Trial Outcomes & Findings for Oral Bioavailability and Mass Balance Trial With Pimasertib (NCT NCT01713036)

NCT ID: NCT01713036

Last Updated: 2017-08-15

Results Overview

• Recruitment status: COMPLETED
• Study phase: PHASE1
• Target enrollment: 6 participants
• Primary outcome timeframe: Pre-dose, 0.5, 1, 1.5, 3, 5, 7, 9, 11, 15, 23, and 47 hours post [14C] intravenous pimasertib dose on Day 1
• Results posted on: 2017-08-15

Participant Flow

First/last subject (informed consent): Nov 2012/Apr 2013. Clinical data cutoff: Jun 2013, Study completion date: Jul 2014 (Part B)

A total of 11 male subjects with locally advanced or metastatic solid cancer were screened for this trial. Six (6) subjects were enrolled and received the trial medication. Of them, 5 subjects completed Part A and further continued in Part B and completed the study.

Participant milestones

Measure	Pimasertib Part A: Subjects were administered with unlabeled pimasertib capsules orally at a single dose of 60 milligram (mg) on Day 1. One hour after administration of the oral unlabeled pimasertib dose, the intravenous (IV) tracer dose of 9 kilobecquerel (kBq) \[14C\] pimasertib was administered as a bolus injection. On Days 3-21 (except Day 8), subjects received unlabeled pimasertib capsules orally at a dose of 60 mg twice daily (BID). In the morning of Day 8, subjects received 60 mg unlabeled pimasertib capsules spiked with a dose of 2.6 megabecquerel (MBq) (70 microcuries \[mcgCi\]) of \[14C\] pimasertib orally. In the evening of Day 8, subjects received the evening dose of 60 mg pimasertib as unlabeled pimasertib capsules orally. Part B : Subjects were administered with 60 mg BID unlabeled pimasertib as oral capsules continuously in cycles of 21 days until progression of the disease, unacceptable toxicity, withdrawal of consent by the subject, loss to follow-up or death.
Overall Study STARTED	6
Overall Study COMPLETED	5
Overall Study NOT COMPLETED	1

Reasons for withdrawal

Measure

Pimasertib Part A: Subjects were administered with unlabeled pimasertib capsules orally at a single dose of 60 milligram (mg) on Day 1. One hour after administration of the oral unlabeled pimasertib dose, the intravenous (IV) tracer dose of 9 kilobecquerel (kBq) \[14C\] pimasertib was administered as a bolus injection. On Days 3-21 (except Day 8), subjects received unlabeled pimasertib capsules orally at a dose of 60 mg twice daily (BID). In the morning of Day 8, subjects received 60 mg unlabeled pimasertib capsules spiked with a dose of 2.6 megabecquerel (MBq) (70 microcuries \[mcgCi\]) of \[14C\] pimasertib orally. In the evening of Day 8, subjects received the evening dose of 60 mg pimasertib as unlabeled pimasertib capsules orally. Part B : Subjects were administered with 60 mg BID unlabeled pimasertib as oral capsules continuously in cycles of 21 days until progression of the disease, unacceptable toxicity, withdrawal of consent by the subject, loss to follow-up or death.

Overall Study Death

1

Baseline Characteristics

Oral Bioavailability and Mass Balance Trial With Pimasertib

Baseline characteristics by cohort

Measure	Pimasertib n=6 Participants Part A: Subjects were administered with unlabeled pimasertib capsules orally at a single dose of 60 mg on Day 1. One hour after administration of the oral unlabeled pimasertib dose, the intravenous (IV) tracer dose of 9 kBq \[14C\] pimasertib was administered as a bolus injection. On Days 3-21 (except Day 8), subjects received unlabeled pimasertib capsules orally at a dose of 60 mg twice daily (BID). In the morning of Day 8, subjects received 60 mg unlabeled pimasertib capsules spiked with a dose of 2.6 MBq (70 mcgCi) of \[14C\] pimasertib orally. In the evening of Day 8, subjects received the evening dose of 60 mg pimasertib as unlabeled pimasertib capsules orally. Part B: Subjects were administered with 60 mg BID unlabeled pimasertib as oral capsules continuously in cycles of 21 days until progression of the disease, unacceptable toxicity, withdrawal of consent by the subject, loss to follow-up or death.
Age, Continuous	56.2 years STANDARD_DEVIATION 8.54 • n=93 Participants
Sex: Female, Male Female	0 Participants n=93 Participants
Sex: Female, Male Male	6 Participants n=93 Participants

PRIMARY outcome

Timeframe: Pre-dose, 0.5, 1, 1.5, 3, 5, 7, 9, 11, 15, 23, and 47 hours post [14C] intravenous pimasertib dose on Day 1

Population: The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A.

Outcome measures

Measure	Pimasertib n=6 Participants Part A: subjects were administered with unlabeled pimasertib capsules orally at a single dose of 60 mg on Day 1. One hour after administration of the oral unlabeled pimasertib dose, the intravenous (IV) tracer dose of 9 kBq \[14C\] pimasertib was administered as a bolus injection.
Area Under the Plasma Concentration Time Curve From Time Zero to the Last Sampling Time Point (AUC0-t) of [14C]-Pimasertib Following Intravenous (IV) Administration on Day 1	36.0 hour*picogram equivalent/milliliter Interval 22.33 to 58.11

PRIMARY outcome

Timeframe: Pre-dose, 0.5, 0.75, 1, 1.5, 2, 2.5, 4, 6, 8, 10, 12, 16, 24, and 48 hours post unlabeled pimasertib dose on Day 1

Population: The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A.

Outcome measures

Measure	Pimasertib n=6 Participants Part A: subjects were administered with unlabeled pimasertib capsules orally at a single dose of 60 mg on Day 1. One hour after administration of the oral unlabeled pimasertib dose, the intravenous (IV) tracer dose of 9 kBq \[14C\] pimasertib was administered as a bolus injection.
Area Under the Plasma Concentration Time Curve From Time Zero to the Last Sampling Time Point (AUC0-t) of Pimasertib Following Oral Administration on Day 1	937.2 hour*nanogram/milliliter Interval 535.9 to 1639.0

PRIMARY outcome

Timeframe: Pre-dose, 0.5, 1, 1.5, 3, 5, 7, 9, 11, 15, 23, and 47 hours post [14C] intravenous pimasertib dose on Day 1

Population: The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A.

Outcome measures

Measure	Pimasertib n=6 Participants Part A: subjects were administered with unlabeled pimasertib capsules orally at a single dose of 60 mg on Day 1. One hour after administration of the oral unlabeled pimasertib dose, the intravenous (IV) tracer dose of 9 kBq \[14C\] pimasertib was administered as a bolus injection.
Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of [14C]-Pimasertib Following IV Administration on Day 1	37.4 hour*picogram equivalent/milliliter Interval 23.28 to 60.02

PRIMARY outcome

Timeframe: Pre-dose, 0.5, 0.75, 1, 1.5, 2, 2.5, 4, 6, 8, 10, 12, 16, 24, and 48 hours post unlabeled pimasertib dose on Day 1

Population: The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A.

Outcome measures

Measure	Pimasertib n=6 Participants Part A: subjects were administered with unlabeled pimasertib capsules orally at a single dose of 60 mg on Day 1. One hour after administration of the oral unlabeled pimasertib dose, the intravenous (IV) tracer dose of 9 kBq \[14C\] pimasertib was administered as a bolus injection.
Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of Pimasertib Following Oral Administration on Day 1	957.4 hour*nanogram/milliliter Interval 548.6 to 1671.0

PRIMARY outcome

Timeframe: Pre-dose, 0.5, 0.75, 1, 1.5, 2, 2.5, 4, 6, 8, 10, 12, 16, 24, and 48 hours post unlabeled pimasertib dose on Day 1; Pre-dose, 0.5, 1, 1.5, 3, 5, 7, 9, 11, 15, 23, and 47 hours post [14C] labeled pimasertib dose on Day 1

Population: The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with investigational medicinal product (IMP) intake for the complete Part A.

Oral bioavailability (F) was calculated using the formula=AUC0-inf oral/dose oral) / (AUC0-inf iv/dose iv) * 100%, where AUC0-inf is the area under the concentration time curve (AUC) from time zero to infinity.

Outcome measures

Measure	Pimasertib n=6 Participants Part A: subjects were administered with unlabeled pimasertib capsules orally at a single dose of 60 mg on Day 1. One hour after administration of the oral unlabeled pimasertib dose, the intravenous (IV) tracer dose of 9 kBq \[14C\] pimasertib was administered as a bolus injection.
Oral Bioavailability of Pimasertib After Single Oral Dose of Unlabeled Pimasertib and Intravenous (IV) Single Tracer Dose of [14C] Pimasertib	73 percentage bioavailability Interval 61.0 to 87.0

PRIMARY outcome

Timeframe: Urine: 0-4, 4-8, 8-12, 12-24, 24-48, 48-72, and 72-96 hours post [14C]-labeled pimasertib dose on Day 8; Feces: 0-12, 12-24, 24-48, 48-72, 72-96, 96-120, 120-144, and 144-168 hours post [14C]-labeled pimasertib dose on Day 8

Population: The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A.

Recovery of total [14C]-radioactivity was determined in excreta, i.e., urine and feces at each sampling period subsequent to oral administration of [14C]-pimasertib on Day 8. Cumulative recovery of total [14C]-radioactivity in terms of percentage of dose recovered in urine and feces and total percentage of dose recovered was reported for the outcome measure.

Outcome measures

Measure	Pimasertib n=6 Participants Part A: subjects were administered with unlabeled pimasertib capsules orally at a single dose of 60 mg on Day 1. One hour after administration of the oral unlabeled pimasertib dose, the intravenous (IV) tracer dose of 9 kBq \[14C\] pimasertib was administered as a bolus injection.
Mass Balance: Amount of Total Radioactivity Recovered Into the Urine and Feces From Time Zero to the Last Sampling Time Point (Ae0-t) Urine	52.8 percentage of dose recovered Interval 43.1 to 67.9
Mass Balance: Amount of Total Radioactivity Recovered Into the Urine and Feces From Time Zero to the Last Sampling Time Point (Ae0-t) Feces	30.7 percentage of dose recovered Interval 17.6 to 43.8
Mass Balance: Amount of Total Radioactivity Recovered Into the Urine and Feces From Time Zero to the Last Sampling Time Point (Ae0-t) Total	85.1 percentage of dose recovered Interval 77.8 to 98.9

PRIMARY outcome

Timeframe: Pre-dose 1.0, 2.0, 4.0, 10 and 24 hours post [14C]-labeled Pimasertib dose on Day 8

Population: The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A.

Outcome measures

Measure	Pimasertib n=6 Participants Part A: subjects were administered with unlabeled pimasertib capsules orally at a single dose of 60 mg on Day 1. One hour after administration of the oral unlabeled pimasertib dose, the intravenous (IV) tracer dose of 9 kBq \[14C\] pimasertib was administered as a bolus injection.
Plasma Concentrations of [14C] Pimasertib Predose	0.0 nanogram equivalent per milliliter Standard Deviation 0.0
Plasma Concentrations of [14C] Pimasertib Hour 1	695.2 nanogram equivalent per milliliter Standard Deviation 213.5
Plasma Concentrations of [14C] Pimasertib Hour 2.0	691.2 nanogram equivalent per milliliter Standard Deviation 164.8
Plasma Concentrations of [14C] Pimasertib Hour 4.0	379.3 nanogram equivalent per milliliter Standard Deviation 108.7
Plasma Concentrations of [14C] Pimasertib Hour 10.0	165.6 nanogram equivalent per milliliter Standard Deviation 62.58
Plasma Concentrations of [14C] Pimasertib Hour 24.0	46.62 nanogram equivalent per milliliter Standard Deviation 14.57

PRIMARY outcome

Timeframe: Predose, 1.0, 2.0, 4.0, 10 and 24 hour post [14C]-labeled pimasertib dose on Day 8

Population: The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A. Here 'n' is the number of subjects analysed at each time point.

Plasma concentration of the Pimasertib metabolite M445 and M554 were presented for the outcome measure.

Outcome measures

Measure	Pimasertib n=6 Participants Part A: subjects were administered with unlabeled pimasertib capsules orally at a single dose of 60 mg on Day 1. One hour after administration of the oral unlabeled pimasertib dose, the intravenous (IV) tracer dose of 9 kBq \[14C\] pimasertib was administered as a bolus injection.
Plasma Concentrations of Pimasertib Metabolites M445 (Predose)(n=6)	0.0 Nanogram equivalent per milliliter Standard Deviation 0.0
Plasma Concentrations of Pimasertib Metabolites M445 (Hour 1.0)(n=6)	285.2 Nanogram equivalent per milliliter Standard Deviation 64.10
Plasma Concentrations of Pimasertib Metabolites M445 (Hour 2.0)(n=6)	262.2 Nanogram equivalent per milliliter Standard Deviation 42.35
Plasma Concentrations of Pimasertib Metabolites M445 (Hour 4.0)(n=6)	85.05 Nanogram equivalent per milliliter Standard Deviation 14.01
Plasma Concentrations of Pimasertib Metabolites M445 (Hour 10.0)(n=5)	28.58 Nanogram equivalent per milliliter Standard Deviation 9.454
Plasma Concentrations of Pimasertib Metabolites M445 (Hour 24.0)(n=3)	0.0 Nanogram equivalent per milliliter Standard Deviation 0.0
Plasma Concentrations of Pimasertib Metabolites M554(Predose)(n=6)	0.0 Nanogram equivalent per milliliter Standard Deviation 0.0
Plasma Concentrations of Pimasertib Metabolites M554(Hour 1.0)(n=6)	87.53 Nanogram equivalent per milliliter Standard Deviation 55.52
Plasma Concentrations of Pimasertib Metabolites M554 (Hour 2.0)(n=6)	167.6 Nanogram equivalent per milliliter Standard Deviation 76.72
Plasma Concentrations of Pimasertib Metabolites M554 (Hour 4.0)(n=6)	169.1 Nanogram equivalent per milliliter Standard Deviation 45.85
Plasma Concentrations of Pimasertib Metabolites M554 (Hour 10.0) (n=5)	108.8 Nanogram equivalent per milliliter Standard Deviation 24.80
Plasma Concentrations of Pimasertib Metabolites M554 (Hour 24.0) (n=3)	51.33 Nanogram equivalent per milliliter Standard Deviation 12.46

PRIMARY outcome

Timeframe: Pre-dose 1.0, 2.0, 4.0, 10 and 24 hours post [14C]-labeled Pimasertib dose on Day 8

Population: The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A.

Identification and profiling of the metabolites was done. The total number of metabolites and the number of metabolites identified as major were reported.

Outcome measures

Measure	Pimasertib n=6 Participants Part A: subjects were administered with unlabeled pimasertib capsules orally at a single dose of 60 mg on Day 1. One hour after administration of the oral unlabeled pimasertib dose, the intravenous (IV) tracer dose of 9 kBq \[14C\] pimasertib was administered as a bolus injection.
Number of Metabolites Identified Overall and as Major Overall	14 metabolites
Number of Metabolites Identified Overall and as Major Major	2 metabolites

SECONDARY outcome

Timeframe: Pre-dose 0.5, 0.75, 1, 1.5, 2, 2.5, 4, 6, 8, 10, 12, 16, 24, and 48 hours post unlabeled pimasertib dose on Day 1

Population: The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A.

Outcome measures

Measure	Pimasertib n=6 Participants Part A: subjects were administered with unlabeled pimasertib capsules orally at a single dose of 60 mg on Day 1. One hour after administration of the oral unlabeled pimasertib dose, the intravenous (IV) tracer dose of 9 kBq \[14C\] pimasertib was administered as a bolus injection.
Maximum Observed Plasma Concentration (Cmax) of Unlabeled Pimasertib	265 ng/mL Interval 130.3 to 539.1

SECONDARY outcome

Timeframe: Pre-dose, 0.5, 1, 1.5, 3, 5, 7, 9, 11, 15, 23, and 47 hours post [14C] intravenous pimasertib dose on Day 1

Population: The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A.

Outcome measures

Measure	Pimasertib n=6 Participants Part A: subjects were administered with unlabeled pimasertib capsules orally at a single dose of 60 mg on Day 1. One hour after administration of the oral unlabeled pimasertib dose, the intravenous (IV) tracer dose of 9 kBq \[14C\] pimasertib was administered as a bolus injection.
Maximum Observed Plasma Concentration (Cmax) of Intravenous [14C] Pimasertib	12.67 picogram equivalent per milliliter Interval 8.051 to 19.938

SECONDARY outcome

Timeframe: Pre-dose 0.5, 0.75, 1, 1.5, 2, 2.5, 4, 6, 8, 10, 12, 16, 24, and 48 hours post unlabeled pimasertib dose on Day 1; Pre-dose, 0.5, 1, 1.5, 3, 5, 7, 9, 11, 15, 23, and 47 hours post intravenous [14C] labeled pimasertib dose on Day 1

Population: The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A.

Outcome measures

Measure	Pimasertib n=6 Participants Part A: subjects were administered with unlabeled pimasertib capsules orally at a single dose of 60 mg on Day 1. One hour after administration of the oral unlabeled pimasertib dose, the intravenous (IV) tracer dose of 9 kBq \[14C\] pimasertib was administered as a bolus injection.
Time to Reach Maximum Plasma Concentration (Tmax) of Unlabeled Pimasertib and Intravenous [14C] Pimasertib Unlabeled pimasertib	0.75 hours Interval 0.5 to 2.5
Time to Reach Maximum Plasma Concentration (Tmax) of Unlabeled Pimasertib and Intravenous [14C] Pimasertib [14C] intravenous pimasertib	0.5 hours Interval 0.5 to 0.5

SECONDARY outcome

Timeframe: Pre-dose, 0.5, 0.75, 1, 1.5, 2, 2.5, 4, 6, 8, 10, 12, 16, 24, and 48 hours post unlabeled pimasertib dose on Day 1; Pre-dose, 0.5, 1, 1.5, 3, 5, 7, 9, 11, 15, 23, and 47 hours post intravenous [14C] labeled pimasertib dose on Day 1

Population: The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A.

Apparent terminal elimination rate constant (λz) was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression on terminal data points of the curve.

Outcome measures

Measure	Pimasertib n=6 Participants Part A: subjects were administered with unlabeled pimasertib capsules orally at a single dose of 60 mg on Day 1. One hour after administration of the oral unlabeled pimasertib dose, the intravenous (IV) tracer dose of 9 kBq \[14C\] pimasertib was administered as a bolus injection.
Apparent Terminal Elimination Rate Constant (λz) of Unlabeled Pimasertib and Intravenous [14C] Pimasertib Unlabeled pimasertib	0.1096 per hour Interval 0.06315 to 0.1902
Apparent Terminal Elimination Rate Constant (λz) of Unlabeled Pimasertib and Intravenous [14C] Pimasertib Intravenous [14C] pimasertib	0.1994 per hour Interval 0.162 to 0.246

SECONDARY outcome

Timeframe: Pre-dose, 0.5, 0.75, 1, 1.5, 2, 2.5, 4, 6, 8, 10, 12, 16, 24, and 48 hours post unlabeled pimasertib dose on Day 1; Pre-dose, 0.5, 1, 1.5, 3, 5, 7, 9, 11, 15, 23, and 47 hours post intravenous [14C] labeled pimasertib dose on Day 1

Population: The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A.

The total body clearance of drug from plasma following oral administration (Cl/f) and the total body clearance of drug from plasma following intravenous administration was calculated by dividing the Dose with area under the plasma concentration time curve from time zero to infinity (AUC0 inf)=Dose/AUC0- inf.

Outcome measures

Measure	Pimasertib n=6 Participants Part A: subjects were administered with unlabeled pimasertib capsules orally at a single dose of 60 mg on Day 1. One hour after administration of the oral unlabeled pimasertib dose, the intravenous (IV) tracer dose of 9 kBq \[14C\] pimasertib was administered as a bolus injection.
Total Body Clearance of Unlabeled Pimasertib (CL/f) and Intravenous [14C] Pimasertib (CL) Unlabeled pimasertib	62.67 liter per hour Interval 35.91 to 109.4
Total Body Clearance of Unlabeled Pimasertib (CL/f) and Intravenous [14C] Pimasertib (CL) Intravenous [14C] pimasertib	45.73 liter per hour Interval 28.57 to 73.21

SECONDARY outcome

Timeframe: Pre-dose, 0.5, 1, 1.5, 3, 5, 7, 9, 11, 15, 23, and 47 hours post intravenous [14C] pimasertib dose on Day 1

Population: The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A.

The volume of distribution of the central or plasma compartment (Vc) was calculated using the formula=Dose/C0

Outcome measures

Measure	Pimasertib n=6 Participants Part A: subjects were administered with unlabeled pimasertib capsules orally at a single dose of 60 mg on Day 1. One hour after administration of the oral unlabeled pimasertib dose, the intravenous (IV) tracer dose of 9 kBq \[14C\] pimasertib was administered as a bolus injection.
The Volume of Distribution of the Central or Plasma Compartment (Vc) of Intravenous [14C] Pimasertib	83.668 Liter Interval 50.4 to 138.9

SECONDARY outcome

Timeframe: Pre-dose, 0.5, 0.75, 1, 1.5, 2, 2.5, 4, 6, 8, 10, 12, 16, 24, and 48 hours post unlabeled pimasertib dose on Day 1; Pre-dose, 0.5, 1, 1.5, 3, 5, 7, 9, 11, 15, 23, and 47 hours post [14C] labeled pimasertib dose on Day 1

Population: The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A.

The apparent volume of distribution during the terminal phase following oral administration (Vz/f) and the apparent volume of distribution during the terminal phase following intravenous administration was calculated by using the formula=Dose/( AUC0-inf* λz).

Outcome measures

Measure	Pimasertib n=6 Participants Part A: subjects were administered with unlabeled pimasertib capsules orally at a single dose of 60 mg on Day 1. One hour after administration of the oral unlabeled pimasertib dose, the intravenous (IV) tracer dose of 9 kBq \[14C\] pimasertib was administered as a bolus injection.
Apparent Volume of Distribution During the Terminal Phase Following Oral Administration (Vz/f) and the Apparent Volume of Distribution During the Terminal Phase Following Intravenous Administration (Vz) of [14C] Pimasertib Unlabeled pimasertib	571.77 Liter Interval 349.5 to 935.3
Apparent Volume of Distribution During the Terminal Phase Following Oral Administration (Vz/f) and the Apparent Volume of Distribution During the Terminal Phase Following Intravenous Administration (Vz) of [14C] Pimasertib Intravenous [14C] pimasertib	229.35 Liter Interval 150.3 to 350.0

SECONDARY outcome

Timeframe: Pre dose, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, 8.0, 10.0, 12.0, 24.0, 48.0, 72.0, 96.0 and 168.0 hours post [14C]-labeled pimasertib dose on Day 8

Population: The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A.

Unit of assessment was nanogram equivalent per milliliter (ng eq/mL).

Outcome measures

Measure	Pimasertib n=6 Participants Part A: subjects were administered with unlabeled pimasertib capsules orally at a single dose of 60 mg on Day 1. One hour after administration of the oral unlabeled pimasertib dose, the intravenous (IV) tracer dose of 9 kBq \[14C\] pimasertib was administered as a bolus injection.
Maximum Observed Plasma Concentration (Cmax) of Total [14C] Radioactivity	774.1 ng eq/mL Interval 577.8 to 1037.0

SECONDARY outcome

Timeframe: Pre dose, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, 8.0, 10.0, 12.0, 24.0, 48.0, 72.0, 96.0 and 168.0 hours post [14C]-labeled pimasertib dose on Day 8

Population: The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A.

Outcome measures

Measure	Pimasertib n=6 Participants Part A: subjects were administered with unlabeled pimasertib capsules orally at a single dose of 60 mg on Day 1. One hour after administration of the oral unlabeled pimasertib dose, the intravenous (IV) tracer dose of 9 kBq \[14C\] pimasertib was administered as a bolus injection.
Time to Reach Maximum Plasma Concentration (Tmax) of Total [14C] Radioactivity	1.5 hour Interval 0.75 to 2.02

SECONDARY outcome

Timeframe: Pre dose, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, 8.0, 10.0, 12.0, 24.0, 48.0, 72.0, 96.0 and 168.0 hours post [14C]-labeled pimasertib dose on Day 8

Population: The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A.

Area under the plasma concentration time curve from time zero to the last sampling time at which the concentration is at or above the lower limit of quantification was calculated by using mixed log linear trapezoidal rule. Unit of assessment was hour*nanogram equivalent per milliliter (hr*ng eq/mL).

Outcome measures

Measure	Pimasertib n=6 Participants Part A: subjects were administered with unlabeled pimasertib capsules orally at a single dose of 60 mg on Day 1. One hour after administration of the oral unlabeled pimasertib dose, the intravenous (IV) tracer dose of 9 kBq \[14C\] pimasertib was administered as a bolus injection.
Area Under the Plasma Concentration Time Curve From Time Zero to the Last Sampling Time at Which the Concentration is at or Above the Lower Limit of Quantification (AUC0-t) of Total [14C] Radioactivity	5318 hr*ng eq/mL Interval 3453.0 to 8189.0

SECONDARY outcome

Timeframe: Pre dose, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, 8.0, 10.0, 12.0, 24.0, 48.0, 72.0, 96.0 and 168.0 hours post [14C]-labeled pimasertib dose on Day 8

Population: The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A.

Area under the concentration time curve (AUC) from time zero to infinity (AUC0-inf) was calculated from AUC0-t + AUCextra, where AUCextra = Clast calc/λz. Clast calc was the calculated plasma concentration at the last sampling time point at which plasma concentration was at or above the lower limit of quantification was measured and λz represents apparent terminal elimination rate constant.

Outcome measures

Measure	Pimasertib n=6 Participants Part A: subjects were administered with unlabeled pimasertib capsules orally at a single dose of 60 mg on Day 1. One hour after administration of the oral unlabeled pimasertib dose, the intravenous (IV) tracer dose of 9 kBq \[14C\] pimasertib was administered as a bolus injection.
Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Total [14C] Radioactivity	5711 hr*ng eq/mL Interval 3725.0 to 8756.0

SECONDARY outcome

Timeframe: Pre dose, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, 8.0, 10.0, 12.0, 24.0, 48.0, 72.0, 96.0 and 168.0 hours post [14C]-labeled pimasertib dose on Day 8

Population: The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A.

λz of total [14C] radioactivity was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression on terminal data points of the curve.

Outcome measures

Measure	Pimasertib n=6 Participants Part A: subjects were administered with unlabeled pimasertib capsules orally at a single dose of 60 mg on Day 1. One hour after administration of the oral unlabeled pimasertib dose, the intravenous (IV) tracer dose of 9 kBq \[14C\] pimasertib was administered as a bolus injection.
Apparent Terminal Elimination Rate Constant (λz) of Total [14C] Radioactivity	0.04084 per hour Interval 0.01986 to 0.08398

SECONDARY outcome

Timeframe: Pre dose, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, 8.0, 10.0, 12.0, 24.0, 48.0, 72.0, 96.0 and 168.0 hours post [14C]-labeled pimasertib dose on Day 8

Population: The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A.

Outcome measures

Measure	Pimasertib n=6 Participants Part A: subjects were administered with unlabeled pimasertib capsules orally at a single dose of 60 mg on Day 1. One hour after administration of the oral unlabeled pimasertib dose, the intravenous (IV) tracer dose of 9 kBq \[14C\] pimasertib was administered as a bolus injection.
Apparent Terminal Half-life (t1/2) of Total [14C] Radioactivity	14.41 hour Interval 8.87 to 59.8

SECONDARY outcome

Timeframe: Pre dose, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, 8.0, 10.0, 12.0, 24.0, 48.0, 72.0, 96.0 and 168.0 hours post [14C]-labeled pimasertib dose on Day 8

Population: The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A.

Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. CL/f was influenced by the fraction absorbed. Apparent body clearance of total radioactivity from plasma was calculated by dividing the dose with area under the plasma concentration time curve from zero to infinity (Dose/AUC0inf).

Outcome measures

Measure	Pimasertib n=6 Participants Part A: subjects were administered with unlabeled pimasertib capsules orally at a single dose of 60 mg on Day 1. One hour after administration of the oral unlabeled pimasertib dose, the intravenous (IV) tracer dose of 9 kBq \[14C\] pimasertib was administered as a bolus injection.
Total Body Clearance of Total [14C] Radioactivity From Plasma Following Oral Administration (CL/f)	10.35 liter per hour Interval 6.822 to 15.72

SECONDARY outcome

Timeframe: Pre dose, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, 8.0, 10.0, 12.0, 24.0, 48.0, 72.0, 96.0 and 168.0 hours post [14C]-labeled pimasertib dose on Day 8

Population: The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A.

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 plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/f) was influenced by the fraction absorbed. Vz/f of total radioactivity during the terminal phase was calculated by dividing the dose with the product of area under the plasma concentration time curve and apparent terminal rate constant (dose/AUC0inf*λz).

Outcome measures

Measure	Pimasertib n=6 Participants Part A: subjects were administered with unlabeled pimasertib capsules orally at a single dose of 60 mg on Day 1. One hour after administration of the oral unlabeled pimasertib dose, the intravenous (IV) tracer dose of 9 kBq \[14C\] pimasertib was administered as a bolus injection.
Apparent Volume of Distribution of Total [14C] Radioactivity During the Terminal Phase Following Oral Administration (Vz/f)	253.5 Liter Interval 159.1 to 403.9

SECONDARY outcome

Timeframe: Predose, 1.0, 2.0, 4.0, 10 and 24 hour post [14C]-labeled pimasertib dose on Day 8

Population: The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A.

Maximum observed plasma concentration (Cmax) for the metabolites M445 and M554 was calculated.

Outcome measures

Measure	Pimasertib n=6 Participants Part A: subjects were administered with unlabeled pimasertib capsules orally at a single dose of 60 mg on Day 1. One hour after administration of the oral unlabeled pimasertib dose, the intravenous (IV) tracer dose of 9 kBq \[14C\] pimasertib was administered as a bolus injection.
Maximum Observed Plasma Concentration (Cmax) of M445 and M554 M445	300.93 Nanogram equivalent per milliliter Interval 256.7 to 352.9
Maximum Observed Plasma Concentration (Cmax) of M445 and M554 M554	174.64 Nanogram equivalent per milliliter Interval 115.0 to 265.3

SECONDARY outcome

Timeframe: Predose, 1.0, 2.0, 4.0, 10 and 24 hour post [14C]-labeled pimasertib dose on Day 8

Population: The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A.

Time to reach maximum plasma concentration (Tmax) for the metabolites M445 and M554 was calculated.

Outcome measures

Measure	Pimasertib n=6 Participants Part A: subjects were administered with unlabeled pimasertib capsules orally at a single dose of 60 mg on Day 1. One hour after administration of the oral unlabeled pimasertib dose, the intravenous (IV) tracer dose of 9 kBq \[14C\] pimasertib was administered as a bolus injection.
Time to Reach Maximum Plasma Concentration (Tmax) of M445 and M554 M445	1.5 hour Interval 1.0 to 2.0
Time to Reach Maximum Plasma Concentration (Tmax) of M445 and M554 M554	4 hour Interval 2.0 to 4.0

SECONDARY outcome

Timeframe: Predose, 1.0, 2.0, 4.0, 10 and 24 hour post [14C]-labeled pimasertib dose on Day 8

Population: The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A.

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	Pimasertib n=6 Participants Part A: subjects were administered with unlabeled pimasertib capsules orally at a single dose of 60 mg on Day 1. One hour after administration of the oral unlabeled pimasertib dose, the intravenous (IV) tracer dose of 9 kBq \[14C\] pimasertib was administered as a bolus injection.
Area Under the Plasma Concentration-time Curve From Time Zero to the Last Sampling Time (AUC0-t) of M445 and M554 M445	976.39 hr*ng eq/mL Interval 808.7 to 1178.8
Area Under the Plasma Concentration-time Curve From Time Zero to the Last Sampling Time (AUC0-t) of M445 and M554 M554	1410.30 hr*ng eq/mL Interval 559.8 to 3552.7

SECONDARY outcome

Timeframe: Predose, 1.0, 2.0, 4.0, 10 and 24 hour post [14C]-labeled pimasertib dose on Day 8

Population: The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A.

AUC from time 0 to infinity (AUC0-inf), was calculated from AUC0-t + AUCextra, where AUCextra = Clast calc/lambda z (λz). Clast calc was the calculated plasma concentration at the last sampling time point at which plasma concentration was at or above the lower limit of quantification was measured and λz represents apparent terminal elimination rate constant.

Outcome measures

Measure	Pimasertib n=6 Participants Part A: subjects were administered with unlabeled pimasertib capsules orally at a single dose of 60 mg on Day 1. One hour after administration of the oral unlabeled pimasertib dose, the intravenous (IV) tracer dose of 9 kBq \[14C\] pimasertib was administered as a bolus injection.
Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of M445 and M554 M445	1134.72 hr*ng eq/mL Interval 938.8 to 1371.5
Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of M445 and M554 M554	3135.61 hr*ng eq/mL Interval 2155.9 to 4560.6

SECONDARY outcome

Timeframe: Predose, 1.0, 2.0, 4.0, 10 and 24 hour post [14C]-labeled pimasertib dose on Day 8

Population: The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A.

The λz of M445 and M554 was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression on terminal data points of the curve.

Outcome measures

Measure	Pimasertib n=6 Participants Part A: subjects were administered with unlabeled pimasertib capsules orally at a single dose of 60 mg on Day 1. One hour after administration of the oral unlabeled pimasertib dose, the intravenous (IV) tracer dose of 9 kBq \[14C\] pimasertib was administered as a bolus injection.
Apparent Terminal Elimination Rate Constant (λz) of M445 and M554 M445	0.2542 per hour Interval 0.202 to 0.32
Apparent Terminal Elimination Rate Constant (λz) of M445 and M554 M554	0.07021 per hour Interval 0.0438 to 0.112

SECONDARY outcome

Timeframe: Predose, 1.0, 2.0, 4.0, 10 and 24 hour post [14C]-labeled pimasertib dose on Day 8

Population: The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A.

Outcome measures

Measure	Pimasertib n=6 Participants Part A: subjects were administered with unlabeled pimasertib capsules orally at a single dose of 60 mg on Day 1. One hour after administration of the oral unlabeled pimasertib dose, the intravenous (IV) tracer dose of 9 kBq \[14C\] pimasertib was administered as a bolus injection.
Apparent Terminal Half-life (t1/2) of M445 and M554 M445	2.653 hour Interval 2.11 to 3.35
Apparent Terminal Half-life (t1/2) of M445 and M554 M554	10.81 hour Interval 6.48 to 12.6

SECONDARY outcome

Timeframe: 1.5 hour post [14C]-labeled pimasertib dose on Day 8

Population: The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A.

Fraction of unbound drug (fu) is defined as the ratio of unbound drug concentration to the total drug concentration multiplied by 100.

Outcome measures

Measure	Pimasertib n=6 Participants Part A: subjects were administered with unlabeled pimasertib capsules orally at a single dose of 60 mg on Day 1. One hour after administration of the oral unlabeled pimasertib dose, the intravenous (IV) tracer dose of 9 kBq \[14C\] pimasertib was administered as a bolus injection.
Fraction Unbound of [14C] Pimasertib	6.702 percentage of unbound drug Standard Deviation 0.6623

SECONDARY outcome

Timeframe: 1.5 hour post [14C]-labeled pimasertib dose on Day 8

Population: The Part A analysis set consists of all subjects who received the Part A medication, had absence of clinical trial protocol deviations affecting mass balance assessments, complied with trial medication with IMP intake for the complete Part A.

Outcome measures

Measure	Pimasertib n=6 Participants Part A: subjects were administered with unlabeled pimasertib capsules orally at a single dose of 60 mg on Day 1. One hour after administration of the oral unlabeled pimasertib dose, the intravenous (IV) tracer dose of 9 kBq \[14C\] pimasertib was administered as a bolus injection.
Blood/ Plasma Concentration Ratios of Total [14C] Radioactivity	0.687 Ratio Standard Deviation 0.0786

SECONDARY outcome

Timeframe: From the screening every 2 cycles until end of the treatment, assessed up to 18 months

Population: Safety analysis set included all subjects who received at least one administration of trial medication and had at least one subsequent safety assessment.

Anti tumor activity defined as CR, PR, or stable disease and PD based on the investigator tumor evaluations performed every 2 cycles in accordance with Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. CR =Disappearance of all target lesions except lymph nodes (LN); LN must have a decrease in the short axis to less than (<)10 millimeter (mm); PR = 30% decrease in sum of diameters of target lesions taking as reference the baseline sum diameters; Progressed Disease (PD) = 20% increase in sum of diameters of target lesions; the appearance of >=1 new lesions; SD= Neither shrinkage to qualify for PR nor increase to qualify for PD taking the smallest sum diameters on study as reference. For non-target lesions a CR = Disappearance of all non-target lesions and all LN must be non-pathological in size <10 mm; Non-CR/Non PD: persistence of one or more non-target lesions; PD = unequivocal progression of existing non-target lesions or appearance of new ones.

Outcome measures

Measure	Pimasertib n=5 Participants Part A: subjects were administered with unlabeled pimasertib capsules orally at a single dose of 60 mg on Day 1. One hour after administration of the oral unlabeled pimasertib dose, the intravenous (IV) tracer dose of 9 kBq \[14C\] pimasertib was administered as a bolus injection.
Part B: Number of Subjects Who Experienced Complete Response (CR), Partial Response (PR), Stable Disease (SD) and Progressive Disease (PD) Stable disease	3 subjects
Part B: Number of Subjects Who Experienced Complete Response (CR), Partial Response (PR), Stable Disease (SD) and Progressive Disease (PD) Progressive disease	1 subjects
Part B: Number of Subjects Who Experienced Complete Response (CR), Partial Response (PR), Stable Disease (SD) and Progressive Disease (PD) Confirmed Response	0 subjects
Part B: Number of Subjects Who Experienced Complete Response (CR), Partial Response (PR), Stable Disease (SD) and Progressive Disease (PD) Partial Response	0 subjects
Part B: Number of Subjects Who Experienced Complete Response (CR), Partial Response (PR), Stable Disease (SD) and Progressive Disease (PD) Non evaluable	1 subjects

SECONDARY outcome

Timeframe: Part A and B: From the first dose of study drug administration until 30+/-2 days after the last dose of study drug administration, assessed up to 18 months

Population: The safety analysis set included all subjects who received at least one administration of trial medication and have at least one subsequent safety assessment.

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug administration until 30+/-2 days after the last dose of study drug administration that were absent before treatment or that worsened relative to pre treatment state.

Outcome measures

Measure	Pimasertib n=6 Participants Part A: subjects were administered with unlabeled pimasertib capsules orally at a single dose of 60 mg on Day 1. One hour after administration of the oral unlabeled pimasertib dose, the intravenous (IV) tracer dose of 9 kBq \[14C\] pimasertib was administered as a bolus injection.
Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death, and TEAEs Leading to Discontinuation TEAEs	6 subjects
Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death, and TEAEs Leading to Discontinuation Serious TEAEs	2 subjects
Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death, and TEAEs Leading to Discontinuation TEAEs leading to death	1 subjects
Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death, and TEAEs Leading to Discontinuation TEAEs leading to discontinuation	3 subjects

Adverse Events

Pimasertib

Serious events: 2 serious events

Other events: 6 other events

Deaths: 0 deaths

Serious adverse events

Measure	Pimasertib n=6 participants at risk Part A: Subjects were administered with unlabeled pimasertib capsules orally at a single dose of 60 mg on Day 1. One hour after administration of the oral unlabeled pimasertib dose, the IV tracer dose of 9 kBq \[14C\] pimasertib was administered as a bolus injection. On Days 3-21 (except Day 8), subjects received unlabeled pimasertib capsules orally at a dose of 60 mg twice daily (BID). In the morning of Day 8, subjects received 60 mg unlabeled pimasertib capsules spiked with a dose of 2.6 MBq (70 μCi) of \[14C\] pimasertib orally. In the evening of Day 8, subjects received the evening dose of 60 mg pimasertib as unlabeled pimasertib capsules orally. Part B: Subjects were administered with 60 mg BID unlabeled pimasertib as oral capsules continuously in cycles of 21 days until progression of the disease, unacceptable toxicity, withdrawal of consent by the subject, loss to follow-up or death.
Infections and infestations Bronchopneumonia	16.7% 1/6 • Part A and B: From the first dose of study drug administration until 30+/-2 days after the last dose of study drug administration, assessed up to 18 months
Gastrointestinal disorders Diarrhoea	16.7% 1/6 • Part A and B: From the first dose of study drug administration until 30+/-2 days after the last dose of study drug administration, assessed up to 18 months
General disorders Pyrexia	16.7% 1/6 • Part A and B: From the first dose of study drug administration until 30+/-2 days after the last dose of study drug administration, assessed up to 18 months

Other adverse events

Measure	Pimasertib n=6 participants at risk Part A: Subjects were administered with unlabeled pimasertib capsules orally at a single dose of 60 mg on Day 1. One hour after administration of the oral unlabeled pimasertib dose, the IV tracer dose of 9 kBq \[14C\] pimasertib was administered as a bolus injection. On Days 3-21 (except Day 8), subjects received unlabeled pimasertib capsules orally at a dose of 60 mg twice daily (BID). In the morning of Day 8, subjects received 60 mg unlabeled pimasertib capsules spiked with a dose of 2.6 MBq (70 μCi) of \[14C\] pimasertib orally. In the evening of Day 8, subjects received the evening dose of 60 mg pimasertib as unlabeled pimasertib capsules orally. Part B: Subjects were administered with 60 mg BID unlabeled pimasertib as oral capsules continuously in cycles of 21 days until progression of the disease, unacceptable toxicity, withdrawal of consent by the subject, loss to follow-up or death.
Gastrointestinal disorders Diarrhoea	66.7% 4/6 • Part A and B: From the first dose of study drug administration until 30+/-2 days after the last dose of study drug administration, assessed up to 18 months
Gastrointestinal disorders Stomatitis	33.3% 2/6 • Part A and B: From the first dose of study drug administration until 30+/-2 days after the last dose of study drug administration, assessed up to 18 months
Gastrointestinal disorders Abdominal pain	16.7% 1/6 • Part A and B: From the first dose of study drug administration until 30+/-2 days after the last dose of study drug administration, assessed up to 18 months
Gastrointestinal disorders Ascites	16.7% 1/6 • Part A and B: From the first dose of study drug administration until 30+/-2 days after the last dose of study drug administration, assessed up to 18 months
Eye disorders Retinal detachment	33.3% 2/6 • Part A and B: From the first dose of study drug administration until 30+/-2 days after the last dose of study drug administration, assessed up to 18 months
Eye disorders Eyelid oedema	16.7% 1/6 • Part A and B: From the first dose of study drug administration until 30+/-2 days after the last dose of study drug administration, assessed up to 18 months
Eye disorders Retinal exudates	16.7% 1/6 • Part A and B: From the first dose of study drug administration until 30+/-2 days after the last dose of study drug administration, assessed up to 18 months
Eye disorders Retinal haemorrhage	16.7% 1/6 • Part A and B: From the first dose of study drug administration until 30+/-2 days after the last dose of study drug administration, assessed up to 18 months
Blood and lymphatic system disorders Hypochromic anaemia	16.7% 1/6 • Part A and B: From the first dose of study drug administration until 30+/-2 days after the last dose of study drug administration, assessed up to 18 months
Cardiac disorders Supraventricular tachycardia	16.7% 1/6 • Part A and B: From the first dose of study drug administration until 30+/-2 days after the last dose of study drug administration, assessed up to 18 months
General disorders Pyrexia	66.7% 4/6 • Part A and B: From the first dose of study drug administration until 30+/-2 days after the last dose of study drug administration, assessed up to 18 months
General disorders Face oedema	33.3% 2/6 • Part A and B: From the first dose of study drug administration until 30+/-2 days after the last dose of study drug administration, assessed up to 18 months
General disorders Oedema peripheral	16.7% 1/6 • Part A and B: From the first dose of study drug administration until 30+/-2 days after the last dose of study drug administration, assessed up to 18 months
Infections and infestations Bacteriuria	16.7% 1/6 • Part A and B: From the first dose of study drug administration until 30+/-2 days after the last dose of study drug administration, assessed up to 18 months
Infections and infestations Bronchitis	16.7% 1/6 • Part A and B: From the first dose of study drug administration until 30+/-2 days after the last dose of study drug administration, assessed up to 18 months
Infections and infestations Conjunctivitis	16.7% 1/6 • Part A and B: From the first dose of study drug administration until 30+/-2 days after the last dose of study drug administration, assessed up to 18 months
Infections and infestations Pharyngitis	16.7% 1/6 • Part A and B: From the first dose of study drug administration until 30+/-2 days after the last dose of study drug administration, assessed up to 18 months
Investigations Blood creatine phosphokinase increased	83.3% 5/6 • Part A and B: From the first dose of study drug administration until 30+/-2 days after the last dose of study drug administration, assessed up to 18 months
Investigations Blood lactate dehydrogenase increased	66.7% 4/6 • Part A and B: From the first dose of study drug administration until 30+/-2 days after the last dose of study drug administration, assessed up to 18 months
Investigations Hepatic enzyme increased	33.3% 2/6 • Part A and B: From the first dose of study drug administration until 30+/-2 days after the last dose of study drug administration, assessed up to 18 months
Investigations Pancreatic enzymes increased	16.7% 1/6 • Part A and B: From the first dose of study drug administration until 30+/-2 days after the last dose of study drug administration, assessed up to 18 months
Investigations Amylase increased	16.7% 1/6 • Part A and B: From the first dose of study drug administration until 30+/-2 days after the last dose of study drug administration, assessed up to 18 months
Investigations Lipase increased	16.7% 1/6 • Part A and B: From the first dose of study drug administration until 30+/-2 days after the last dose of study drug administration, assessed up to 18 months
Investigations Gamma-glutamyltransferase increased	16.7% 1/6 • Part A and B: From the first dose of study drug administration until 30+/-2 days after the last dose of study drug administration, assessed up to 18 months
Nervous system disorders Headache	33.3% 2/6 • Part A and B: From the first dose of study drug administration until 30+/-2 days after the last dose of study drug administration, assessed up to 18 months
Nervous system disorders Toxic neuropathy	16.7% 1/6 • Part A and B: From the first dose of study drug administration until 30+/-2 days after the last dose of study drug administration, assessed up to 18 months
Metabolism and nutrition disorders Hypokalaemia	16.7% 1/6 • Part A and B: From the first dose of study drug administration until 30+/-2 days after the last dose of study drug administration, assessed up to 18 months
Psychiatric disorders Hallucination	16.7% 1/6 • Part A and B: From the first dose of study drug administration until 30+/-2 days after the last dose of study drug administration, assessed up to 18 months
Skin and subcutaneous tissue disorders Rash	66.7% 4/6 • Part A and B: From the first dose of study drug administration until 30+/-2 days after the last dose of study drug administration, assessed up to 18 months
Skin and subcutaneous tissue disorders Acute generalised exanthematous pustulosis	16.7% 1/6 • Part A and B: From the first dose of study drug administration until 30+/-2 days after the last dose of study drug administration, assessed up to 18 months
Skin and subcutaneous tissue disorders Seborrhoeic dermatitis	16.7% 1/6 • Part A and B: From the first dose of study drug administration until 30+/-2 days after the last dose of study drug administration, assessed up to 18 months
Respiratory, thoracic and mediastinal disorders Epistaxis	33.3% 2/6 • Part A and B: From the first dose of study drug administration until 30+/-2 days after the last dose of study drug administration, assessed up to 18 months
Renal and urinary disorders Chromaturia	16.7% 1/6 • Part A and B: From the first dose of study drug administration until 30+/-2 days after the last dose of study drug administration, assessed up to 18 months
Vascular disorders Hypertension	16.7% 1/6 • Part A and B: From the first dose of study drug administration until 30+/-2 days after the last dose of study drug administration, assessed up to 18 months

Additional Information

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Results disclosure agreements

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