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

Genentech

Status and phase: Completed; Phase 1

Conditions: Non-Small Cell Lung Cancer, Metastatic Colorectal Cancer, Metastatic Non Small Cell Lung Cancer, Metastatic Cancers, Melanoma

Treatments: Drug: Cobimetinib; Drug: GDC-0994

Study type: Interventional

Funder types: Industry

Identifiers

NCT02457793

2015-000092-27 (EudraCT Number)

GO29653

Details and patient eligibility

About

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.

Enrollment: 24 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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24 participants in 6 patient groups

Not assigned

Experimental group

Description:

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.

Treatment:

Drug: GDC-0994

Drug: Cobimetinib

COB 20 mg + GDC 200 mg

Experimental group

Description:

Concurrent or intermittent dosing of cobimetinib 20 mg, concurrent with GDC-0994 200 mg for 21 consecutive days, followed by 7 days off.

Treatment:

Drug: GDC-0994

Drug: Cobimetinib

COB 40 mg + GDC 200 mg

Experimental group

Description:

Concurrent or intermittent dosing of cobimetinib 40 mg, concurrent with GDC-0994 200 mg for 21 consecutive days, followed by 7 days off.

Treatment:

Drug: GDC-0994

Drug: Cobimetinib

COB 80 mg + GDC 200 mg

Experimental group

Description:

Concurrent or intermittent dosing of cobimetinib 80 mg, concurrent with GDC-0994 200 mg for 21 consecutive days, followed by 7 days off.

Treatment:

Drug: GDC-0994

Drug: Cobimetinib

COB 80 mg + GDC 400 mg

Experimental group

Description:

Concurrent or intermittent dosing of cobimetinib 80 mg, concurrent with GDC-0994 400 mg for 21 consecutive days, followed by 7 days off.

Treatment:

Drug: GDC-0994

Drug: Cobimetinib

COB 100 mg + GDC 200 mg

Experimental group

Description:

Concurrent or intermittent dosing of cobimetinib 100 mg, concurrent with GDC-0994 200 mg for 21 consecutive days, followed by 7 days off.

Treatment:

Drug: GDC-0994

Drug: Cobimetinib