Trial Outcomes & Findings for Safety, Tolerability and Pharmacokinetics of Cobimetinib in Combination With Pictilisib in Patients With Locally Advanced or Metastatic Solid Tumors (NCT NCT00996892)

Last Updated: 2016-12-30

Results Overview

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.

Recruitment status

TERMINATED

Study phase

PHASE1

Target enrollment

178 participants

Primary outcome timeframe

Cohorts 1-3: Day 1 to Day 35, All other cohorts: Day 1 to Day 28

Results posted on

2016-12-30

Participant Flow

Study was terminated before initiation of Stage 2B; hence Stage 2B cohorts were not applicable.

Participant milestones

Participant milestones
Measure	S1 C1: 20 mg Cobimetinib + 80 mg Pictilisib Stage 1 Cohort 1 (S1 C1): Participants received a single oral dose of pictilisib 80 milligrams (mg) capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1 C2: 20 mg Cobimetinib + 100 mg Pictilisib Stage 1 Cohort 2 (S1 C2): Participants received a single oral dose of pictilisib 100 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1 C3: 40 mg Cobimetinib + 80 mg Pictilisib Stage 1 Cohort 3 (S1 C3): Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 40 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1 C4: 40 mg Cobimetinib + 100 mg Pictilisib Stage 1 Cohort 4 (S1 C4): Participants received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1 C5: 40 mg Cobimetinib + 130 mg Pictilisib Stage 1 Cohort 5 (S1 C5): Participants received cobimetinib 40 mg capsules and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1 C6: 60 mg Cobimetinib + 100 mg Pictilisib Stage 1 Cohort 6 (S1 C6): Participants received cobimetinib 60 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1 C6A: 80 mg Cobimetinib + 100 mg Pictilisib Stage 1 Cohort 6A (S1 C6A): Participants received cobimetinib 80 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1A CA: 100 mg Cobimetinib + 130 mg Pictilisib Stage 1A Cohort A (S1A CA): Participants received cobimetinib 100 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1A CB: 100 mg Cobimetinib + 180 mg Pictilisib Stage 1A Cohort B (S1A CB): Participants received cobimetinib 100 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1A CC: 125 mg Cobimetinib + 130 mg Pictilisib Stage 1A Cohort C (S1A CC): Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1A CD: 125 mg Cobimetinib + 180 mg Pictilisib Stage 1A Cohort D (S1A CD): Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1A CE: 125 mg Cobimetinib + 245 mg Pictilisib Stage 1A Cohort E (S1A CE): Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 245 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1A CF: 150 mg Cobimetinib + 180 mg Pictilisib Stage 1A Cohort F (S1A CF): Participants received cobimetinib 150 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1A CG: 150 mg Cobimetinib + 245 mg Pictilisib Stage 1A Cohort G (S1A CG): Participants received cobimetinib 150 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 245 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1B CAX: 40 mg Cobimetinib + 130 mg Pictilisib Stage 1B Cohort AX (S1B CAX): Participants received cobimetinib 40 mg capsules and pictilisib 130 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1B CBX: 40 mg Cobimetinib + 180 mg Pictilisib Stage 1B Cohort BX (S1B CBX): Participants received cobimetinib 40 mg capsules and pictilisib 180 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1B CCX: 60 mg Cobimetinib + 130 mg Pictilisib Stage 1B Cohort CX (S1B CCX): Participants received cobimetinib 60 mg capsules and pictilisib 130 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1B CDX: 60 mg Cobimetinib + 180 mg Pictilisib Stage 1B Cohort DX (S1B CDX): Participants received cobimetinib 60 mg capsules and pictilisib 180 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S2 Expansion: 40 mg Cobimetinib + 100 mg Pictilisib Stage 2 (S2) expansion cohort: Participants received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. This indication specific cohort included 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).	S2A Expansion: 125 mg Cobimetinib + 180 mg Pictilisib Stage 2A (S2A) expansion cohort: Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. This indication specific cohort included participants with KRAS mutant NSCLC; EGFR T790M mutant and EGFR inhibitor-progressing NSCLC; pancreatic adenocarcinoma; KRAS mutant CRC, and KRAS mutant endometrioid carcinoma.
Dose-Escalation Stage 1 STARTED	4	3	3	9	11	10	4	0	0	0	0	0	0	0	0	0	0	0	0	0
Dose-Escalation Stage 1 COMPLETED	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Dose-Escalation Stage 1 NOT COMPLETED	4	3	3	9	11	10	4	0	0	0	0	0	0	0	0	0	0	0	0	0
Dose-Escalation Stage 1A STARTED	0	0	0	0	0	0	0	3	3	4	7	9	8	5	0	0	0	0	0	0
Dose-Escalation Stage 1A COMPLETED	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Dose-Escalation Stage 1A NOT COMPLETED	0	0	0	0	0	0	0	3	3	4	7	9	8	5	0	0	0	0	0	0
Dose-Escalation Stage 1B STARTED	0	0	0	0	0	0	0	0	0	0	0	0	0	0	4	3	3	5	0	0
Dose-Escalation Stage 1B COMPLETED	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Dose-Escalation Stage 1B NOT COMPLETED	0	0	0	0	0	0	0	0	0	0	0	0	0	0	4	3	3	5	0	0
Expansion Stage 2 STARTED	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	35	0
Expansion Stage 2 COMPLETED	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Expansion Stage 2 NOT COMPLETED	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	35	0
Expansion Stage 2A STARTED	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	45
Expansion Stage 2A COMPLETED	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Expansion Stage 2A NOT COMPLETED	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	45

Reasons for withdrawal

Reasons for withdrawal
Measure	S1 C1: 20 mg Cobimetinib + 80 mg Pictilisib Stage 1 Cohort 1 (S1 C1): Participants received a single oral dose of pictilisib 80 milligrams (mg) capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1 C2: 20 mg Cobimetinib + 100 mg Pictilisib Stage 1 Cohort 2 (S1 C2): Participants received a single oral dose of pictilisib 100 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1 C3: 40 mg Cobimetinib + 80 mg Pictilisib Stage 1 Cohort 3 (S1 C3): Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 40 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1 C4: 40 mg Cobimetinib + 100 mg Pictilisib Stage 1 Cohort 4 (S1 C4): Participants received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1 C5: 40 mg Cobimetinib + 130 mg Pictilisib Stage 1 Cohort 5 (S1 C5): Participants received cobimetinib 40 mg capsules and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1 C6: 60 mg Cobimetinib + 100 mg Pictilisib Stage 1 Cohort 6 (S1 C6): Participants received cobimetinib 60 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1 C6A: 80 mg Cobimetinib + 100 mg Pictilisib Stage 1 Cohort 6A (S1 C6A): Participants received cobimetinib 80 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1A CA: 100 mg Cobimetinib + 130 mg Pictilisib Stage 1A Cohort A (S1A CA): Participants received cobimetinib 100 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1A CB: 100 mg Cobimetinib + 180 mg Pictilisib Stage 1A Cohort B (S1A CB): Participants received cobimetinib 100 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1A CC: 125 mg Cobimetinib + 130 mg Pictilisib Stage 1A Cohort C (S1A CC): Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1A CD: 125 mg Cobimetinib + 180 mg Pictilisib Stage 1A Cohort D (S1A CD): Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1A CE: 125 mg Cobimetinib + 245 mg Pictilisib Stage 1A Cohort E (S1A CE): Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 245 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1A CF: 150 mg Cobimetinib + 180 mg Pictilisib Stage 1A Cohort F (S1A CF): Participants received cobimetinib 150 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1A CG: 150 mg Cobimetinib + 245 mg Pictilisib Stage 1A Cohort G (S1A CG): Participants received cobimetinib 150 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 245 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1B CAX: 40 mg Cobimetinib + 130 mg Pictilisib Stage 1B Cohort AX (S1B CAX): Participants received cobimetinib 40 mg capsules and pictilisib 130 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1B CBX: 40 mg Cobimetinib + 180 mg Pictilisib Stage 1B Cohort BX (S1B CBX): Participants received cobimetinib 40 mg capsules and pictilisib 180 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1B CCX: 60 mg Cobimetinib + 130 mg Pictilisib Stage 1B Cohort CX (S1B CCX): Participants received cobimetinib 60 mg capsules and pictilisib 130 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1B CDX: 60 mg Cobimetinib + 180 mg Pictilisib Stage 1B Cohort DX (S1B CDX): Participants received cobimetinib 60 mg capsules and pictilisib 180 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S2 Expansion: 40 mg Cobimetinib + 100 mg Pictilisib Stage 2 (S2) expansion cohort: Participants received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. This indication specific cohort included 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).	S2A Expansion: 125 mg Cobimetinib + 180 mg Pictilisib Stage 2A (S2A) expansion cohort: Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. This indication specific cohort included participants with KRAS mutant NSCLC; EGFR T790M mutant and EGFR inhibitor-progressing NSCLC; pancreatic adenocarcinoma; KRAS mutant CRC, and KRAS mutant endometrioid carcinoma.
Dose-Escalation Stage 1 Adverse Event	0	0	0	2	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0
Dose-Escalation Stage 1 Death	1	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Dose-Escalation Stage 1 Physician Decision	1	0	0	1	0	1	2	0	0	0	0	0	0	0	0	0	0	0	0	0
Dose-Escalation Stage 1 Withdrawal by Subject	0	1	0	2	1	1	1	0	0	0	0	0	0	0	0	0	0	0	0	0
Dose-Escalation Stage 1 Disease Progression	2	2	3	4	10	7	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Dose-Escalation Stage 1A Adverse Event	0	0	0	0	0	0	0	0	0	0	1	0	0	1	0	0	0	0	0	0
Dose-Escalation Stage 1A Death	0	0	0	0	0	0	0	0	0	2	0	1	1	0	0	0	0	0	0	0
Dose-Escalation Stage 1A Physician Decision	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Dose-Escalation Stage 1A Withdrawal by Subject	0	0	0	0	0	0	0	0	0	1	1	1	1	0	0	0	0	0	0	0
Dose-Escalation Stage 1A Disease Progression	0	0	0	0	0	0	0	2	3	1	5	7	6	4	0	0	0	0	0	0
Dose-Escalation Stage 1B Physician Decision	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	2	0	0
Dose-Escalation Stage 1B Disease Progression	0	0	0	0	0	0	0	0	0	0	0	0	0	0	4	3	3	3	0	0
Expansion Stage 2 Adverse Event	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	3	0
Expansion Stage 2 Death	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	2	0
Expansion Stage 2 Physician Decision	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0
Expansion Stage 2 Withdrawal by Subject	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0
Expansion Stage 2 Disease Progression	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	28	0
Expansion Stage 2A Adverse Event	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	8
Expansion Stage 2A Physician Decision	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	2
Expansion Stage 2A Withdrawal by Subject	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	4
Expansion Stage 2A Disease Progression	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	31

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	All Participants n=178 Participants All participants who received cobimetinib and pictilisib in any dose combination until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
Age, Continuous	56.6 years STANDARD_DEVIATION 12.0 • n=5 Participants
Gender Female	109 Participants n=5 Participants
Gender Male	69 Participants n=5 Participants

PRIMARY outcome

Timeframe: Cohorts 1-3: Day 1 to Day 35, All other cohorts: Day 1 to Day 28

Population: Safety-evaluable population included all participants who received at least one dose of study drug. Here, number of participants analyzed = participants who were evaluable for this outcome.

Outcome measures

Outcome measures
Measure	S1 C1: 20 mg Cobimetinib + 80 mg Pictilisib n=4 Participants Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1 C2: 20 mg Cobimetinib + 100 mg Pictilisib n=3 Participants Participants received a single oral dose of pictilisib 100 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1 C3: 40 mg Cobimetinib + 80 mg Pictilisib n=3 Participants Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 40 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1 C4: 40 mg Cobimetinib + 100 mg Pictilisib n=9 Participants Participants received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1 C5: 40 mg Cobimetinib + 130 mg Pictilisib n=11 Participants Participants received cobimetinib 40 mg capsules and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1 C6: 60 mg Cobimetinib + 100 mg Pictilisib n=10 Participants Participants received cobimetinib 60 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1 C6A: 80 mg Cobimetinib + 100 mg Pictilisib n=4 Participants Participants received cobimetinib 80 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1A CA: 100 mg Cobimetinib + 130 mg Pictilisib n=3 Participants Participants received cobimetinib 100 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1A CB: 100 mg Cobimetinib + 180 mg Pictilisib n=3 Participants Participants received cobimetinib 100 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1A CC: 125 mg Cobimetinib + 130 mg Pictilisib n=4 Participants Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1A CD: 125 mg Cobimetinib + 180 mg Pictilisib n=7 Participants Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1A CE: 125 mg Cobimetinib + 245 mg Pictilisib n=9 Participants Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 245 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1A CF: 150 mg Cobimetinib + 180 mg Pictilisib n=8 Participants Participants received cobimetinib 150 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1A CG: 150 mg Cobimetinib + 245 mg Pictilisib n=5 Participants Participants received cobimetinib 150 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 245 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1B CAX: 40 mg Cobimetinib + 130 mg Pictilisib n=4 Participants Participants received cobimetinib 40 mg capsules and pictilisib 130 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1B CBX: 40 mg Cobimetinib + 180 mg Pictilisib n=3 Participants Participants received cobimetinib 40 mg capsules and pictilisib 180 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1B CCX: 60 mg Cobimetinib + 130 mg Pictilisib n=3 Participants Participants received cobimetinib 60 mg capsules and pictilisib 130 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1B CDX: 60 mg Cobimetinib + 180 mg Pictilisib n=5 Participants Participants received cobimetinib 60 mg capsules and pictilisib 180 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
Number of Participants With Dose-Limiting Toxicities (DLTs) During Dose Escalation Stages 1, 1A and 1B	0 participants	0 participants	0 participants	1 participants	1 participants	0 participants	0 participants	0 participants	0 participants	0 participants	0 participants	0 participants	1 participants	2 participants	0 participants	0 participants	0 participants	1 participants

PRIMARY outcome

Timeframe: Cohorts 1-3: Day 1 to Day 35, All other cohorts: Day 1 to Day 28

Population: Safety-evaluable population. Here, number of participants analyzed = participants who were evaluable for this outcome and n = participants evaluable for specified categories.

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.

Outcome measures

Outcome measures
Measure	S1 C1: 20 mg Cobimetinib + 80 mg Pictilisib n=98 Participants Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1 C2: 20 mg Cobimetinib + 100 mg Pictilisib Participants received a single oral dose of pictilisib 100 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1 C3: 40 mg Cobimetinib + 80 mg Pictilisib Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 40 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1 C4: 40 mg Cobimetinib + 100 mg Pictilisib Participants received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1 C5: 40 mg Cobimetinib + 130 mg Pictilisib Participants received cobimetinib 40 mg capsules and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1 C6: 60 mg Cobimetinib + 100 mg Pictilisib Participants received cobimetinib 60 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1 C6A: 80 mg Cobimetinib + 100 mg Pictilisib Participants received cobimetinib 80 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1A CA: 100 mg Cobimetinib + 130 mg Pictilisib Participants received cobimetinib 100 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1A CB: 100 mg Cobimetinib + 180 mg Pictilisib Participants received cobimetinib 100 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1A CC: 125 mg Cobimetinib + 130 mg Pictilisib Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1A CD: 125 mg Cobimetinib + 180 mg Pictilisib Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1A CE: 125 mg Cobimetinib + 245 mg Pictilisib Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 245 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1A CF: 150 mg Cobimetinib + 180 mg Pictilisib Participants received cobimetinib 150 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1A CG: 150 mg Cobimetinib + 245 mg Pictilisib Participants received cobimetinib 150 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 245 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1B CAX: 40 mg Cobimetinib + 130 mg Pictilisib Participants received cobimetinib 40 mg capsules and pictilisib 130 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1B CBX: 40 mg Cobimetinib + 180 mg Pictilisib Participants received cobimetinib 40 mg capsules and pictilisib 180 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1B CCX: 60 mg Cobimetinib + 130 mg Pictilisib Participants received cobimetinib 60 mg capsules and pictilisib 130 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.	S1B CDX: 60 mg Cobimetinib + 180 mg Pictilisib Participants received cobimetinib 60 mg capsules and pictilisib 180 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
Maximum Tolerated Combination Doses of Cobimetinib and Pictilisib During Dose-Escalation Stages 1, 1A and 1B Stage 1: Cobimetinib (n = 44)	40 mg	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Maximum Tolerated Combination Doses of Cobimetinib and Pictilisib During Dose-Escalation Stages 1, 1A and 1B Stage 1: Pictilisib (n = 44)	100 mg	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Maximum Tolerated Combination Doses of Cobimetinib and Pictilisib During Dose-Escalation Stages 1, 1A and 1B Stage 1A: Cobimetinib (n = 34)	125 mg	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Maximum Tolerated Combination Doses of Cobimetinib and Pictilisib During Dose-Escalation Stages 1, 1A and 1B Stage 1A: Pictilisib (n = 34)	180 mg	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Maximum Tolerated Combination Doses of Cobimetinib and Pictilisib During Dose-Escalation Stages 1, 1A and 1B Stage 1B: Cobimetinib (n = 20)	NA mg MTD for Stage 1B was not determined as the study was terminated prior to initiation of Stage 2B.	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Maximum Tolerated Combination Doses of Cobimetinib and Pictilisib During Dose-Escalation Stages 1, 1A and 1B Stage 1B: Pictilisib (n = 20)	NA mg MTD for Stage 1B was not determined as the study was terminated prior to initiation of Stage 2B.	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—

PRIMARY outcome

Timeframe: 0-4 hours pre-cobimetinib (Pr-C) dose, 0.5, 2, 4, 6 hours post-cobimetinib (Po-C) dose on Day 3, Day 4

Population: Pharmacokinetic (PK) population included all participants who had at least one cobimetinib and pictilisib plasma concentration available. Here, number of participants analyzed = participants who were evaluable for this outcome.