measure: Maximum Serum Concentration (Cmax) for GDC-0994
timeFrame: Up to Day 22
measure: Median Time to Maximum Serum Concentration (Tmax) for GDC-0994
timeFrame: Up to Day 22
measure: Maximum Serum Concentration (Cmax) for Cobimetinib
timeFrame: Up to Day 22
measure: Median Time to Maximum Serum Concentration (Tmax) for Cobimetinib
timeFrame: Up to Day 22
measure: Total Exposure (AUC From Time 0 to 24 Hour After Dose) for GDC-0994
timeFrame: 0 to 24 hours post-dose (Up to Day 22)
measure: Total Exposure (AUC From Time 0 to 24 Hour After Dose) for Cobimetinib
timeFrame: 0 to 24 hours post-dose (Up to Day 22)
measure: Mean Accumulation Ratio
timeFrame: 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
measure: Mean Terminal Half-life (t1/2)
timeFrame: Up to day 22 of study
measure: Change From Baseline in Fluorodeoxyglucose Positron Emission Tomography (FDG-PET)
timeFrame: Baseline, Day 15
measure: Change From Baseline in Tumor Tissue Biomarkers
timeFrame: Up to 15 months
Other outcomes:
Locations:
city: Aurora
country: United States
facility: University of Colorado
state: Colorado
city: New Haven
country: United States
facility: Yale Cancer Center
state: Connecticut
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Nashville
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
Study officials:
affiliation: Genentech, Inc.
name: Clinical Trials
role: STUDY_DIRECTOR
References: