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

Phase 1TerminatedNCT00996892

Genentech, Inc.178 enrolled

Overview

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 Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

178

Conditions

Solid Tumors

Interventions

CobimetinibDRUG

Repeated oral dosing.

PictilisibDRUG

Repeated oral dosing.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (6)

Unnamed facility

Baltimore, Maryland, United States

Unnamed facility

Boston, Massachusetts, United States

Unnamed facility

Boston, Massachusetts, United States

Unnamed facility

Detroit, Michigan, United States

Outcomes

Primary Outcomes

Number of Participants With Dose-Limiting Toxicities (DLTs) During Dose Escalation Stages 1, 1A and 1B

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.

Time frame: 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

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.

Time frame: 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

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.

Secondary Outcomes

Tmax of Cobimetinib on Cycle 1 Day 1 (Cycle 1 Day 8 for Cohorts 1-3) - Stage 1 All Cohorts

Time frame: Cohorts 1-3: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 8, Cycle 1 Days 9, 15, 21; Cohorts 4-6A: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 1, Cycle 1 Day 2, 8, 14

Cmax of Cobimetinib on Cycle 1 Day 1 (Cycle 1 Day 8 for Cohorts 1-3) - Stage 1 All Cohorts

Time frame: Cohorts 1-3: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 8, Cycle 1 Days 9, 15, 21; Cohorts 4-6A: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 1, Cycle 1 Day 2, 8, 14

AUC0-24 of Cobimetinib on Cycle 1 Day 1 (Cycle 1 Day 8 for Cohorts 1-3) - Stage 1 All Cohorts

Time frame: Cohorts 1-3: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 8, Cycle 1 Days 9; Cohorts 4-6A: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 1, Cycle 1 Day 2

Tmax of Cobimetinib on Cycle 1 Day 21 (Cycle 1 Day 28 for Cohorts 1-3) - Stage 1 All Cohorts

Time frame: Cohorts 1-3: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 28, Cycle 1 Day 29, Cycle 2 Days 1, 15, 21; Cohorts 4-6A: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 21, Cycle 1 Day 22, Cycle 2 Days 1, 15, 21

Cmax of Cobimetinib on Cycle 1 Day 21 (Cycle 1 Day 28 for Cohorts 1-3) - Stage 1 All Cohorts

AUC0-24 of Cobimetinib on Cycle 1 Day 21 (Cycle 1 Day 28 for Cohorts 1-3) - Stage 1 All Cohorts

Time frame: Cohorts 1-3: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 28, Cycle 1 Day 29; Cohorts 4-6A: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 21, Cycle 1 Day 22

Terminal Half-life (t1/2) of Cobimetinib on Cycle 1 Day 21 (Cycle 1 Day 28 for Cohorts 1-3) - Stage 1 All Cohorts

Half-life is the time measured for the plasma concentration to decrease by one half.

Apparent Clearance (CL/F) of Cobimetinib on Cycle 1 Day 21 (Cycle 1 Day 28 for Cohorts 1-3) - Stage 1 All Cohorts

Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.

Accumulation Ratio of Cobimetinib on Cycle 1 Day 21 (Cycle 1 Day 28 for Cohorts 1-3) - Stage 1 All Cohorts

Accumulation ratio was calculated as: AUC0-24 at Cycle 1 Day 21 (Cycle 1 Day 28 for Cohorts 1-3) divided by AUC0-24 at Cycle 1 Day 1 (Cycle 1 Day 8 for Cohorts 1-3).

Time frame: Cohorts 1-3: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Days 8 and 28, Cycle 1 Days 9, 29; Cohorts 4-6A: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Days 1 and 21, Cycle 1 Days 2, 22

Tmax of Pictilisib on Cycle 1 Day 1 (Cycle 1 Day 8 for Cohorts 1-3) - Stage 1 All Cohorts

Time frame: Cohorts 1-3: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 8, Cycle 1 Day 9, 15, 21; Cohorts 4-6A: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 1, Cycle 1 Day 2, 8, 14

Cmax of Pictilisib on Cycle 1 Day 1 (Cycle 1 Day 8 for Cohorts 1-3) - Stage 1 All Cohorts

Time frame: Cohorts 1-3: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 8, Cycle 1 Day 9, 15, 21; Cohorts 4-6A: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 1, Cycle 1 Day 2, 8, 14

AUC0-24 of Pictilisib on Cycle 1 Day 1 (Cycle 1 Day 8 for Cohorts 1-3) - Stage 1 All Cohorts

Time frame: Cohorts 1-3: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 8, Cycle 1 Day 9; Cohorts 4-6A: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 1, Cycle 1 Day 2

Tmax of Pictilisib on Cycle 1 Day 21 (Cycle 1 Day 28 for Cohorts 1-3) - Stage 1 All Cohorts

Time frame: Cohorts 1-3: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 28, Cycle 1 Day 29, Cycle 2 Days 1, 15, 21; Cohorts 4-6A: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 21, Cycle 1 Day 22, Cycle 2 Days 1, 15, 21

Cmax of Pictilisib on Cycle 1 Day 21 (Cycle 1 Day 28 for Cohorts 1-3) - Stage 1 All Cohorts

AUC0-24 of Pictilisib on Cycle 1 Day 21 (Cycle 1 Day 28 for Cohorts 1-3) - Stage 1 All Cohorts

Time frame: Cohorts 1-3: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 28, Cycle 1 Day 29; Cohorts 4-6A: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 21, Cycle 1 Day 22

t1/2 of Pictilisib on Cycle 1 Day 21 (Cycle 1 Day 28 for Cohorts 1-3) - Stage 1 All Cohorts

Half-life is the time measured for the plasma concentration to decrease by one half. As planned, summary statistics were not derived if fewer than 3 participants had available data; however, if the number of participants analyzed = 1, then the observed data of the single participant was reported as geometric mean.

CL/F of Pictilisib on Cycle 1 Day 21 (Cycle 1 Day 28 for Cohorts 1-3) - Stage 1 All Cohorts

Accumulation Ratio of Pictilisib on Cycle 1 Day 21 (Cycle 1 Day 28 for Cohorts 1-3) - Stage 1 All Cohorts

Accumulation ratio was calculated as: AUC0-24 at Cycle 1 Day 21 (Cycle 1 Day 28 for Cohorts 1-3) divided by AUC0-24 at Cycle 1 Day 1 (Cycle 1 Day 8 for Cohorts 1-3).

Time frame: Cohorts 1-3: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Days 8 and 28, Cycle 1 Days 9, 29; Cohorts 4-6A: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Days 1 and 21, Cycle 1 Day 2, 22

Tmax of Cobimetinib on Cycle 1 Day 1 - Stage 1A All Cohorts

Time frame: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 1, Cycle 1 Days 2, 8, 15-17

Cmax of Cobimetinib on Cycle 1 Day 1 - Stage 1A All Cohorts

Time frame: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 1, Cycle 1 Days 2, 8, 15-17

AUC0-24 of Cobimetinib on Cycle 1 Day 1 - Stage 1A All Cohorts

Time frame: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 1, Cycle 1 Days 2

Tmax of Cobimetinib on Cycle 1 Day 18 - Stage 1A All Cohorts

Time frame: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 18, Cycle 1 Day 19, Cycle 2 Days 1, 15, 21

Cmax of Cobimetinib on Cycle 1 Day 18 - Stage 1A All Cohorts

Time frame: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 18, Cycle 1 Day 19, Cycle 2 Days 1, 15, 21

AUC0-24 of Cobimetinib on Cycle 1 Day 18 - Stage 1A All Cohorts

Time frame: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 18, Cycle 1 Day 19

t1/2 of Cobimetinib on Cycle 1 Day 18 - Stage 1A All Cohorts

Half-life is the time measured for the plasma concentration to decrease by one half.

Time frame: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 18, Cycle 1 Day 19, Cycle 2 Days 1, 15, 21

CL/F of Cobimetinib on Cycle 1 Day 18 - Stage 1A All Cohorts

Time frame: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 18, Cycle 1 Day 19, Cycle 2 Days 1, 15, 21

Accumulation Ratio of Cobimetinib on Cycle 1 Day 18 - Stage 1A All Cohorts

Accumulation ratio was calculated as: AUC0-24 at Cycle 1 Day 18 divided by AUC0-24 at Cycle 1 Day 1.

Time frame: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Days 1 and 18, Cycle 1 Days 2, 19

Tmax of Pictilisib on Cycle 1 Day 1 - Stage 1A All Cohorts

Time frame: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 1, Cycle 1 Days 2, 8, 15-17

Cmax of Pictilisib on Cycle 1 Day 1 - Stage 1A All Cohorts

Time frame: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 1, Cycle 1 Days 2, 8, 15-17

AUC0-24 of Pictilisib on Cycle 1 Day 1 - Stage 1A All Cohorts

Time frame: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 1, Cycle 1 Days 2

Tmax of Pictilisib on Cycle 1 Day 18 - Stage 1A All Cohorts

Time frame: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 18, Cycle 1 Day 19, Cycle 2 Days 1, 15, 21

Cmax of Pictilisib on Cycle 1 Day 18 - Stage 1A All Cohorts

Time frame: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 18, Cycle 1 Day 19, Cycle 2 Days 1, 15, 21

AUC0-24 of Pictilisib on Cycle 1 Day 18 - Stage 1A All Cohorts

Time frame: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 18, Cycle 1 Day 19

t1/2 of Pictilisib on Cycle 1 Day 18 - Stage 1A All Cohorts

Time frame: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 18, Cycle 1 Day 19, Cycle 2 Days 1, 15, 21

CL/F of Pictilisib on Cycle 1 Day 18 - Stage 1A All Cohorts

Time frame: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 18, Cycle 1 Day 19, Cycle 2 Days 1, 15, 21

Accumulation Ratio of Pictilisib on Cycle 1 Day 18 - Stage 1A All Cohorts

Accumulation ratio was calculated as: AUC0-24 at Cycle 1 Day 18 divided by AUC0-24 at Cycle 1 Day 1.

Time frame: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Days 1 and 18, Cycle 1 Days 2, 19

Tmax of Cobimetinib on Cycle 1 Day 1 - Stage 1B All Cohorts

Time frame: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 1, Cycle 1 Day 2

Cmax of Cobimetinib on Cycle 1 Day 1 - Stage 1B All Cohorts

Time frame: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 1, Cycle 1 Day 2

AUC0-24 of Cobimetinib on Cycle 1 Day 1 - Stage 1B All Cohorts

Time frame: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 1, Cycle 1 Day 2

Tmax of Cobimetinib on Cycle 1 Day 21 - Stage 1B All Cohorts

Time frame: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 21, Cycle 1 Day 22

Cmax of Cobimetinib on Cycle 1 Day 21 - Stage 1B All Cohorts

Time frame: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 21, Cycle 1 Day 22

AUC0-24 of Cobimetinib on Cycle 1 Day 21 - Stage 1B All Cohorts

Time frame: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 21, Cycle 1 Day 22

CL/F of Cobimetinib on Cycle 1 Day 21 - Stage 1B All Cohorts

Time frame: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 21, Cycle 1 Day 22

Accumulation Ratio of Cobimetinib on Cycle 1 Day 21 - Stage 1B All Cohorts

Accumulation ratio was calculated as: AUC0-24 at Cycle 1 Day 21 divided by AUC0-24 at Cycle 1 Day 1.

Time frame: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Days 1 and 21, Cycle 1 Days 2 and 22

Tmax of Pictilisib on Cycle 1 Day 1 - Stage 1B All Cohorts

Time frame: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 1, Cycle 1 Day 2

Cmax of Pictilisib on Cycle 1 Day 1 - Stage 1B All Cohorts

Time frame: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 1, Cycle 1 Day 2

AUC0-24 of Pictilisib on Cycle 1 Day 1 - Stage 1B All Cohorts

Time frame: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 1, Cycle 1 Day 2

Tmax of Pictilisib on Cycle 1 Day 21 - Stage 1B All Cohorts

Time frame: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 21, Cycle 1 Day 22

Cmax of Pictilisib on Cycle 1 Day 21 - Stage 1B All Cohorts

Time frame: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 21, Cycle 1 Day 22

AUC0-24 of Pictilisib on Cycle 1 Day 21 - Stage 1B All Cohorts

Time frame: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 21, Cycle 1 Day 22

CL/F of Pictilisib on Cycle 1 Day 21 - Stage 1B All Cohorts

Time frame: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 21, Cycle 1 Day 22

Accumulation Ratio of Pictilisib on Cycle 1 Day 21 - Stage 1B All Cohorts

Accumulation ratio was calculated as: AUC0-24 at Cycle 1 Day 21 divided by AUC0-24 at Cycle 1 Day 1.

Time frame: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Days 1 and 21, Cycle 1 Days 2 and 22

Tmax of Cobimetinib on Cycle 1 Day 1 - Stage 2 Individual Indication Specific Cohorts

Stage 2 PK data were reported for each indication specific cohort separately.

Time frame: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 1, Cycle 1 Days 2, 8, 14

Cmax of Cobimetinib on Cycle 1 Day 1 - Stage 2 Individual Indication Specific Cohorts

Stage 2 PK data were reported for each indication specific cohort separately.

Time frame: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 1, Cycle 1 Days 2, 8, 14

AUC0-24 of Cobimetinib on Cycle 1 Day 1 - Stage 2 All Cohorts

Stage 2 PK data were reported for each indication specific cohort separately.

Time frame: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 1, Cycle 1 Days 2

Tmax of Cobimetinib on Cycle 1 Day 21 - Stage 2 Individual Indication Specific Cohorts

Stage 2 PK data were reported for each indication specific cohort separately.

Time frame: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 21, Cycle 1 Day 22, Cycle 2 Days 1, 15, 21

Cmax of Cobimetinib on Cycle 1 Day 21 - Stage 2 Individual Indication Specific Cohorts

Stage 2 PK data were reported for each indication specific cohort separately.

Time frame: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 21, Cycle 1 Day 22, Cycle 2 Days 1, 15, 21

AUC0-24 of Cobimetinib on Cycle 1 Day 21 - Stage 2 Individual Indication Specific Cohorts

Stage 2 PK data were reported for each indication specific cohort separately.

Time frame: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 21, Cycle 1 Day 22

t1/2 of Cobimetinib on Cycle 1 Day 21 - Stage 2 Individual Indication Specific Cohorts

Stage 2 PK data were reported for each indication specific cohort separately. Half-life is the time measured for the plasma concentration to decrease by one half.

Time frame: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 21, Cycle 1 Day 22

CL/F of Cobimetinib on Cycle 1 Day 21 - Stage 2 Individual Indication Specific Cohorts

Stage 2 PK data were reported for each indication specific cohort separately. Half-life is the time measured for the plasma concentration to decrease by one half. Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.

Time frame: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 21, Cycle 1 Day 22, Cycle 2 Days 1, 15, 21

Accumulation Ratio of Cobimetinib on Cycle 1 Day 21 - Stage 2 Individual Indication Specific Cohorts

Stage 2 PK data were reported for each indication specific cohort separately. Accumulation ratio was calculated as: AUC0-24 at Cycle 1 Day 21 divided by AUC0-24 at Cycle 1 Day 1.

Time frame: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Days 1 and 21, Cycle 1 Days 2 and 22

Tmax of Pictilisib on Cycle 1 Day 1 - Stage 2 Individual Indication Specific Cohorts

Stage 2 PK data were reported for each indication specific cohort separately.

Time frame: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 1, Cycle 1 Days 2, 8, 14

Cmax of Pictilisib on Cycle 1 Day 1 - Stage 2 Individual Indication Specific Cohorts

Stage 2 PK data were reported for each indication specific cohort separately.

Time frame: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 1, Cycle 1 Days 2, 8, 14

AUC0-24 of Pictilisib on Cycle 1 Day 1 - Stage 2 Individual Indication Specific Cohorts

Stage 2 PK data were reported for each indication specific cohort separately.

Time frame: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 1, Cycle 1 Days 2

Tmax of Pictilisib on Cycle 1 Day 21 - Stage 2 Individual Indication Specific Cohorts

Stage 2 PK data were reported for each indication specific cohort separately.

Time frame: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 21, Cycle 1 Day 22, Cycle 2 Days 1, 15, 21

Cmax of Pictilisib on Cycle 1 Day 21 - Stage 2 Individual Indication Specific Cohorts

Stage 2 PK data were reported for each indication specific cohort separately.

Time frame: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 21, Cycle 1 Day 22, Cycle 2 Days 1, 15, 21

AUC0-24 of Pictilisib on Cycle 1 Day 21 - Stage 2 Individual Indication Specific Cohorts

Stage 2 PK data were reported for each indication specific cohort separately.

Time frame: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 21, Cycle 1 Day 22

t1/2 of Pictilisib on Cycle 1 Day 21 - Stage 2 Individual Indication Specific Cohorts

Stage 2 PK data were reported for each indication specific cohort separately. Half-life is the time measured for the plasma concentration to decrease by one half.

Time frame: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 21, Cycle 1 Day 22, Cycle 2 Days 1, 15, 21

CL/F of Pictilisib on Cycle 1 Day 21 - Stage 2 Individual Indication Specific Cohorts

Time frame: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 21, Cycle 1 Day 22, Cycle 2 Days 1, 15, 21

Accumulation Ratio of Pictilisib on Cycle 1 Day 21 - Stage 2 Individual Indication Specific Cohorts

Stage 2 PK data were reported for each indication specific cohort separately. Accumulation ratio was calculated as: AUC0-24 at Cycle 1 Day 21 divided by AUC0-24 at Cycle 1 Day 1.

Time frame: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Days 1 and 21, Cycle 1 Days 2 and 22

Tmax of Cobimetinib on Cycle 1 Day 1 - Stage 2A Individual Indication Specific Cohorts

Stage 2A PK data were reported for each indication specific cohort separately.

Time frame: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 1, Cycle 1 Days 2, 8, 15-17

Cmax of Cobimetinib on Cycle 1 Day 1 - Stage 2A Individual Indication Specific Cohorts

Stage 2A PK data were reported for each indication specific cohort separately.

Time frame: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 1, Cycle 1 Days 2, 8, 15-17

AUC0-24 of Cobimetinib on Cycle 1 Day 1 - Stage 2A Individual Indication Specific Cohorts

Stage 2A PK data were reported for each indication specific cohort separately.

Time frame: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 1, Cycle 1 Days 2

Tmax of Cobimetinib on Cycle 1 Day 18 - Stage 2A Individual Indication Specific Cohorts

Stage 2A PK data were reported for each indication specific cohort separately. As planned, summary statistics were not derived if fewer than 3 participants had available data; however, if the number of participants analyzed = 1, then the observed data of the single participant was reported as median.

Time frame: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 18, Cycle 1 Day 19, Cycle 2 Days 1, 15, 21

Cmax of Cobimetinib on Cycle 1 Day 18 - Stage 2A Individual Indication Specific Cohorts

Time frame: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 18, Cycle 1 Day 19, Cycle 2 Days 1, 15, 21

AUC0-24 of Cobimetinib on Cycle 1 Day 18 - Stage 2A Individual Indication Specific Cohorts

Time frame: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 18, Cycle 1 Day 19, Cycle 2 Days 1, 15, 21

t1/2 of Cobimetinib on Cycle 1 Day 18 - Stage 2A Individual Indication Specific Cohorts

Stage 2A PK data were reported for each indication specific cohort separately. Half-life is the time measured for the plasma concentration to decrease by one half. As planned, summary statistics were not derived if fewer than 3 participants had available data; however, if the number of participants analyzed = 1, then the observed data of the single participant was reported as geometric mean.

Time frame: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 18, Cycle 1 Day 19, Cycle 2 Days 1, 15, 21

CL/F of Cobimetinib on Cycle 1 Day 18 - Stage 2A Individual Indication Specific Cohorts

Stage 2A PK data were reported for each indication specific cohort separately. Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. As planned, summary statistics were not derived if fewer than 3 participants had available data; however, if the number of participants analyzed = 1, then the observed data of the single participant was reported as geometric mean.

Time frame: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 18, Cycle 1 Day 19, Cycle 2 Days 1, 15, 21

Accumulation Ratio of Cobimetinib on Cycle 1 Day 18 - Stage 2A Individual Indication Specific Cohorts

Stage 2A PK data were reported for each indication specific cohort separately. Accumulation ratio was calculated as: AUC0-24 at Cycle 1 Day 21 divided by AUC0-24 at Cycle 1 Day 1. As planned, summary statistics were not derived if fewer than 3 participants had available data; however, if the number of participants analyzed = 1, then the observed data of the single participant was reported as geometric mean.

Time frame: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 18, Cycle 1 Day 19, Cycle 2 Days 1, 15, 21

Tmax of Pictilisib on Cycle 1 Day 1 - Stage 2A Individual Indication Specific Cohorts

Stage 2A PK data were reported for each indication specific cohort separately.

Time frame: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 1, Cycle 1 Days 2, 8, 15-17

Cmax of Pictilisib on Cycle 1 Day 1 - Stage 2A Individual Indication Specific Cohorts

Stage 2A PK data were reported for each indication specific cohort separately.

Time frame: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 1, Cycle 1 Days 2, 8, 15-17

AUC0-24 of Pictilisib on Cycle 1 Day 1 - Stage 2A Individual Indication Specific Cohorts

Stage 2A PK data were reported for each indication specific cohort separately.

Time frame: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 1, Cycle 1 Days 2

Tmax of Pictilisib on Cycle 1 Day 18 - Stage 2A Individual Indication Specific Cohorts

Time frame: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 18, Cycle 1 Day 19, Cycle 2 Days 1, 15, 21

Cmax of Pictilisib on Cycle 1 Day 18 - Stage 2A Individual Indication Specific Cohorts

Time frame: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 18, Cycle 1 Day 19, Cycle 2 Days 1, 15, 21

AUC0-24 of Pictilisib on Cycle 1 Day 18 - Stage 2A Individual Indication Specific Cohorts

Time frame: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 18, Cycle 1 Day 19, Cycle 2 Days 1, 15, 21

t1/2 of Pictilisib on Cycle 1 Day 18 - Stage 2A Individual Indication Specific Cohorts

Stage 2A PK data were reported for each indication specific cohort separately. Half-life is the time measured for the plasma concentration to decrease by one half.

Time frame: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 18, Cycle 1 Day 19, Cycle 2 Days 1, 15, 21

CL/F of Pictilisib on Cycle 1 Day 18 - Stage 2A Individual Indication Specific Cohorts

Time frame: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 18, Cycle 1 Day 19, Cycle 2 Days 1, 15, 21

Accumulation Ratio of Pictilisib on Cycle 1 Day 18 - Stage 2A Individual Indication Specific Cohorts

Time frame: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 18, Cycle 1 Day 19, Cycle 2 Days 1, 15, 21

Number of Participants With Best Overall Response - Dose Escalation Stages 1, 1A and 1B

Tumor response was assessed using Response Evaluation Criteria in Solid Tumors (RECIST). Complete response (CR) = disappearance of all target and non-target lesions. Partial Response (PR) = at least 30 percent (%) decrease in sum of the longest diameter of measured lesions taking as reference the baseline sum of the longest diameter. Progressive disease (PD) = at least 20% increase in the sum of the longest diameter of measured lesions taking as reference the smallest sum of the longest diameter since treatment start or appearance of one or more new lesions. Stable disease (SD) = neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of the longest diameter since treatment start.

Time frame: Up to 30 days after last dose (last dose = up to Cycle 15, cycle length = 28 days)

Duration of Objective Response - Dose Escalation Stages 1, 1A and 1B

Duration of objective response was defined as the time from first occurrence of a documented objective response (CR or PR) until the time of disease progression, as determined by investigator review of tumor assessments using RECIST, or death from any cause during the study (within 30 days after the last dose of study treatment). CR = disappearance of all target and non-target lesions. PR = at least 30 % decrease in sum of the longest diameter of measured lesions taking as reference the baseline sum of the longest diameter. PD = at least 20% increase in the sum of the longest diameter of measured lesions taking as reference the smallest sum of the longest diameter since treatment start or appearance of one or more new lesions.

Time frame: Up to 30 days after last dose (last dose = up to Cycle 15, cycle length = 28 days)

Progression-Free Survival (PFS) - Dose Escalation Stages 1, 1A and 1B

PFS was the time from study treatment initiation to the first occurrence of disease progression, as determined by investigator review of tumor assessments using RECIST, or death from any cause during the study (within 30 days after the last dose of study treatment). PD = at least 20% increase in the sum of the longest diameter of measured lesions taking as reference the smallest sum of the longest diameter since treatment start or appearance of one or more new lesions.

Time frame: Up to 30 days after last dose (last dose = up to Cycle 15, cycle length = 28 days)