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

Study Overview
=================
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.

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

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

Intervention / Treatment
-----------------
* Drug: Cobimetinib
* Drug: GDC-0994


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Not assigned<br>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. | Drug: Cobimetinib<br>* Cobimetinib given concurrently or intermittently with GDC-0994 for 21 consecutive days followed by 7 days off.<br>Drug: GDC-0994<br>* GDC-0994 given for 21 consecutive days followed by 7 days off, along with concurrent or intermittent dosing of cobimetinib.<br>|
| Experimental: COB 20 mg + GDC 200 mg<br>Concurrent or intermittent dosing of cobimetinib 20 mg, concurrent with GDC-0994 200 mg for 21 consecutive days, followed by 7 days off. | Drug: Cobimetinib<br>* Cobimetinib given concurrently or intermittently with GDC-0994 for 21 consecutive days followed by 7 days off.<br>Drug: GDC-0994<br>* GDC-0994 given for 21 consecutive days followed by 7 days off, along with concurrent or intermittent dosing of cobimetinib.<br>|
| Experimental: COB 40 mg + GDC 200 mg<br>Concurrent or intermittent dosing of cobimetinib 40 mg, concurrent with GDC-0994 200 mg for 21 consecutive days, followed by 7 days off. | Drug: Cobimetinib<br>* Cobimetinib given concurrently or intermittently with GDC-0994 for 21 consecutive days followed by 7 days off.<br>Drug: GDC-0994<br>* GDC-0994 given for 21 consecutive days followed by 7 days off, along with concurrent or intermittent dosing of cobimetinib.<br>|
| Experimental: COB 80 mg + GDC 200 mg<br>Concurrent or intermittent dosing of cobimetinib 80 mg, concurrent with GDC-0994 200 mg for 21 consecutive days, followed by 7 days off. | Drug: Cobimetinib<br>* Cobimetinib given concurrently or intermittently with GDC-0994 for 21 consecutive days followed by 7 days off.<br>Drug: GDC-0994<br>* GDC-0994 given for 21 consecutive days followed by 7 days off, along with concurrent or intermittent dosing of cobimetinib.<br>|
| Experimental: COB 80 mg + GDC 400 mg<br>Concurrent or intermittent dosing of cobimetinib 80 mg, concurrent with GDC-0994 400 mg for 21 consecutive days, followed by 7 days off. | Drug: Cobimetinib<br>* Cobimetinib given concurrently or intermittently with GDC-0994 for 21 consecutive days followed by 7 days off.<br>Drug: GDC-0994<br>* GDC-0994 given for 21 consecutive days followed by 7 days off, along with concurrent or intermittent dosing of cobimetinib.<br>|
| Experimental: COB 100 mg + GDC 200 mg<br>Concurrent or intermittent dosing of cobimetinib 100 mg, concurrent with GDC-0994 200 mg for 21 consecutive days, followed by 7 days off. | Drug: Cobimetinib<br>* Cobimetinib given concurrently or intermittently with GDC-0994 for 21 consecutive days followed by 7 days off.<br>Drug: GDC-0994<br>* GDC-0994 given for 21 consecutive days followed by 7 days off, along with concurrent or intermittent dosing of cobimetinib.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose-Limiting Toxicities (DLTs) | DLTs include symptoms considered by the investigator to be possibly related to study drug. | 28 days (Cycle 1) | 
| Percentage of Participants With at Least One Adverse Event | An adverse event is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. | Up to 15 months | 
| Percentage of Participants With at Least One Adverse Event of Special Interest | 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. | Up to 15 months | 
| Percentage of Participants With at Least One Serious Adverse Event (SAE) | 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. | Up to 15 months | 
| Percentage of Participants With Laboratory Abnormalities | 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 | Up to 15 months | 
| Mean Change From Baseline in Diastolic Blood Pressure |  | Baseline, up to 15 months | 
| Mean Change From Baseline in Lean Body Mass |  | Baseline, Day 15 | 
| Mean Change From Baseline in Pulse Rate |  | Baseline, up to 15 months | 
| Mean Change From Baseline in Respiratory Rate |  | Baseline, up to 15 months | 
| Mean Change From Baseline in Systolic Blood Pressure |  | Baseline, up to 15 months | 
| Mean Change From Baseline in Temperature |  | Baseline, up to 15 months | 
| Mean Change From Baseline in Weight |  | Baseline, up to 15 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Serum Concentration (Cmax) for GDC-0994 |  | Up to Day 22 | 
| Median Time to Maximum Serum Concentration (Tmax) for GDC-0994 |  | Up to Day 22 | 
| Maximum Serum Concentration (Cmax) for Cobimetinib |  | Up to Day 22 | 
| Median Time to Maximum Serum Concentration (Tmax) for Cobimetinib |  | Up to Day 22 | 
| Total Exposure (AUC From Time 0 to 24 Hour After Dose) for GDC-0994 | Data are reported for evaluable participants. | 0 to 24 hours post-dose (Up to Day 22) | 
| Total Exposure (AUC From Time 0 to 24 Hour After Dose) for Cobimetinib |  | 0 to 24 hours post-dose (Up to Day 22) | 
| Mean Accumulation Ratio |  | 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) |  | Up to day 22 of study | 
| Change From Baseline in Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) |  | Baseline, Day 15 | 
| Change From Baseline in Tumor Tissue Biomarkers |  | Up to 15 months |