A Phase Ib, Open-Label, Dose-Escalation Study Evaluating the Safety, Tolerability and Pharmacokinetics of GDC-0973 in Combination With GDC-0941 When Administered in Patients With Locally Advanced or Metastatic Solid Tumors
Overview
- Phase
- Phase 1
- Intervention
- Cobimetinib
- Conditions
- Solid Tumors
- Sponsor
- Genentech, Inc.
- Enrollment
- 178
- Primary Endpoint
- Number of Participants With Dose-Limiting Toxicities (DLTs) During Dose Escalation Stages 1, 1A and 1B
- Status
- Terminated
- Last Updated
- 9 years ago
Overview
Brief Summary
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.
Investigators
Eligibility Criteria
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
Arms & Interventions
Dose Escalation Stage 1: Cobimetinib + Pictilisib
Participants will receive cobimetinib capsules (at a starting dose of 20 milligrams \[mg\]) and pictilisib capsules (at a starting dose of 80 mg) from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Doses will be increased to identify maximum tolerated dose (MTD) or potential recommended Phase 2 dose (RP2D). Treatment will continue until disease progression, unacceptable toxicity, or any other discontinuation criterion meets.
Intervention: Cobimetinib
Dose Escalation Stage 1: Cobimetinib + Pictilisib
Participants will receive cobimetinib capsules (at a starting dose of 20 milligrams \[mg\]) and pictilisib capsules (at a starting dose of 80 mg) from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Doses will be increased to identify maximum tolerated dose (MTD) or potential recommended Phase 2 dose (RP2D). Treatment will continue until disease progression, unacceptable toxicity, or any other discontinuation criterion meets.
Intervention: Pictilisib
Dose Escalation Stage 1A: Cobimetinib + Pictilisib
Participants will receive cobimetinib capsules (at a starting dose of 100 mg) on Days 1, 4, 8, 11, 15, and 18 and pictilisib capsules (at a starting dose of 130 mg) from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Doses will be increased to identify MTD or potential RP2D.Treatment will continue until disease progression, unacceptable toxicity, or any other discontinuation criterion meets.
Intervention: Cobimetinib
Dose Escalation Stage 1A: Cobimetinib + Pictilisib
Participants will receive cobimetinib capsules (at a starting dose of 100 mg) on Days 1, 4, 8, 11, 15, and 18 and pictilisib capsules (at a starting dose of 130 mg) from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Doses will be increased to identify MTD or potential RP2D.Treatment will continue until disease progression, unacceptable toxicity, or any other discontinuation criterion meets.
Intervention: Pictilisib
Dose Escalation Stage 1B: Cobimetinib + Pictilisib
Participants will receive cobimetinib capsules (at a starting dose of 40 mg) and pictilisib capsules (at a starting dose of 130 mg) from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants will be off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment will continue until disease progression, unacceptable toxicity, or any other discontinuation criterion meets.
Intervention: Cobimetinib
Dose Escalation Stage 1B: Cobimetinib + Pictilisib
Participants will receive cobimetinib capsules (at a starting dose of 40 mg) and pictilisib capsules (at a starting dose of 130 mg) from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants will be off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment will continue until disease progression, unacceptable toxicity, or any other discontinuation criterion meets.
Intervention: Pictilisib
Dose Expansion Stage 2: Cobimetinib + Pictilisib
Participants will received cobimetinib capsules and pictilisib capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles, at doses identified as MTD/potential RP2D from Stage 1. Treatment will continue until disease progression, unacceptable toxicity, or any other discontinuation criterion meets. This indication specific cohort will include participants with Kirsten rat sarcoma viral oncogene homolog (KRAS) mutant non-small cell lung cancer (NSCLC); epidermal growth factor receptor (EGFR) T790M mutant and EGFR inhibitor-progressing NSCLC; pancreatic adenocarcinoma; and KRAS mutant colorectal cancer (CRC).
Intervention: Cobimetinib
Dose Expansion Stage 2: Cobimetinib + Pictilisib
Participants will received cobimetinib capsules and pictilisib capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles, at doses identified as MTD/potential RP2D from Stage 1. Treatment will continue until disease progression, unacceptable toxicity, or any other discontinuation criterion meets. This indication specific cohort will include participants with Kirsten rat sarcoma viral oncogene homolog (KRAS) mutant non-small cell lung cancer (NSCLC); epidermal growth factor receptor (EGFR) T790M mutant and EGFR inhibitor-progressing NSCLC; pancreatic adenocarcinoma; and KRAS mutant colorectal cancer (CRC).
Intervention: Pictilisib
Dose Expansion Stage 2A: Cobimetinib + Pictilisib
Participants received cobimetinib capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles, at doses identified as MTD/potential RP2D from Stage 1A. Treatment will continue until disease progression, unacceptable toxicity, or any other discontinuation criterion meets. This indication specific cohort will include participants with KRAS mutant NSCLC; EGFR T790M mutant and EGFR inhibitor-progressing NSCLC; pancreatic adenocarcinoma; KRAS mutant CRC, and KRAS mutant endometrioid carcinoma.
Intervention: Cobimetinib
Dose Expansion Stage 2A: Cobimetinib + Pictilisib
Participants received cobimetinib capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles, at doses identified as MTD/potential RP2D from Stage 1A. Treatment will continue until disease progression, unacceptable toxicity, or any other discontinuation criterion meets. This indication specific cohort will include participants with KRAS mutant NSCLC; EGFR T790M mutant and EGFR inhibitor-progressing NSCLC; pancreatic adenocarcinoma; KRAS mutant CRC, and KRAS mutant endometrioid carcinoma.
Intervention: Pictilisib
Dose Expansion Stage 2B: Cobimetinib + Pictilisib
Participants will receive cobimetinib capsules and pictilisib capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles, at doses identified as MTD/potential RP2D from Stage 1B. Participants will be off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment will continue until disease progression, unacceptable toxicity, or any other discontinuation criterion meets. This indication specific cohort will include participants with KRAS mutant endometrioid carcinoma.
Intervention: Cobimetinib
Dose Expansion Stage 2B: Cobimetinib + Pictilisib
Participants will receive cobimetinib capsules and pictilisib capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles, at doses identified as MTD/potential RP2D from Stage 1B. Participants will be off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment will continue until disease progression, unacceptable toxicity, or any other discontinuation criterion meets. This indication specific cohort will include participants with KRAS mutant endometrioid carcinoma.
Intervention: Pictilisib
Outcomes
Primary Outcomes
Number of Participants With Dose-Limiting Toxicities (DLTs) During Dose Escalation Stages 1, 1A and 1B
Time Frame: Cohorts 1-3: Day 1 to Day 35, All other cohorts: Day 1 to Day 28
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.
Maximum Tolerated Combination Doses of Cobimetinib and Pictilisib During Dose-Escalation Stages 1, 1A and 1B
Time Frame: Cohorts 1-3: Day 1 to Day 35, All other cohorts: Day 1 to Day 28
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 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
Maximum Plasma Concentration (Cmax) of Cobimetinib on Day 3 - Stage 1, Cohorts 1-3
Time Frame: 0-4 hours Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Day 3, Day 4
Area Under the Concentration-Time Curve From Time 0 to 24 Hours Post-Dose (AUC0-24) of Cobimetinib on Day 3 - Stage 1, Cohorts 1-3
Time Frame: 0-4 hours Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Day 3, Day 4
Tmax of Pictilisib on Day 1 - Stage 1, Cohorts 1-3
Time Frame: 0-4 hours pre-pictilisib (Pr-P) dose, 0.5, 2, 4, 6 hours post-pictilisib (Po-P) dose on Day 1, Day 2, 0-4 hours Pr-C dose on Day 3
AUC0-24 of Pictilisib on Day 1 - Stage 1, Cohorts 1-3
Time Frame: 0-4 hours Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Day 1, Day 2, 0-4 hours Pr-C dose on Day 3
Cmax of Pictilisib on Day 1 - Stage 1, Cohorts 1-3
Time Frame: 0-4 hours Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Day 1, Day 2, 0-4 hours Pr-C dose on Day 3
Secondary Outcomes
- Cmax of Pictilisib on Cycle 1 Day 21 - Stage 2 Individual Indication Specific Cohorts(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(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 1 - Stage 2 Individual Indication Specific Cohorts(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(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(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)
- t1/2 of Pictilisib on Cycle 1 Day 21 - Stage 2 Individual Indication Specific Cohorts(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(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(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(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(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(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(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(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(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(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(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(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(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(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(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(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(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(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(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(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(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(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(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(Up to 30 days after last dose (last dose = up to Cycle 15, cycle length = 28 days))
- Tmax of Cobimetinib on Cycle 1 Day 1 (Cycle 1 Day 8 for Cohorts 1-3) - Stage 1 All Cohorts(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(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(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(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(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)
- AUC0-24 of Cobimetinib on Cycle 1 Day 21 (Cycle 1 Day 28 for Cohorts 1-3) - Stage 1 All Cohorts(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(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)
- Apparent Clearance (CL/F) of Cobimetinib on Cycle 1 Day 21 (Cycle 1 Day 28 for Cohorts 1-3) - Stage 1 All Cohorts(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)
- Accumulation Ratio of Cobimetinib on Cycle 1 Day 21 (Cycle 1 Day 28 for Cohorts 1-3) - Stage 1 All Cohorts(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(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(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(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(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(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)
- AUC0-24 of Cobimetinib on Cycle 1 Day 21 - Stage 1B All Cohorts(Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 21, Cycle 1 Day 22)
- AUC0-24 of Pictilisib on Cycle 1 Day 21 (Cycle 1 Day 28 for Cohorts 1-3) - Stage 1 All Cohorts(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(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)
- CL/F of Pictilisib on Cycle 1 Day 21 (Cycle 1 Day 28 for Cohorts 1-3) - Stage 1 All Cohorts(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)
- Accumulation Ratio of Pictilisib on Cycle 1 Day 21 (Cycle 1 Day 28 for Cohorts 1-3) - Stage 1 All Cohorts(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(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(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(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(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 Pictilisib on Cycle 1 Day 18 - Stage 1A All Cohorts(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 Cobimetinib on Cycle 1 Day 18 - Stage 1A All Cohorts(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(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(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(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(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(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(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(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(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(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(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(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(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(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(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(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(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(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(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(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(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(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(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(Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 21, Cycle 1 Day 22)
- Cmax of Cobimetinib on Cycle 1 Day 1 - Stage 2 Individual Indication Specific Cohorts(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 Pictilisib on Cycle 1 Day 21 - Stage 1B All Cohorts(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(Pr-P dose, 0.5, 2, 4, 6 hours Po-P 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(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(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(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 21 - Stage 1B All Cohorts(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(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(Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 1, Cycle 1 Days 2, 8, 14)
- Tmax of Cobimetinib on Cycle 1 Day 21 - Stage 2 Individual Indication Specific Cohorts(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(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 1 - Stage 2 All Cohorts(Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 1, Cycle 1 Days 2)
- AUC0-24 of Cobimetinib on Cycle 1 Day 21 - Stage 2 Individual Indication Specific Cohorts(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(Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 21, Cycle 1 Day 22)