Trial Outcomes & Findings for MEK Inhibitor MSC1936369B Plus FOLFIRI in Second Line K-Ras Mutated Metastatic Colorectal Cancer (mCRC) (NCT NCT01085331)

NCT ID: NCT01085331

Last Updated: 2016-10-19

Results Overview

MTD was defined as the dose level, at which the treatment-related dose limiting toxicity (DLT) occurred in \>1 of 3 subjects or in \>1 of 6 subjects. DLT was defined using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Any Grade \>=3 non-hematological toxicity except for Grade 4 asymptomatic increases in liver function tests (LFTs) reversible within 7 days in subjects with liver involvement, Grade 3 asymptomatic increases in LFTs reversible within 7 days in subjects without liver involvement, Grade 3 vomiting controlled with adequate and optimal therapy and prophylaxis, and Grade 3 diarrhea controlled with adequate and optimal anti-diarrhea therapy; any Grade 4 neutropenia lasing \>5 days/ febrile neutropenia lasting \>1 day; any Grade 4 thrombocytopenia/Grade 3 with bleeding; any treatment delay \>2 weeks due to trial treatment-related adverse effects at any dose level and judged to be possibly or probably related to the trial treatment.

• Recruitment status: TERMINATED
• Study phase: PHASE1/PHASE2
• Target enrollment: 16 participants
• Primary outcome timeframe: Baseline up to Day 28 (Part 1)
• Results posted on: 2016-10-19

Participant Flow

First/last subject (informed consent): March 2010/September 2011. Last subject completed:May 2012.

Enrolled: 22 screened for eligibility; 6 were excluded (mainly non-fulfillment of inclusion or exclusion). 16 subjects were treated in a total of 4 centers (2 in Spain and 1 each in Belgium and Italy).

Participant milestones

Measure	Part 1 or Safety Run-in Part: Pimasertib 45 mg +FOLFIRI Pimasertib was administered orally at a dose of 45 milligrams per day (mg/day) once daily on Days 1-5, 8-12, 15-19, and 22-26 of a 28 day cycle along with FOLFIRI (laevoleucovorin 200 milligram per square meter \[mg/m\^2\] intravenous \[i.v\] infusion over 90 minutes or leucovorin \[dl-leucovorin\] 400 mg/m\^2 i.v. infusion over 90 minutes; followed by irinotecan 180 mg/m\^2 given as a 90-minute infusion in 500 milliliter \[mL\] dextrose 5%; followed by a bolus 5-fluorouracil \[FU\] 400 mg/m\^2 and a 46-hour infusion 5-FU 2400 mg/m\^2.) at conventional doses on days 1 and 15 of the same 28 day cycle.	Part 1 or Safety Run-in Part: Pimasertib 60 mg +FOLFIRI Pimasertib was administered orally at a dose of 60 mg/day once daily on Days 1-5, 8-12, 15-19, and 22-26 of a 28 day cycle along with FOLFIRI (laevoleucovorin 200 milligram per square meter \[mg/m\^2\] intravenous \[i.v\] infusion over 90 minutes or leucovorin \[dl-leucovorin\] 400 mg/m\^2 i.v. infusion over 90 minutes; Irinotecan 180 mg/m\^2 given as a 90-minute infusion in 500 milliliter \[mL\] dextrose 5%; followed by a bolus 5-fluorouracil \[FU\] 400 mg/m\^2 and a 46-hour infusion 5-FU 2400 mg/m\^2) at conventional doses on days 1 and 15 of the same 28 day cycle.
Overall Study STARTED	10	6
Overall Study COMPLETED	10	6
Overall Study NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

MEK Inhibitor MSC1936369B Plus FOLFIRI in Second Line K-Ras Mutated Metastatic Colorectal Cancer (mCRC)

Baseline characteristics by cohort

Measure	Part 1 or Safety Run-in Part: Pimasertib 45 mg +FOLFIRI n=10 Participants Pimasertib was administered orally at a dose of 45 mg/day once daily on Days 1-5, 8-12, 15-19, and 22-26 of a 28 day cycle along with FOLFIRI (laevoleucovorin 200 mg/m\^2 i.v infusion over 90 minutes or leucovorin \[dl-leucovorin\] 400 mg/m\^2 i.v. infusion over 90 minutes; followed by irinotecan 180 mg/m\^2 given as a 90-minute infusion in 500 mL dextrose 5%; followed by a bolus 5-fluorouracil \[FU\] 400 mg/m\^2 and a 46-hour infusion 5-FU 2400 mg/m\^2) at conventional doses on days 1 and 15 of the same 28 day cycle.	Part 1 or Safety Run-in Part: Pimasertib 60 mg +FOLFIRI n=6 Participants Pimasertib was administered orally at a dose of 60 mg/day once daily on Days 1-5, 8-12, 15-19, and 22-26 of a 28 day cycle along with FOLFIRI (laevoleucovorin 200 mg/m\^2 i.v infusion over 90 minutes or leucovorin \[dl-leucovorin\] 400 mg/m\^2 i.v. infusion over 90 minutes; followed by irinotecan 180 mg/m\^2 given as a 90-minute infusion in 500 mL dextrose 5%; followed by a bolus 5-fluorouracil \[FU\] 400 mg/m\^2 and a 46-hour infusion 5-FU 2400 mg/m\^2) at conventional doses on days 1 and 15 of the same 28 day cycle.	Total n=16 Participants Total of all reporting groups
Age, Continuous	62.3 Years STANDARD_DEVIATION 12.0 • n=5 Participants	60.4 Years STANDARD_DEVIATION 17.2 • n=7 Participants	61.6 Years STANDARD_DEVIATION 13.7 • n=5 Participants
Sex: Female, Male Female	5 Participants n=5 Participants	2 Participants n=7 Participants	7 Participants n=5 Participants
Sex: Female, Male Male	5 Participants n=5 Participants	4 Participants n=7 Participants	9 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline up to Day 28 (Part 1)

Population: The safety analysis set included all subjects who received at least one (non-zero) administration of the trial medication (any of the 3 FOLFIRI drugs and pimasertib).

MTD was defined as the dose level, at which the treatment-related dose limiting toxicity (DLT) occurred in >1 of 3 subjects or in >1 of 6 subjects. DLT was defined using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Any Grade >=3 non-hematological toxicity except for Grade 4 asymptomatic increases in liver function tests (LFTs) reversible within 7 days in subjects with liver involvement, Grade 3 asymptomatic increases in LFTs reversible within 7 days in subjects without liver involvement, Grade 3 vomiting controlled with adequate and optimal therapy and prophylaxis, and Grade 3 diarrhea controlled with adequate and optimal anti-diarrhea therapy; any Grade 4 neutropenia lasing >5 days/ febrile neutropenia lasting >1 day; any Grade 4 thrombocytopenia/Grade 3 with bleeding; any treatment delay >2 weeks due to trial treatment-related adverse effects at any dose level and judged to be possibly or probably related to the trial treatment.

Outcome measures

Measure	Part 1 or Safety Run-in Part: Pimasertib 45 mg +FOLFIRI n=16 Participants Pimasertib was administered orally at a dose of 45 mg/day once daily on Days 1-5, 8-12, 15-19, and 22-26 of a 28 day cycle along with FOLFIRI (laevoleucovorin 200 mg/m\^2 i.v infusion over 90 minutes or leucovorin \[dl-leucovorin\] 400 mg/m\^2 i.v. infusion over 90 minutes; followed by irinotecan 180 mg/m\^2 given as a 90-minute infusion in 500 mL dextrose 5%; followed by a bolus 5-fluorouracil \[FU\] 400 mg/m\^2 and a 46-hour infusion 5-FU 2400 mg/m\^2) at conventional doses on days 1 and 15 of the same 28 day cycle.	Part 1 or Safety Run-in Part: Pimasertib 60 mg +FOLFIRI Pimasertib was administered orally at a dose of 60 mg/day once daily on Days 1-5, 8-12, 15-19, and 22-26 of a 28 day cycle along with FOLFIRI (laevoleucovorin 200 mg/m\^2 i.v infusion over 90 minutes or leucovorin \[dl-leucovorin\] 400 mg/m\^2 i.v. infusion over 90 minutes; followed by irinotecan 180 mg/m\^2 given as a 90-minute infusion in 500 mL dextrose 5%; followed by a bolus 5-fluorouracil \[FU\] 400 mg/m\^2 and a 46-hour infusion 5-FU 2400 mg/m\^2) at conventional doses on days 1 and 15 of the same 28 day cycle.
Part 1 or Safety Run-in Part: Maximum Tolerated Dose (MTD)	45 mg	—

PRIMARY outcome

Timeframe: From randomization up to first documented disease progression maximum up to 2 years

Population: Part 2 or Phase 2 Randomized Part of the trial was not conducted. Hence, PFS was not evaluated for this study.

PFS was defined as time (in months) from the date of randomization to the first documentation of disease progression as reported and documented by the Investigator (i.e. radiological progression per RECIST v1.0) or death for any cause.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: From the first dose of study drug administration up to 28 days after the last dose of study drug administration

Population: The safety analysis set included all subjects who received at least one (non-zero) administration of the trial medication (any of the 3 FOLFIRI drugs and pimasertib).

An AE is defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. An SAE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect. Treatment-emergent are events between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state.

Outcome measures

Measure	Part 1 or Safety Run-in Part: Pimasertib 45 mg +FOLFIRI n=10 Participants Pimasertib was administered orally at a dose of 45 mg/day once daily on Days 1-5, 8-12, 15-19, and 22-26 of a 28 day cycle along with FOLFIRI (laevoleucovorin 200 mg/m\^2 i.v infusion over 90 minutes or leucovorin \[dl-leucovorin\] 400 mg/m\^2 i.v. infusion over 90 minutes; followed by irinotecan 180 mg/m\^2 given as a 90-minute infusion in 500 mL dextrose 5%; followed by a bolus 5-fluorouracil \[FU\] 400 mg/m\^2 and a 46-hour infusion 5-FU 2400 mg/m\^2) at conventional doses on days 1 and 15 of the same 28 day cycle.	Part 1 or Safety Run-in Part: Pimasertib 60 mg +FOLFIRI n=6 Participants Pimasertib was administered orally at a dose of 60 mg/day once daily on Days 1-5, 8-12, 15-19, and 22-26 of a 28 day cycle along with FOLFIRI (laevoleucovorin 200 mg/m\^2 i.v infusion over 90 minutes or leucovorin \[dl-leucovorin\] 400 mg/m\^2 i.v. infusion over 90 minutes; followed by irinotecan 180 mg/m\^2 given as a 90-minute infusion in 500 mL dextrose 5%; followed by a bolus 5-fluorouracil \[FU\] 400 mg/m\^2 and a 46-hour infusion 5-FU 2400 mg/m\^2) at conventional doses on days 1 and 15 of the same 28 day cycle.
Part 1 or Safety Run-in Part: Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation and TEAEs Leading to Death TEAEs leading to death	0 Subjects	0 Subjects
Part 1 or Safety Run-in Part: Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation and TEAEs Leading to Death TEAE	10 Subjects	6 Subjects
Part 1 or Safety Run-in Part: Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation and TEAEs Leading to Death Serious TEAE	4 Subjects	4 Subjects
Part 1 or Safety Run-in Part: Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation and TEAEs Leading to Death TEAEs leading to discontinuation	6 Subjects	4 Subjects

SECONDARY outcome

Timeframe: Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38

Population: The pharmacokinetic (PK) evaluation set included subjects who had an evaluable plasma concentration-time profile on any of the PK sampling days (Day 1 or 8 or 15). "n" signifies number of subjects evaluable in each category, respectively.

Outcome measures

Measure	Part 1 or Safety Run-in Part: Pimasertib 45 mg +FOLFIRI n=10 Participants Pimasertib was administered orally at a dose of 45 mg/day once daily on Days 1-5, 8-12, 15-19, and 22-26 of a 28 day cycle along with FOLFIRI (laevoleucovorin 200 mg/m\^2 i.v infusion over 90 minutes or leucovorin \[dl-leucovorin\] 400 mg/m\^2 i.v. infusion over 90 minutes; followed by irinotecan 180 mg/m\^2 given as a 90-minute infusion in 500 mL dextrose 5%; followed by a bolus 5-fluorouracil \[FU\] 400 mg/m\^2 and a 46-hour infusion 5-FU 2400 mg/m\^2) at conventional doses on days 1 and 15 of the same 28 day cycle.	Part 1 or Safety Run-in Part: Pimasertib 60 mg +FOLFIRI n=6 Participants Pimasertib was administered orally at a dose of 60 mg/day once daily on Days 1-5, 8-12, 15-19, and 22-26 of a 28 day cycle along with FOLFIRI (laevoleucovorin 200 mg/m\^2 i.v infusion over 90 minutes or leucovorin \[dl-leucovorin\] 400 mg/m\^2 i.v. infusion over 90 minutes; followed by irinotecan 180 mg/m\^2 given as a 90-minute infusion in 500 mL dextrose 5%; followed by a bolus 5-fluorouracil \[FU\] 400 mg/m\^2 and a 46-hour infusion 5-FU 2400 mg/m\^2) at conventional doses on days 1 and 15 of the same 28 day cycle.
Part 1 or Safety Run-in Part: Maximum Observed Plasma Concentration (Cmax) of Pimasertib, Irinotecan and SN-38 Pimasertib: Day 1 (n=9, 6)	145 nanogram per milliliter (ng/mL) Interval 82.3 to 418.0	386 nanogram per milliliter (ng/mL) Interval 163.0 to 516.0
Part 1 or Safety Run-in Part: Maximum Observed Plasma Concentration (Cmax) of Pimasertib, Irinotecan and SN-38 Pimasertib: Day 8 (n=9, 6)	196 nanogram per milliliter (ng/mL) Interval 71.6 to 660.0	332 nanogram per milliliter (ng/mL) Interval 214.0 to 638.0
Part 1 or Safety Run-in Part: Maximum Observed Plasma Concentration (Cmax) of Pimasertib, Irinotecan and SN-38 Irinotecan: Day 1 (n=10, 6)	2070 nanogram per milliliter (ng/mL) Interval 1590.0 to 3060.0	1850 nanogram per milliliter (ng/mL) Interval 1230.0 to 2110.0
Part 1 or Safety Run-in Part: Maximum Observed Plasma Concentration (Cmax) of Pimasertib, Irinotecan and SN-38 Irinotecan: Day 15 (n=8, 6)	2120 nanogram per milliliter (ng/mL) Interval 1760.0 to 2840.0	1540 nanogram per milliliter (ng/mL) Interval 1330.0 to 2420.0
Part 1 or Safety Run-in Part: Maximum Observed Plasma Concentration (Cmax) of Pimasertib, Irinotecan and SN-38 SN-38: Day 1 (n=10, 6)	20.4 nanogram per milliliter (ng/mL) Interval 11.4 to 37.6	21.9 nanogram per milliliter (ng/mL) Interval 15.8 to 46.3
Part 1 or Safety Run-in Part: Maximum Observed Plasma Concentration (Cmax) of Pimasertib, Irinotecan and SN-38 SN-38: Day 15 (n=8, 6)	15.1 nanogram per milliliter (ng/mL) Interval 9.28 to 37.5	27 nanogram per milliliter (ng/mL) Interval 9.31 to 51.2

SECONDARY outcome

Timeframe: Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38

Population: The pharmacokinetic (PK) evaluation set included subjects who had an evaluable plasma concentration-time profile on any of the PK sampling days (Day 1 or 8 or 15). "n" signifies number of subjects evaluable in each category, respectively.

Outcome measures

Measure	Part 1 or Safety Run-in Part: Pimasertib 45 mg +FOLFIRI n=10 Participants Pimasertib was administered orally at a dose of 45 mg/day once daily on Days 1-5, 8-12, 15-19, and 22-26 of a 28 day cycle along with FOLFIRI (laevoleucovorin 200 mg/m\^2 i.v infusion over 90 minutes or leucovorin \[dl-leucovorin\] 400 mg/m\^2 i.v. infusion over 90 minutes; followed by irinotecan 180 mg/m\^2 given as a 90-minute infusion in 500 mL dextrose 5%; followed by a bolus 5-fluorouracil \[FU\] 400 mg/m\^2 and a 46-hour infusion 5-FU 2400 mg/m\^2) at conventional doses on days 1 and 15 of the same 28 day cycle.	Part 1 or Safety Run-in Part: Pimasertib 60 mg +FOLFIRI n=6 Participants Pimasertib was administered orally at a dose of 60 mg/day once daily on Days 1-5, 8-12, 15-19, and 22-26 of a 28 day cycle along with FOLFIRI (laevoleucovorin 200 mg/m\^2 i.v infusion over 90 minutes or leucovorin \[dl-leucovorin\] 400 mg/m\^2 i.v. infusion over 90 minutes; followed by irinotecan 180 mg/m\^2 given as a 90-minute infusion in 500 mL dextrose 5%; followed by a bolus 5-fluorouracil \[FU\] 400 mg/m\^2 and a 46-hour infusion 5-FU 2400 mg/m\^2) at conventional doses on days 1 and 15 of the same 28 day cycle.
Part 1 or Safety Run-in Part: Time to Reach Maximum Observed Concentration (Tmax) of Pimasertib, Irinotecan and SN-38 Pimasertib: Day 1 (n=9, 6)	2 hour Interval 1.0 to 6.0	0.79 hour Interval 0.5 to 4.0
Part 1 or Safety Run-in Part: Time to Reach Maximum Observed Concentration (Tmax) of Pimasertib, Irinotecan and SN-38 Pimasertib: Day 8 (n=9, 6)	1.5 hour Interval 0.53 to 2.0	1.25 hour Interval 0.5 to 2.5
Part 1 or Safety Run-in Part: Time to Reach Maximum Observed Concentration (Tmax) of Pimasertib, Irinotecan and SN-38 Irinotecan: Day 1 (n=10, 6)	1.5 hour Interval 1.25 to 2.5	1.5 hour Interval 1.5 to 2.5
Part 1 or Safety Run-in Part: Time to Reach Maximum Observed Concentration (Tmax) of Pimasertib, Irinotecan and SN-38 Irinotecan: Day 15 (n=8, 6)	1.54 hour Interval 1.5 to 2.5	1.56 hour Interval 1.5 to 4.0
Part 1 or Safety Run-in Part: Time to Reach Maximum Observed Concentration (Tmax) of Pimasertib, Irinotecan and SN-38 SN-38: Day 1 (n=10, 6)	1.5 hour Interval 1.5 to 2.25	1.5 hour Interval 1.5 to 4.0
Part 1 or Safety Run-in Part: Time to Reach Maximum Observed Concentration (Tmax) of Pimasertib, Irinotecan and SN-38 SN-38: Day 15 (n=8, 6)	1.6 hour Interval 1.5 to 2.5	2.5 hour Interval 1.5 to 4.33

SECONDARY outcome

Timeframe: Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38

Population: The pharmacokinetic (PK) evaluation set included subjects who had an evaluable plasma concentration-time profile on any of the PK sampling days (Day 1 or 8 or 15). "n" signifies number of subjects evaluable in each category, respectively.

Area under the plasma concentration-time curve from time zero to the last sampling time (AUC0-t) at which the concentration is at or above the lower limit of quantification.

Outcome measures

Measure	Part 1 or Safety Run-in Part: Pimasertib 45 mg +FOLFIRI n=10 Participants Pimasertib was administered orally at a dose of 45 mg/day once daily on Days 1-5, 8-12, 15-19, and 22-26 of a 28 day cycle along with FOLFIRI (laevoleucovorin 200 mg/m\^2 i.v infusion over 90 minutes or leucovorin \[dl-leucovorin\] 400 mg/m\^2 i.v. infusion over 90 minutes; followed by irinotecan 180 mg/m\^2 given as a 90-minute infusion in 500 mL dextrose 5%; followed by a bolus 5-fluorouracil \[FU\] 400 mg/m\^2 and a 46-hour infusion 5-FU 2400 mg/m\^2) at conventional doses on days 1 and 15 of the same 28 day cycle.	Part 1 or Safety Run-in Part: Pimasertib 60 mg +FOLFIRI n=6 Participants Pimasertib was administered orally at a dose of 60 mg/day once daily on Days 1-5, 8-12, 15-19, and 22-26 of a 28 day cycle along with FOLFIRI (laevoleucovorin 200 mg/m\^2 i.v infusion over 90 minutes or leucovorin \[dl-leucovorin\] 400 mg/m\^2 i.v. infusion over 90 minutes; followed by irinotecan 180 mg/m\^2 given as a 90-minute infusion in 500 mL dextrose 5%; followed by a bolus 5-fluorouracil \[FU\] 400 mg/m\^2 and a 46-hour infusion 5-FU 2400 mg/m\^2) at conventional doses on days 1 and 15 of the same 28 day cycle.
Part 1 or Safety Run-in Part: Area Under the Concentration-time Curve From Time Zero to the Time of Last Observation (AUC0-t) of Pimasertib, Irinotecan and SN-38 Pimasertib: Day 1 (n=9, 5)	1120 (nanogram/milliliter)*hour([ng/mL]*hour) Interval 194.0 to 1860.0	1390 (nanogram/milliliter)*hour([ng/mL]*hour) Interval 666.0 to 2190.0
Part 1 or Safety Run-in Part: Area Under the Concentration-time Curve From Time Zero to the Time of Last Observation (AUC0-t) of Pimasertib, Irinotecan and SN-38 Pimasertib: Day 8 (n=8, 5)	1270 (nanogram/milliliter)*hour([ng/mL]*hour) Interval 190.0 to 2030.0	1260 (nanogram/milliliter)*hour([ng/mL]*hour) Interval 858.0 to 2060.0
Part 1 or Safety Run-in Part: Area Under the Concentration-time Curve From Time Zero to the Time of Last Observation (AUC0-t) of Pimasertib, Irinotecan and SN-38 Irinotecan: Day 1 (n=10, 6)	10500 (nanogram/milliliter)*hour([ng/mL]*hour) Interval 7130.0 to 18500.0	10200 (nanogram/milliliter)*hour([ng/mL]*hour) Interval 6220.0 to 11300.0
Part 1 or Safety Run-in Part: Area Under the Concentration-time Curve From Time Zero to the Time of Last Observation (AUC0-t) of Pimasertib, Irinotecan and SN-38 Irinotecan: Day 15 (n=8, 6)	12700 (nanogram/milliliter)*hour([ng/mL]*hour) Interval 7040.0 to 17900.0	11400 (nanogram/milliliter)*hour([ng/mL]*hour) Interval 7050.0 to 13400.0
Part 1 or Safety Run-in Part: Area Under the Concentration-time Curve From Time Zero to the Time of Last Observation (AUC0-t) of Pimasertib, Irinotecan and SN-38 SN-38: Day 1 (n=10, 6)	10500 (nanogram/milliliter)*hour([ng/mL]*hour) Interval 7130.0 to 18500.0	10200 (nanogram/milliliter)*hour([ng/mL]*hour) Interval 6220.0 to 11300.0
Part 1 or Safety Run-in Part: Area Under the Concentration-time Curve From Time Zero to the Time of Last Observation (AUC0-t) of Pimasertib, Irinotecan and SN-38 SN-38: Day 15 (n=8, 6)	12700 (nanogram/milliliter)*hour([ng/mL]*hour) Interval 7040.0 to 17900.0	11400 (nanogram/milliliter)*hour([ng/mL]*hour) Interval 7050.0 to 13400.0

SECONDARY outcome

Timeframe: Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38

Population: The PK analysis population set included all subjects who had an evaluable plasma concentration-time profile on any of the PK sampling days (Day 1 or 8 or 15). Here, N (total number of subjects analyzed) signifies number of evaluable subjects for this outcome measure. "n" signifies number of subjects evaluable per each category, respectively.

The AUC(0-inf) of pimasertib and irinotecan was estimated by determining the total area under the concentration time curve extrapolated to infinity.

Outcome measures

Measure	Part 1 or Safety Run-in Part: Pimasertib 45 mg +FOLFIRI n=9 Participants Pimasertib was administered orally at a dose of 45 mg/day once daily on Days 1-5, 8-12, 15-19, and 22-26 of a 28 day cycle along with FOLFIRI (laevoleucovorin 200 mg/m\^2 i.v infusion over 90 minutes or leucovorin \[dl-leucovorin\] 400 mg/m\^2 i.v. infusion over 90 minutes; followed by irinotecan 180 mg/m\^2 given as a 90-minute infusion in 500 mL dextrose 5%; followed by a bolus 5-fluorouracil \[FU\] 400 mg/m\^2 and a 46-hour infusion 5-FU 2400 mg/m\^2) at conventional doses on days 1 and 15 of the same 28 day cycle.	Part 1 or Safety Run-in Part: Pimasertib 60 mg +FOLFIRI n=6 Participants Pimasertib was administered orally at a dose of 60 mg/day once daily on Days 1-5, 8-12, 15-19, and 22-26 of a 28 day cycle along with FOLFIRI (laevoleucovorin 200 mg/m\^2 i.v infusion over 90 minutes or leucovorin \[dl-leucovorin\] 400 mg/m\^2 i.v. infusion over 90 minutes; followed by irinotecan 180 mg/m\^2 given as a 90-minute infusion in 500 mL dextrose 5%; followed by a bolus 5-fluorouracil \[FU\] 400 mg/m\^2 and a 46-hour infusion 5-FU 2400 mg/m\^2) at conventional doses on days 1 and 15 of the same 28 day cycle.
Part 1 or Safety Run-in Part: Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Pimasertib, Irinotecan and SN-38 Pimasertib: Day 1 (n=7, 5)	1160 ng/mL*hour Interval 226.0 to 1950.0	1430 ng/mL*hour Interval 673.0 to 2310.0
Part 1 or Safety Run-in Part: Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Pimasertib, Irinotecan and SN-38 Pimasertib: Day 8 (n=8, 5)	1340 ng/mL*hour Interval 244.0 to 2140.0	1340 ng/mL*hour Interval 869.0 to 2170.0
Part 1 or Safety Run-in Part: Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Pimasertib, Irinotecan and SN-38 Irinotecan: Day 1 (n=9, 6)	10600 ng/mL*hour Interval 7650.0 to 20600.0	11200 ng/mL*hour Interval 6560.0 to 12500.0
Part 1 or Safety Run-in Part: Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Pimasertib, Irinotecan and SN-38 Irinotecan: Day 15 (n=8, 6)	13600 ng/mL*hour Interval 7330.0 to 20400.0	12300 ng/mL*hour Interval 7520.0 to 14500.0
Part 1 or Safety Run-in Part: Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Pimasertib, Irinotecan and SN-38 SN-38: Day 1 (n=9, 6)	10600 ng/mL*hour Interval 7650.0 to 20600.0	11200 ng/mL*hour Interval 6560.0 to 12500.0
Part 1 or Safety Run-in Part: Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Pimasertib, Irinotecan and SN-38 SN-38: Day 15 (n=8, 6)	13600 ng/mL*hour Interval 7330.0 to 20400.0	12300 ng/mL*hour Interval 7520.0 to 14500.0

SECONDARY outcome

Timeframe: Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38

Population: The PK analysis population set included all subjects who had an evaluable plasma concentration-time profile on any of the PK sampling days (Day 1 or 8 or 15). Here, N (total number of subjects analyzed) signifies number of evaluable subjects for this outcome measure. "n" signifies number of subjects evaluable per each category, respectively.

The t1/2 was defined as the time required for the plasma concentration of pimasertib and irinotecan to decrease 50% in the final stage of elimination.

Outcome measures

Measure	Part 1 or Safety Run-in Part: Pimasertib 45 mg +FOLFIRI n=9 Participants Pimasertib was administered orally at a dose of 45 mg/day once daily on Days 1-5, 8-12, 15-19, and 22-26 of a 28 day cycle along with FOLFIRI (laevoleucovorin 200 mg/m\^2 i.v infusion over 90 minutes or leucovorin \[dl-leucovorin\] 400 mg/m\^2 i.v. infusion over 90 minutes; followed by irinotecan 180 mg/m\^2 given as a 90-minute infusion in 500 mL dextrose 5%; followed by a bolus 5-fluorouracil \[FU\] 400 mg/m\^2 and a 46-hour infusion 5-FU 2400 mg/m\^2) at conventional doses on days 1 and 15 of the same 28 day cycle.	Part 1 or Safety Run-in Part: Pimasertib 60 mg +FOLFIRI n=6 Participants Pimasertib was administered orally at a dose of 60 mg/day once daily on Days 1-5, 8-12, 15-19, and 22-26 of a 28 day cycle along with FOLFIRI (laevoleucovorin 200 mg/m\^2 i.v infusion over 90 minutes or leucovorin \[dl-leucovorin\] 400 mg/m\^2 i.v. infusion over 90 minutes; followed by irinotecan 180 mg/m\^2 given as a 90-minute infusion in 500 mL dextrose 5%; followed by a bolus 5-fluorouracil \[FU\] 400 mg/m\^2 and a 46-hour infusion 5-FU 2400 mg/m\^2) at conventional doses on days 1 and 15 of the same 28 day cycle.
Part 1 or Safety Run-in Part: Apparent Terminal Half Life (t1/2) of Pimasertib, Irinotecan and SN-38 Pimasertib: Day 1 (n=7, 5)	5.31 hour Interval 2.37 to 5.97	5.56 hour Interval 3.53 to 6.56
Part 1 or Safety Run-in Part: Apparent Terminal Half Life (t1/2) of Pimasertib, Irinotecan and SN-38 Pimasertib: Day 8 (n=8, 5)	5.12 hour Interval 3.88 to 7.27	5.08 hour Interval 4.27 to 6.25
Part 1 or Safety Run-in Part: Apparent Terminal Half Life (t1/2) of Pimasertib, Irinotecan and SN-38 Irinotecan: Day 1 (n=9, 6)	6.43 hour Interval 5.32 to 7.63	6.83 hour Interval 5.46 to 7.85
Part 1 or Safety Run-in Part: Apparent Terminal Half Life (t1/2) of Pimasertib, Irinotecan and SN-38 Irinotecan: Day 15 (n=8, 6)	6.21 hour Interval 5.54 to 8.77	6.45 hour Interval 5.59 to 7.21
Part 1 or Safety Run-in Part: Apparent Terminal Half Life (t1/2) of Pimasertib, Irinotecan and SN-38 SN-38: Day 1 (n=9, 6)	6.43 hour Interval 5.32 to 7.63	6.83 hour Interval 5.46 to 7.85
Part 1 or Safety Run-in Part: Apparent Terminal Half Life (t1/2) of Pimasertib, Irinotecan and SN-38 SN-38: Day 15 (n=8, 6)	6.21 hour Interval 5.54 to 8.77	6.45 hour Interval 5.59 to 7.21

SECONDARY outcome

Timeframe: Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38

Population: The PK analysis population set included all subjects who had an evaluable plasma concentration-time profile on any of the PK sampling days (Day 1 or 8 or 15). Here, N (total number of subjects analyzed) signifies number of evaluable subjects for this outcome measure. "n" signifies number of subjects evaluable per each category, respectively.

Clearance of a drug was a measure of the rate at which drug was metabolized or eliminated by normal biological processes. Apparent clearance after oral dose (CL/f) is influenced by the fraction absorbed.

Outcome measures

Measure	Part 1 or Safety Run-in Part: Pimasertib 45 mg +FOLFIRI n=9 Participants Pimasertib was administered orally at a dose of 45 mg/day once daily on Days 1-5, 8-12, 15-19, and 22-26 of a 28 day cycle along with FOLFIRI (laevoleucovorin 200 mg/m\^2 i.v infusion over 90 minutes or leucovorin \[dl-leucovorin\] 400 mg/m\^2 i.v. infusion over 90 minutes; followed by irinotecan 180 mg/m\^2 given as a 90-minute infusion in 500 mL dextrose 5%; followed by a bolus 5-fluorouracil \[FU\] 400 mg/m\^2 and a 46-hour infusion 5-FU 2400 mg/m\^2) at conventional doses on days 1 and 15 of the same 28 day cycle.	Part 1 or Safety Run-in Part: Pimasertib 60 mg +FOLFIRI n=6 Participants Pimasertib was administered orally at a dose of 60 mg/day once daily on Days 1-5, 8-12, 15-19, and 22-26 of a 28 day cycle along with FOLFIRI (laevoleucovorin 200 mg/m\^2 i.v infusion over 90 minutes or leucovorin \[dl-leucovorin\] 400 mg/m\^2 i.v. infusion over 90 minutes; followed by irinotecan 180 mg/m\^2 given as a 90-minute infusion in 500 mL dextrose 5%; followed by a bolus 5-fluorouracil \[FU\] 400 mg/m\^2 and a 46-hour infusion 5-FU 2400 mg/m\^2) at conventional doses on days 1 and 15 of the same 28 day cycle.
Part 1 or Safety Run-in Part: Apparent Oral Clearance (CL/f) of Pimasertib, (CL) Irinotecan and SN-38 Pimasertib: Day 1 (n=7, 5)	38.7 Liter per hour Interval 23.1 to 199.0	42.1 Liter per hour Interval 25.9 to 89.1
Part 1 or Safety Run-in Part: Apparent Oral Clearance (CL/f) of Pimasertib, (CL) Irinotecan and SN-38 Pimasertib: Day 8 (n=8, 5)	34.2 Liter per hour Interval 21.0 to 184.0	44.6 Liter per hour Interval 27.6 to 69.1
Part 1 or Safety Run-in Part: Apparent Oral Clearance (CL/f) of Pimasertib, (CL) Irinotecan and SN-38 Irinotecan: Day 1 (n=9, 6)	29.4 Liter per hour Interval 16.4 to 47.0	29.7 Liter per hour Interval 25.9 to 42.7
Part 1 or Safety Run-in Part: Apparent Oral Clearance (CL/f) of Pimasertib, (CL) Irinotecan and SN-38 Irinotecan: Day 15 (n=8, 6)	23.5 Liter per hour Interval 15.6 to 46.8	26.2 Liter per hour Interval 20.9 to 37.3
Part 1 or Safety Run-in Part: Apparent Oral Clearance (CL/f) of Pimasertib, (CL) Irinotecan and SN-38 SN-38: Day 1 (n=9, 6)	29.4 Liter per hour Interval 16.4 to 47.0	29.7 Liter per hour Interval 25.9 to 42.7
Part 1 or Safety Run-in Part: Apparent Oral Clearance (CL/f) of Pimasertib, (CL) Irinotecan and SN-38 SN-38: Day 15 (n=8, 6)	23.5 Liter per hour Interval 15.6 to 46.8	26.2 Liter per hour Interval 20.9 to 37.3

SECONDARY outcome

Timeframe: Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38

Population: The PK analysis population set included all subjects who had an evaluable plasma concentration-time profile on any of the PK sampling days (Day 1 or 8 or 15). Here, N (total number of subjects analyzed) signifies number of evaluable subjects for this outcome measure. "n" signifies number of subjects evaluable per each category, respectively.

Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired serum concentration. Apparent volume of distribution after oral dose (Vz/f) was influenced by the fraction absorbed.

Outcome measures

Measure	Part 1 or Safety Run-in Part: Pimasertib 45 mg +FOLFIRI n=9 Participants Pimasertib was administered orally at a dose of 45 mg/day once daily on Days 1-5, 8-12, 15-19, and 22-26 of a 28 day cycle along with FOLFIRI (laevoleucovorin 200 mg/m\^2 i.v infusion over 90 minutes or leucovorin \[dl-leucovorin\] 400 mg/m\^2 i.v. infusion over 90 minutes; followed by irinotecan 180 mg/m\^2 given as a 90-minute infusion in 500 mL dextrose 5%; followed by a bolus 5-fluorouracil \[FU\] 400 mg/m\^2 and a 46-hour infusion 5-FU 2400 mg/m\^2) at conventional doses on days 1 and 15 of the same 28 day cycle.	Part 1 or Safety Run-in Part: Pimasertib 60 mg +FOLFIRI n=6 Participants Pimasertib was administered orally at a dose of 60 mg/day once daily on Days 1-5, 8-12, 15-19, and 22-26 of a 28 day cycle along with FOLFIRI (laevoleucovorin 200 mg/m\^2 i.v infusion over 90 minutes or leucovorin \[dl-leucovorin\] 400 mg/m\^2 i.v. infusion over 90 minutes; followed by irinotecan 180 mg/m\^2 given as a 90-minute infusion in 500 mL dextrose 5%; followed by a bolus 5-fluorouracil \[FU\] 400 mg/m\^2 and a 46-hour infusion 5-FU 2400 mg/m\^2) at conventional doses on days 1 and 15 of the same 28 day cycle.
Part 1 or Safety Run-in Part: Apparent Oral Volume of Distribution (Vz f) Pimasertib, (Vz) of Irinotecan and SN-38 Pimasertib: Day 1 (n=7, 5)	276 Liter Interval 197.0 to 680.0	348 Liter Interval 210.0 to 570.0
Part 1 or Safety Run-in Part: Apparent Oral Volume of Distribution (Vz f) Pimasertib, (Vz) of Irinotecan and SN-38 Pimasertib: Day 8 (n=8, 5)	265 Liter Interval 189.0 to 1030.0	395 Liter Interval 246.0 to 425.0
Part 1 or Safety Run-in Part: Apparent Oral Volume of Distribution (Vz f) Pimasertib, (Vz) of Irinotecan and SN-38 Irinotecan: Day 1 (n=9, 6)	297 Liter Interval 147.0 to 455.0	313 Liter Interval 241.0 to 395.0
Part 1 or Safety Run-in Part: Apparent Oral Volume of Distribution (Vz f) Pimasertib, (Vz) of Irinotecan and SN-38 Irinotecan: Day 15 (n=8, 6)	212 Liter Interval 143.0 to 382.0	253 Liter Interval 182.0 to 336.0
Part 1 or Safety Run-in Part: Apparent Oral Volume of Distribution (Vz f) Pimasertib, (Vz) of Irinotecan and SN-38 SN-38: Day 1 (n=9, 6)	297 Liter Interval 147.0 to 455.0	313 Liter Interval 241.0 to 395.0
Part 1 or Safety Run-in Part: Apparent Oral Volume of Distribution (Vz f) Pimasertib, (Vz) of Irinotecan and SN-38 SN-38: Day 15 (n=8, 6)	212 Liter Interval 143.0 to 382.0	253 Liter Interval 182.0 to 336.0

SECONDARY outcome

Timeframe: Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan and SN-38

Population: The PK analysis population set included all subjects who had an evaluable plasma concentration-time profile on any of the PK sampling days (Day 1 or 8 or 15). Here, N (total number of subjects analyzed) signifies number of evaluable subjects for this outcome measure. "n" signifies number of subjects evaluable per each category, respectively.

Outcome measures

Measure	Part 1 or Safety Run-in Part: Pimasertib 45 mg +FOLFIRI n=8 Participants Pimasertib was administered orally at a dose of 45 mg/day once daily on Days 1-5, 8-12, 15-19, and 22-26 of a 28 day cycle along with FOLFIRI (laevoleucovorin 200 mg/m\^2 i.v infusion over 90 minutes or leucovorin \[dl-leucovorin\] 400 mg/m\^2 i.v. infusion over 90 minutes; followed by irinotecan 180 mg/m\^2 given as a 90-minute infusion in 500 mL dextrose 5%; followed by a bolus 5-fluorouracil \[FU\] 400 mg/m\^2 and a 46-hour infusion 5-FU 2400 mg/m\^2) at conventional doses on days 1 and 15 of the same 28 day cycle.	Part 1 or Safety Run-in Part: Pimasertib 60 mg +FOLFIRI n=6 Participants Pimasertib was administered orally at a dose of 60 mg/day once daily on Days 1-5, 8-12, 15-19, and 22-26 of a 28 day cycle along with FOLFIRI (laevoleucovorin 200 mg/m\^2 i.v infusion over 90 minutes or leucovorin \[dl-leucovorin\] 400 mg/m\^2 i.v. infusion over 90 minutes; followed by irinotecan 180 mg/m\^2 given as a 90-minute infusion in 500 mL dextrose 5%; followed by a bolus 5-fluorouracil \[FU\] 400 mg/m\^2 and a 46-hour infusion 5-FU 2400 mg/m\^2) at conventional doses on days 1 and 15 of the same 28 day cycle.
Part 1 or Safety Run-in Part: Ratio of Cmax for Pimasertib (Day 1/Day 8), Irinotecan and SN-38 (Day 1/Day 15) Pimasertib (n=8, 5)	0.837 Ratio of Cmax Interval 0.345 to 1.18	0.751 Ratio of Cmax Interval 0.359 to 2.22
Part 1 or Safety Run-in Part: Ratio of Cmax for Pimasertib (Day 1/Day 8), Irinotecan and SN-38 (Day 1/Day 15) Irinotecan (n=8, 6)	0.973 Ratio of Cmax Interval 0.623 to 1.13	1.09 Ratio of Cmax Interval 0.774 to 1.4
Part 1 or Safety Run-in Part: Ratio of Cmax for Pimasertib (Day 1/Day 8), Irinotecan and SN-38 (Day 1/Day 15) SN-38 (n=8, 6)	0.973 Ratio of Cmax Interval 0.623 to 1.13	1.09 Ratio of Cmax Interval 0.774 to 1.4

SECONDARY outcome

Timeframe: Day 1 and Day 8 for pimasertib; Day 1 and Day 15 for Irinotecan

Population: The PK analysis population set included all subjects who had an evaluable plasma concentration-time profile on any of the PK sampling days (Day 1 or 8 or 15). Here, N (total number of subjects analyzed) signifies number of evaluable subjects for this outcome measure. "n" signifies number of subjects evaluable per each category, respectively.

The AUC(0-inf) was estimated by determining the total area under the concentration time curve extrapolated to infinity.

Outcome measures

Measure	Part 1 or Safety Run-in Part: Pimasertib 45 mg +FOLFIRI n=8 Participants Pimasertib was administered orally at a dose of 45 mg/day once daily on Days 1-5, 8-12, 15-19, and 22-26 of a 28 day cycle along with FOLFIRI (laevoleucovorin 200 mg/m\^2 i.v infusion over 90 minutes or leucovorin \[dl-leucovorin\] 400 mg/m\^2 i.v. infusion over 90 minutes; followed by irinotecan 180 mg/m\^2 given as a 90-minute infusion in 500 mL dextrose 5%; followed by a bolus 5-fluorouracil \[FU\] 400 mg/m\^2 and a 46-hour infusion 5-FU 2400 mg/m\^2) at conventional doses on days 1 and 15 of the same 28 day cycle.	Part 1 or Safety Run-in Part: Pimasertib 60 mg +FOLFIRI n=6 Participants Pimasertib was administered orally at a dose of 60 mg/day once daily on Days 1-5, 8-12, 15-19, and 22-26 of a 28 day cycle along with FOLFIRI (laevoleucovorin 200 mg/m\^2 i.v infusion over 90 minutes or leucovorin \[dl-leucovorin\] 400 mg/m\^2 i.v. infusion over 90 minutes; followed by irinotecan 180 mg/m\^2 given as a 90-minute infusion in 500 mL dextrose 5%; followed by a bolus 5-fluorouracil \[FU\] 400 mg/m\^2 and a 46-hour infusion 5-FU 2400 mg/m\^2) at conventional doses on days 1 and 15 of the same 28 day cycle.
Part 1 or Safety Run-in Part: Ratio of AUC0-inf of Pimasertib (Day 1/Day 8), Irinotecan and SN-38 (Day 1/Day 15) Pimasertib (n=7, 4)	0.917 Ratio Interval 0.738 to 1.22	0.825 Ratio Interval 0.759 to 1.21
Part 1 or Safety Run-in Part: Ratio of AUC0-inf of Pimasertib (Day 1/Day 8), Irinotecan and SN-38 (Day 1/Day 15) Irinotecan (n=8, 6)	0.911 Ratio Interval 0.577 to 1.08	0.844 Ratio Interval 0.697 to 1.17
Part 1 or Safety Run-in Part: Ratio of AUC0-inf of Pimasertib (Day 1/Day 8), Irinotecan and SN-38 (Day 1/Day 15) SN-38 (n=8, 6)	0.911 Ratio Interval 0.577 to 1.08	0.844 Ratio Interval 0.697 to 1.17

SECONDARY outcome

Timeframe: Up to 2 years

Population: The efficacy analysis set included all subjects who received at least 1 trial drug dose (any of the three FOLFIRI drugs and pimasertib) and had a baseline tumor assessment and at least 1 post-baseline efficacy assessment.

BOR was defined based on Response Evaluation Criteria in Solid Tumors Version 1.0 (RECIST V1.0) as following: Complete response (CR) was defined as the disappearance of all target and non-target lesions and no appearance of new lesions. Partial response (PR) was defined as at least a 30 percent (%) decrease in the sum of the longest diameters (SLD) of the targeted lesions. CR and PR had to be documented on 2 occasions separated by at least 4 weeks (28 days). Stable disease (SD) was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify as progressive disease (PD) being demonstrated during the first 4 weeks. PD was defined as at least a 20% increase in the SLD of target lesions compared to the smallest SLD since the study treatment started.

Outcome measures

Measure	Part 1 or Safety Run-in Part: Pimasertib 45 mg +FOLFIRI n=9 Participants Pimasertib was administered orally at a dose of 45 mg/day once daily on Days 1-5, 8-12, 15-19, and 22-26 of a 28 day cycle along with FOLFIRI (laevoleucovorin 200 mg/m\^2 i.v infusion over 90 minutes or leucovorin \[dl-leucovorin\] 400 mg/m\^2 i.v. infusion over 90 minutes; followed by irinotecan 180 mg/m\^2 given as a 90-minute infusion in 500 mL dextrose 5%; followed by a bolus 5-fluorouracil \[FU\] 400 mg/m\^2 and a 46-hour infusion 5-FU 2400 mg/m\^2) at conventional doses on days 1 and 15 of the same 28 day cycle.	Part 1 or Safety Run-in Part: Pimasertib 60 mg +FOLFIRI n=6 Participants Pimasertib was administered orally at a dose of 60 mg/day once daily on Days 1-5, 8-12, 15-19, and 22-26 of a 28 day cycle along with FOLFIRI (laevoleucovorin 200 mg/m\^2 i.v infusion over 90 minutes or leucovorin \[dl-leucovorin\] 400 mg/m\^2 i.v. infusion over 90 minutes; followed by irinotecan 180 mg/m\^2 given as a 90-minute infusion in 500 mL dextrose 5%; followed by a bolus 5-fluorouracil \[FU\] 400 mg/m\^2 and a 46-hour infusion 5-FU 2400 mg/m\^2) at conventional doses on days 1 and 15 of the same 28 day cycle.
Part 1 or Safety Run-in Part: Number of Subjects With Best Overall Response (BOR) CR	0 Subjects	0 Subjects
Part 1 or Safety Run-in Part: Number of Subjects With Best Overall Response (BOR) PR	1 Subjects	1 Subjects
Part 1 or Safety Run-in Part: Number of Subjects With Best Overall Response (BOR) SD	6 Subjects	3 Subjects
Part 1 or Safety Run-in Part: Number of Subjects With Best Overall Response (BOR) PD	1 Subjects	2 Subjects
Part 1 or Safety Run-in Part: Number of Subjects With Best Overall Response (BOR) Not evaluable	1 Subjects	0 Subjects

SECONDARY outcome

Timeframe: Predose, Day 1, 2 and 16 of cycle 1 followed by Day 1 pre-dose of every second cycle up to 2 years

Population: Number of subjects enrolled in the safety run-in part of the trial was less and it would not provide sufficient statistical power to perform any analysis. Hence, the biomarker samples were not analyzed as part of the trial.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Predose, Day 1, 2 and 16 of cycle 1 followed by Day 1 pre-dose of every second cycle up to 2 years

Population: Part 2 or Phase 2 Randomized Part of the trial was not conducted. Hence, circulating biomarkers were not evaluated.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Up to 2 years

Population: Part 2 or Phase 2 Randomized Part of the trial was not conducted. Hence, Best overall response was not evaluated.

BOR was defined based on Response Evaluation Criteria In Solid Tumors Version 1.0 (RECIST V1.0) as following: Complete response (CR) was defined as the disappearance of all target and non-target lesions and no appearance of new lesions. Partial response (PR) was defined as at least a 30 percent (%) decrease in the sum of the longest diameters (SLD) of the targeted lesions. CR and PR had to be documented on 2 occasions separated by at least 4 weeks (28 days). Stable disease (SD) was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify as progressive disease (PD) being demonstrated during the first 4 weeks. PD was defined as at least a 20% increase in the SLD of target lesions compared to the smallest SLD since the study treatment started.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: From the first dose of study drug administration up to 28 days after the last dose of study drug administration

Population: Part 2 or Phase 2 Randomized Part of the trial was not conducted. Hence, safety outcome measure could not be performed.

An AE is defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. An SAE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect. TEAES between first dose of study drug administration and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state.

Outcome measures

Outcome data not reported

Adverse Events

Part 1 or Safety Run-in Part: Pimasertib 45 mg +FOLFIRI

Serious events: 4 serious events

Other events: 10 other events

Deaths: 0 deaths

Part 1 or Safety Run-in Part: Pimasertib 60 mg +FOLFIRI

Serious events: 4 serious events

Other events: 6 other events

Deaths: 0 deaths

Serious adverse events

Measure	Part 1 or Safety Run-in Part: Pimasertib 45 mg +FOLFIRI n=10 participants at risk Pimasertib was administered orally at a dose of 45 mg/day once daily on Days 1-5, 8-12, 15-19, and 22-26 of a 28 day cycle along with FOLFIRI (laevoleucovorin 200 mg/m\^2 i.v infusion over 90 minutes or leucovorin \[dl-leucovorin\] 400 mg/m\^2 i.v. infusion over 90 minutes; followed by irinotecan 180 mg/m\^2 given as a 90-minute infusion in 500 mL dextrose 5%; followed by a bolus 5-fluorouracil \[FU\] 400 mg/m\^2 and a 46-hour infusion 5-FU 2400 mg/m\^2) at conventional doses on days 1 and 15 of the same 28 day cycle.	Part 1 or Safety Run-in Part: Pimasertib 60 mg +FOLFIRI n=6 participants at risk Pimasertib was administered orally at a dose of 60 mg/day once daily on Days 1-5, 8-12, 15-19, and 22-26 of a 28 day cycle along with FOLFIRI (laevoleucovorin 200 mg/m\^2 i.v infusion over 90 minutes or leucovorin \[dl-leucovorin\] 400 mg/m\^2 i.v. infusion over 90 minutes; followed by irinotecan 180 mg/m\^2 given as a 90-minute infusion in 500 mL dextrose 5%; followed by a bolus 5-fluorouracil \[FU\] 400 mg/m\^2 and a 46-hour infusion 5-FU 2400 mg/m\^2) at conventional doses on days 1 and 15 of the same 28 day cycle.
Gastrointestinal disorders Diarrhoea	10.0% 1/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	0.00% 0/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Gastrointestinal disorders Enteritis	0.00% 0/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	16.7% 1/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Gastrointestinal disorders Intestinal obstruction	10.0% 1/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	0.00% 0/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Gastrointestinal disorders Vomiting	10.0% 1/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	0.00% 0/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
General disorders Mucosal inflammation	0.00% 0/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	33.3% 2/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
General disorders Asthenia	10.0% 1/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	0.00% 0/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
General disorders General physical health deterioration	0.00% 0/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	16.7% 1/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
General disorders Pyrexia	0.00% 0/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	16.7% 1/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Cardiac disorders Cardiomyopathy	10.0% 1/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	0.00% 0/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Infections and infestations Perirectal abscess	10.0% 1/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	0.00% 0/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Investigations Electrocardiogram QT prolonged	10.0% 1/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	0.00% 0/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Metabolism and nutrition disorders Dehydration	10.0% 1/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	0.00% 0/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Nervous system disorders Memory impairment	0.00% 0/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	16.7% 1/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Renal and urinary disorders Nephrolithiasis	10.0% 1/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	0.00% 0/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	10.0% 1/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	0.00% 0/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Vascular disorders Deep vein thrombosis	10.0% 1/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	0.00% 0/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.

Other adverse events

Measure	Part 1 or Safety Run-in Part: Pimasertib 45 mg +FOLFIRI n=10 participants at risk Pimasertib was administered orally at a dose of 45 mg/day once daily on Days 1-5, 8-12, 15-19, and 22-26 of a 28 day cycle along with FOLFIRI (laevoleucovorin 200 mg/m\^2 i.v infusion over 90 minutes or leucovorin \[dl-leucovorin\] 400 mg/m\^2 i.v. infusion over 90 minutes; followed by irinotecan 180 mg/m\^2 given as a 90-minute infusion in 500 mL dextrose 5%; followed by a bolus 5-fluorouracil \[FU\] 400 mg/m\^2 and a 46-hour infusion 5-FU 2400 mg/m\^2) at conventional doses on days 1 and 15 of the same 28 day cycle.	Part 1 or Safety Run-in Part: Pimasertib 60 mg +FOLFIRI n=6 participants at risk Pimasertib was administered orally at a dose of 60 mg/day once daily on Days 1-5, 8-12, 15-19, and 22-26 of a 28 day cycle along with FOLFIRI (laevoleucovorin 200 mg/m\^2 i.v infusion over 90 minutes or leucovorin \[dl-leucovorin\] 400 mg/m\^2 i.v. infusion over 90 minutes; followed by irinotecan 180 mg/m\^2 given as a 90-minute infusion in 500 mL dextrose 5%; followed by a bolus 5-fluorouracil \[FU\] 400 mg/m\^2 and a 46-hour infusion 5-FU 2400 mg/m\^2) at conventional doses on days 1 and 15 of the same 28 day cycle.
Infections and infestations Bronchitis	10.0% 1/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	0.00% 0/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Infections and infestations Rash pustular	0.00% 0/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	16.7% 1/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Infections and infestations Respiratory tract infection viral	10.0% 1/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	0.00% 0/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Infections and infestations Upper respiratory tract infection	0.00% 0/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	16.7% 1/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Infections and infestations Urinary tract infection	10.0% 1/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	0.00% 0/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Infections and infestations Vulvovaginal candidiasis	10.0% 1/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	0.00% 0/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	10.0% 1/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	16.7% 1/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Musculoskeletal and connective tissue disorders Arthralgia	0.00% 0/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	16.7% 1/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Musculoskeletal and connective tissue disorders Neck pain	10.0% 1/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	0.00% 0/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Musculoskeletal and connective tissue disorders Pain in extremity	0.00% 0/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	16.7% 1/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Respiratory, thoracic and mediastinal disorders cough	10.0% 1/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	0.00% 0/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Respiratory, thoracic and mediastinal disorders Dry throat	10.0% 1/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	0.00% 0/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	16.7% 1/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Respiratory, thoracic and mediastinal disorders Hiccups	10.0% 1/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	0.00% 0/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Respiratory, thoracic and mediastinal disorders Nasal dryness	10.0% 1/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	0.00% 0/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Respiratory, thoracic and mediastinal disorders Upper airway obstruction	10.0% 1/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	0.00% 0/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Investigations Alanine aminotransferase increased	0.00% 0/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	16.7% 1/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Investigations Electrocardiogram T wave inversion	10.0% 1/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	0.00% 0/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Renal and urinary disorders Dysuria	10.0% 1/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	0.00% 0/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Renal and urinary disorders Faecaluria	10.0% 1/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	0.00% 0/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Renal and urinary disorders Renal failure	10.0% 1/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	0.00% 0/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Renal and urinary disorders Renal pain	10.0% 1/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	0.00% 0/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Cardiac disorders Palpitations	0.00% 0/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	16.7% 1/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Ear and labyrinth disorders Tinnitus	10.0% 1/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	0.00% 0/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
General disorders Asthenia	60.0% 6/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	66.7% 4/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Gastrointestinal disorders Diarrhoea	80.0% 8/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	83.3% 5/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Gastrointestinal disorders Nausea	50.0% 5/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	50.0% 3/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Gastrointestinal disorders Vomiting	40.0% 4/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	66.7% 4/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Gastrointestinal disorders Stomatitis	20.0% 2/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	83.3% 5/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Gastrointestinal disorders Abdominal pain	30.0% 3/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	50.0% 3/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Gastrointestinal disorders Constipation	20.0% 2/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	0.00% 0/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Gastrointestinal disorders Dyspepsia	0.00% 0/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	33.3% 2/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Gastrointestinal disorders Abdominal pain upper	0.00% 0/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	16.7% 1/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Gastrointestinal disorders Aphthous stomatitis	10.0% 1/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	0.00% 0/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Gastrointestinal disorders Cheilitis	10.0% 1/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	0.00% 0/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Gastrointestinal disorders Dysphagia	0.00% 0/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	16.7% 1/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Gastrointestinal disorders Gastrooesophageal reflux disease	10.0% 1/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	0.00% 0/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Gastrointestinal disorders Proctalgia	10.0% 1/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	0.00% 0/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
General disorders Mucosal inflammation	30.0% 3/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	33.3% 2/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
General disorders Pyrexia	30.0% 3/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	33.3% 2/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
General disorders fatigue	10.0% 1/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	16.7% 1/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Metabolism and nutrition disorders Decreased appetite	20.0% 2/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	50.0% 3/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Metabolism and nutrition disorders Hypomagnesaemia	30.0% 3/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	0.00% 0/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Metabolism and nutrition disorders Hyperglycaemia	10.0% 1/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	16.7% 1/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Metabolism and nutrition disorders Hypokalaemia	10.0% 1/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	16.7% 1/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Metabolism and nutrition disorders Hyponatraemia	20.0% 2/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	0.00% 0/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Metabolism and nutrition disorders Fluid retention	10.0% 1/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	0.00% 0/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Metabolism and nutrition disorders Hyperuricaemia	0.00% 0/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	16.7% 1/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Metabolism and nutrition disorders Hypophosphataemia	10.0% 1/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	0.00% 0/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Metabolism and nutrition disorders Iron deficiency	0.00% 0/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	16.7% 1/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Skin and subcutaneous tissue disorders Rash	40.0% 4/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	66.7% 4/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Skin and subcutaneous tissue disorders Alopecia	20.0% 2/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	0.00% 0/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Skin and subcutaneous tissue disorders Dermatitis acneiform	10.0% 1/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	16.7% 1/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Skin and subcutaneous tissue disorders Dry skin	0.00% 0/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	16.7% 1/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Skin and subcutaneous tissue disorders Palmar-plantar erythrodysaesthesia syndrome	10.0% 1/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	0.00% 0/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Blood and lymphatic system disorders Neutropenia	20.0% 2/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	66.7% 4/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Blood and lymphatic system disorders Anaemia	30.0% 3/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	0.00% 0/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Blood and lymphatic system disorders Anaemia macrocytic	0.00% 0/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	16.7% 1/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Blood and lymphatic system disorders Iron deficiency anaemia	10.0% 1/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	0.00% 0/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Nervous system disorders Headache	20.0% 2/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	16.7% 1/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Nervous system disorders Dizziness	10.0% 1/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	16.7% 1/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Nervous system disorders Dysgeusia	10.0% 1/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	16.7% 1/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Nervous system disorders Neurotoxicity	0.00% 0/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	16.7% 1/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Nervous system disorders Presyncope	0.00% 0/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	16.7% 1/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Nervous system disorders Syncope	0.00% 0/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	16.7% 1/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Nervous system disorders Visual field defect	10.0% 1/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	0.00% 0/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Eye disorders Detachment of retinal pigment epithelium	30.0% 3/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	0.00% 0/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Eye disorders Macular degeneration	20.0% 2/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	16.7% 1/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Eye disorders Maculopathy	0.00% 0/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	16.7% 1/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Eye disorders Visual impairment	10.0% 1/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	0.00% 0/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Hepatobiliary disorders Hypertransaminasaemia	0.00% 0/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	16.7% 1/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Injury, poisoning and procedural complications Procedural pain	10.0% 1/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	0.00% 0/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Injury, poisoning and procedural complications Procedural site reaction	10.0% 1/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	0.00% 0/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Psychiatric disorders Depressed mood	10.0% 1/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	0.00% 0/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.
Vascular disorders Embolism	0.00% 0/10 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.	16.7% 1/6 • From the first dose of study drug administration up to 28 days after the last dose of study drug administration.

Additional Information

Merck KGaA Communication Center

Merck Serono, a division of Merck KGaA

Phone: +49-6151-72-5200

Email: service@merckgroup.com

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place

Restriction type: OTHER