Trial Outcomes & Findings for Refametinib (BAY86-9766) in Combination With Regorafenib (Stivarga, BAY73-4506) in Patients With Advanced or Metastatic Cancer (NCT NCT02168777)

NCT ID: NCT02168777

Last Updated: 2018-01-26

Results Overview

Maximum drug concentration in plasma after multiple dose for Refametinib. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.

• Recruitment status: TERMINATED
• Study phase: PHASE1
• Target enrollment: 20 participants
• Primary outcome timeframe: Cycle 1 Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8 and 12 hours post-dose
• Results posted on: 2018-01-26

Participant Flow

Study was planned to have two parts, Phase 1b part and Phase 2 part. For the Phase 1b part, altogether 34 participants were screened, and 14 out of them were screening failures.

The remaining 20 participants were assigned to and started treatment in one of three dose escalation cohorts. The Phase 2 part was not conducted.

Participant milestones

Measure	Ph1b-Refametinib/Regorafenib Cohort 0 Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort 0: Refametinib 30mg twice daily (b.i.d) + Regorafenib 80mg once daily (q.d), 3 weeks on/1 week off.	Ph1b-Refametinib/Regorafenib Cohort -1 Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort -1: Refametinib 20mg b.i.d + Regorafenib 80mg q.d, 3 weeks on/1 week off.	Ph1b-Refametinib/Regorafenib Cohort -1a Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort -1a: Refametinib 20mg b.i.d + Regorafenib 120mg q.d, 3 weeks on/1 week off.
Overall Study STARTED	2	7	11
Overall Study COMPLETED	0	0	0
Overall Study NOT COMPLETED	2	7	11

Reasons for withdrawal

Measure	Ph1b-Refametinib/Regorafenib Cohort 0 Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort 0: Refametinib 30mg twice daily (b.i.d) + Regorafenib 80mg once daily (q.d), 3 weeks on/1 week off.	Ph1b-Refametinib/Regorafenib Cohort -1 Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort -1: Refametinib 20mg b.i.d + Regorafenib 80mg q.d, 3 weeks on/1 week off.	Ph1b-Refametinib/Regorafenib Cohort -1a Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort -1a: Refametinib 20mg b.i.d + Regorafenib 120mg q.d, 3 weeks on/1 week off.
Overall Study Withdrawal by Subject	1	0	2
Overall Study Adverse Event	1	0	1
Overall Study Disease recurrence	0	0	1
Overall Study Radiological disease progression	0	5	5
Overall Study Clinical disease progression	0	1	2
Overall Study Other reason	0	1	0

Baseline Characteristics

Refametinib (BAY86-9766) in Combination With Regorafenib (Stivarga, BAY73-4506) in Patients With Advanced or Metastatic Cancer

Baseline characteristics by cohort

Measure	Ph1b-Refametinib/Regorafenib Cohort 0 n=2 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort 0: Refametinib 30mg twice daily (b.i.d) + Regorafenib 80mg once daily (q.d), 3 weeks on/1 week off.	Ph1b-Refametinib/Regorafenib Cohort -1 n=7 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort -1: Refametinib 20mg b.i.d + Regorafenib 80mg q.d, 3 weeks on/1 week off.	Ph1b-Refametinib/Regorafenib Cohort -1a n=11 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort -1a: Refametinib 20mg b.i.d + Regorafenib 120mg q.d, 3 weeks on/1 week off.	Total n=20 Participants Total of all reporting groups
Age, Continuous	57.0 Years STANDARD_DEVIATION 14.1 • n=5 Participants	56.6 Years STANDARD_DEVIATION 5.7 • n=7 Participants	58.6 Years STANDARD_DEVIATION 7.3 • n=5 Participants	57.8 Years STANDARD_DEVIATION 7.1 • n=4 Participants
Sex: Female, Male Female	1 Participants n=5 Participants	4 Participants n=7 Participants	4 Participants n=5 Participants	9 Participants n=4 Participants
Sex: Female, Male Male	1 Participants n=5 Participants	3 Participants n=7 Participants	7 Participants n=5 Participants	11 Participants n=4 Participants
Cancer types Colon and rectal cancer	1 Participants n=5 Participants	0 Participants n=7 Participants	4 Participants n=5 Participants	5 Participants n=4 Participants
Cancer types Other	1 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants	5 Participants n=4 Participants
Cancer types Non-small cell lung cancer	0 Participants n=5 Participants	3 Participants n=7 Participants	1 Participants n=5 Participants	4 Participants n=4 Participants
Cancer types Breast cancer	0 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants	4 Participants n=4 Participants
Cancer types Pancreatic adenocarcinoma	0 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants	2 Participants n=4 Participants

PRIMARY outcome

Timeframe: Cycle 1 Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8 and 12 hours post-dose

Population: Pharmacokinetic (PK) analysis set for multiple dose.

Maximum drug concentration in plasma after multiple dose for Refametinib. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.

Outcome measures

Measure	Ph1b-Refametinib/Regorafenib Cohort 0 n=2 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort 0: Refametinib 30mg twice daily (b.i.d) + Regorafenib 80mg once daily (q.d), 3 weeks on/1 week off.	Ph1b-Refametinib/Regorafenib Cohort -1 n=2 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort -1: Refametinib 20mg b.i.d + Regorafenib 80mg q.d, 3 weeks on/1 week off.	Ph1b-Refametinib/Regorafenib Cohort -1a n=9 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort -1a: Refametinib 20mg b.i.d + Regorafenib 120mg q.d, 3 weeks on/1 week off.
Maximum Drug Concentration in Plasma After Multiple Dose (Cmax,md) for Refametinib	NA μg/L Geometric Coefficient of Variation NA Both patients were either dose interrupted or discontinued the study.	315.9 μg/L Geometric Coefficient of Variation 43	390.7 μg/L Geometric Coefficient of Variation 52

PRIMARY outcome

Timeframe: Cycle 1 Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8 and 12 hours post-dose

Population: PK analysis set for multiple dose.

Maximum drug concentration in plasma after multiple dose for Refametinib metabolite M-11. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.

Outcome measures

Measure	Ph1b-Refametinib/Regorafenib Cohort 0 n=2 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort 0: Refametinib 30mg twice daily (b.i.d) + Regorafenib 80mg once daily (q.d), 3 weeks on/1 week off.	Ph1b-Refametinib/Regorafenib Cohort -1 n=2 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort -1: Refametinib 20mg b.i.d + Regorafenib 80mg q.d, 3 weeks on/1 week off.	Ph1b-Refametinib/Regorafenib Cohort -1a n=9 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort -1a: Refametinib 20mg b.i.d + Regorafenib 120mg q.d, 3 weeks on/1 week off.
Maximum Drug Concentration in Plasma After Multiple Dose (Cmax,md) for Refametinib Metabolite M-11	NA μg/L Geometric Coefficient of Variation NA Both patients were either dose interrupted or discontinued the study.	104.9 μg/L Geometric Coefficient of Variation 36	112.3 μg/L Geometric Coefficient of Variation 44

PRIMARY outcome

Timeframe: Cycle 1 Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8 and 12 hours post-dose

Population: PK analysis set for multiple dose.

Area under the plasma concentration-time curve from 0 to 12 h after multiple dose for Refametinib. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.

Outcome measures

Measure	Ph1b-Refametinib/Regorafenib Cohort 0 n=2 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort 0: Refametinib 30mg twice daily (b.i.d) + Regorafenib 80mg once daily (q.d), 3 weeks on/1 week off.	Ph1b-Refametinib/Regorafenib Cohort -1 n=2 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort -1: Refametinib 20mg b.i.d + Regorafenib 80mg q.d, 3 weeks on/1 week off.	Ph1b-Refametinib/Regorafenib Cohort -1a n=9 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort -1a: Refametinib 20mg b.i.d + Regorafenib 120mg q.d, 3 weeks on/1 week off.
Area Under the Plasma Concentration-time Curve From 0 to 12 h After Multiple Dose (AUC(0-12)md) for Refametinib	NA μg*h/L Geometric Coefficient of Variation NA Both patients were either dose interrupted or discontinued the study.	2399.2 μg*h/L Geometric Coefficient of Variation 65	3632.3 μg*h/L Geometric Coefficient of Variation 51

PRIMARY outcome

Timeframe: Cycle 1 Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8 and 12 hours post-dose

Population: PK analysis set for multiple dose.

Area under the plasma concentration-time curve from 0 to 12 h after multiple dose for Refametinib metabolite M-11. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.

Outcome measures

Measure	Ph1b-Refametinib/Regorafenib Cohort 0 n=2 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort 0: Refametinib 30mg twice daily (b.i.d) + Regorafenib 80mg once daily (q.d), 3 weeks on/1 week off.	Ph1b-Refametinib/Regorafenib Cohort -1 n=2 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort -1: Refametinib 20mg b.i.d + Regorafenib 80mg q.d, 3 weeks on/1 week off.	Ph1b-Refametinib/Regorafenib Cohort -1a n=9 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort -1a: Refametinib 20mg b.i.d + Regorafenib 120mg q.d, 3 weeks on/1 week off.
Area Under the Plasma Concentration-time Curve From 0 to 12 h After Multiple Dose (AUC(0-12)md) for Refametinib Metabolite M-11	NA μg*h/L Geometric Coefficient of Variation NA Both patients were either dose interrupted or discontinued the study.	1013.4 μg*h/L Geometric Coefficient of Variation 40	1144.7 μg*h/L Geometric Coefficient of Variation 39

PRIMARY outcome

Timeframe: Cycle 1 Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose

Population: PK analysis set for multiple dose.

Maximum drug concentration in plasma after multiple dose for Regorafenib. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.

Outcome measures

Measure	Ph1b-Refametinib/Regorafenib Cohort 0 n=2 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort 0: Refametinib 30mg twice daily (b.i.d) + Regorafenib 80mg once daily (q.d), 3 weeks on/1 week off.	Ph1b-Refametinib/Regorafenib Cohort -1 n=2 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort -1: Refametinib 20mg b.i.d + Regorafenib 80mg q.d, 3 weeks on/1 week off.	Ph1b-Refametinib/Regorafenib Cohort -1a n=8 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort -1a: Refametinib 20mg b.i.d + Regorafenib 120mg q.d, 3 weeks on/1 week off.
Maximum Drug Concentration in Plasma After Multiple Dose (Cmax,md) for Regorafenib	NA μg/L Geometric Coefficient of Variation NA Both patients were either dose interrupted or discontinued the study.	1966.0 μg/L Geometric Coefficient of Variation 17	2206.4 μg/L Geometric Coefficient of Variation 34

PRIMARY outcome

Timeframe: Cycle 1 Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose

Population: PK analysis set for multiple dose.

Maximum drug concentration in plasma after multiple dose for Regorafenib metabolite M-2. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.

Outcome measures

Measure	Ph1b-Refametinib/Regorafenib Cohort 0 n=2 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort 0: Refametinib 30mg twice daily (b.i.d) + Regorafenib 80mg once daily (q.d), 3 weeks on/1 week off.	Ph1b-Refametinib/Regorafenib Cohort -1 n=2 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort -1: Refametinib 20mg b.i.d + Regorafenib 80mg q.d, 3 weeks on/1 week off.	Ph1b-Refametinib/Regorafenib Cohort -1a n=8 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort -1a: Refametinib 20mg b.i.d + Regorafenib 120mg q.d, 3 weeks on/1 week off.
Maximum Drug Concentration in Plasma After Multiple Dose (Cmax,md) for Regorafenib Metabolite M-2	NA μg/L Geometric Coefficient of Variation NA Both patients were either dose interrupted or discontinued the study.	1409.1 μg/L Geometric Coefficient of Variation 20	1642.7 μg/L Geometric Coefficient of Variation 98

PRIMARY outcome

Timeframe: Cycle 1 Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose

Population: PK analysis set for multiple dose.

Maximum drug concentration in plasma after multiple dose for Regorafenib metabolite M-5. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.

Outcome measures

Measure	Ph1b-Refametinib/Regorafenib Cohort 0 n=2 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort 0: Refametinib 30mg twice daily (b.i.d) + Regorafenib 80mg once daily (q.d), 3 weeks on/1 week off.	Ph1b-Refametinib/Regorafenib Cohort -1 n=2 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort -1: Refametinib 20mg b.i.d + Regorafenib 80mg q.d, 3 weeks on/1 week off.	Ph1b-Refametinib/Regorafenib Cohort -1a n=8 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort -1a: Refametinib 20mg b.i.d + Regorafenib 120mg q.d, 3 weeks on/1 week off.
Maximum Drug Concentration in Plasma After Multiple Dose (Cmax,md) for Regorafenib Metabolite M-5	NA μg/L Geometric Coefficient of Variation NA Both patients were either dose interrupted or discontinued the study.	1148.8 μg/L Geometric Coefficient of Variation 90	1485.7 μg/L Geometric Coefficient of Variation 255

PRIMARY outcome

Timeframe: Cycle 1 Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose

Population: PK analysis set for multiple dose.

Area under the plasma concentration-time curve from 0 to 24 h after multiple dose for Regorafenib. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.

Outcome measures

Measure	Ph1b-Refametinib/Regorafenib Cohort 0 n=2 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort 0: Refametinib 30mg twice daily (b.i.d) + Regorafenib 80mg once daily (q.d), 3 weeks on/1 week off.	Ph1b-Refametinib/Regorafenib Cohort -1 n=2 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort -1: Refametinib 20mg b.i.d + Regorafenib 80mg q.d, 3 weeks on/1 week off.	Ph1b-Refametinib/Regorafenib Cohort -1a n=8 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort -1a: Refametinib 20mg b.i.d + Regorafenib 120mg q.d, 3 weeks on/1 week off.
Area Under the Plasma Concentration-time Curve From 0 to 24 h After Multiple Dose (AUC(0-24)md) for Regorafenib	NA μg*h/L Geometric Coefficient of Variation NA Both patients were either dose interrupted or discontinued the study.	32359.4 μg*h/L Geometric Coefficient of Variation 32	34352.2 μg*h/L Geometric Coefficient of Variation 38

PRIMARY outcome

Timeframe: Cycle 1 Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose

Population: PK analysis set for multiple dose.

Area under the plasma concentration-time curve from 0 to 24 h after multiple dose for Regorafenib metabolite M-2. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.

Outcome measures

Measure	Ph1b-Refametinib/Regorafenib Cohort 0 n=2 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort 0: Refametinib 30mg twice daily (b.i.d) + Regorafenib 80mg once daily (q.d), 3 weeks on/1 week off.	Ph1b-Refametinib/Regorafenib Cohort -1 n=2 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort -1: Refametinib 20mg b.i.d + Regorafenib 80mg q.d, 3 weeks on/1 week off.	Ph1b-Refametinib/Regorafenib Cohort -1a n=8 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort -1a: Refametinib 20mg b.i.d + Regorafenib 120mg q.d, 3 weeks on/1 week off.
Area Under the Plasma Concentration-time Curve From 0 to 24 h After Multiple Dose (AUC(0-24)md) for Regorafenib Metabolite M-2	NA μg*h/L Geometric Coefficient of Variation NA Both patients were either dose interrupted or discontinued the study.	24139.7 μg*h/L Geometric Coefficient of Variation 34	25826.2 μg*h/L Geometric Coefficient of Variation 100

PRIMARY outcome

Timeframe: Cycle 1 Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose

Population: PK analysis set for multiple dose.

Area under the plasma concentration-time curve from 0 to 24 h after multiple dose for Regorafenib metabolite M-5. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.

Outcome measures

Measure	Ph1b-Refametinib/Regorafenib Cohort 0 n=2 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort 0: Refametinib 30mg twice daily (b.i.d) + Regorafenib 80mg once daily (q.d), 3 weeks on/1 week off.	Ph1b-Refametinib/Regorafenib Cohort -1 n=2 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort -1: Refametinib 20mg b.i.d + Regorafenib 80mg q.d, 3 weeks on/1 week off.	Ph1b-Refametinib/Regorafenib Cohort -1a n=8 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort -1a: Refametinib 20mg b.i.d + Regorafenib 120mg q.d, 3 weeks on/1 week off.
Area Under the Plasma Concentration-time Curve From 0 to 24 h After Multiple Dose (AUC(0-24)md) for Regorafenib Metabolite M-5	NA μg*h/L Geometric Coefficient of Variation NA Both patients were either dose interrupted or discontinued the study.	20531.8 μg*h/L Geometric Coefficient of Variation 106	24029.3 μg*h/L Geometric Coefficient of Variation 265

PRIMARY outcome

Timeframe: Up to 12 months

Population: Phase 2 part was not conducted.

Tumor Response was defined as the best tumor response (Complete Response (CR), Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD)) observed during trial period assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. CR was defined as disappearance of tumor lesions, PR was defined as a decrease of at least 30% in the sum of tumor lesion sizes, SD was defined as steady state of disease, PD was defined as an increase of at least 20% in the sum of tumor lesions sizes.

Outcome measures

Outcome data not reported

PRIMARY outcome

Timeframe: At Cycle 1

Population: MTD analysis set: all participants who completed Cycle 1 or discontinued during Cycle 1 due to an adverse event or DLT in the dose escalation part.

Dose-limiting toxicities (DLTs) were analyzed in the maximum tolerated dose (MTD) analysis set, in which only the six first patients of each dose escalation Cohort could be included according to the modified Rolling-6 method that was applied in this study.

Outcome measures

Measure	Ph1b-Refametinib/Regorafenib Cohort 0 n=2 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort 0: Refametinib 30mg twice daily (b.i.d) + Regorafenib 80mg once daily (q.d), 3 weeks on/1 week off.	Ph1b-Refametinib/Regorafenib Cohort -1 n=6 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort -1: Refametinib 20mg b.i.d + Regorafenib 80mg q.d, 3 weeks on/1 week off.	Ph1b-Refametinib/Regorafenib Cohort -1a n=6 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort -1a: Refametinib 20mg b.i.d + Regorafenib 120mg q.d, 3 weeks on/1 week off.
Number of Participants With Dose Limiting Toxicities (DLTs) No	0 Participants NA	6 Participants 106	6 Participants 265
Number of Participants With Dose Limiting Toxicities (DLTs) Yes	2 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Cycle 1 Day 1 at 0 (pre-dose), 0.5, 1, 2, 4 and 8 hours post-dose

Population: PK analysis set for single dose.

Maximum drug concentration in plasma after single (first) dose for Refametinib and its metabolite M-11. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.

Outcome measures

Measure	Ph1b-Refametinib/Regorafenib Cohort 0 n=2 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort 0: Refametinib 30mg twice daily (b.i.d) + Regorafenib 80mg once daily (q.d), 3 weeks on/1 week off.	Ph1b-Refametinib/Regorafenib Cohort -1 n=7 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort -1: Refametinib 20mg b.i.d + Regorafenib 80mg q.d, 3 weeks on/1 week off.	Ph1b-Refametinib/Regorafenib Cohort -1a n=11 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort -1a: Refametinib 20mg b.i.d + Regorafenib 120mg q.d, 3 weeks on/1 week off.
Maximum Drug Concentration in Plasma After Single (First) Dose (Cmax) for Refametinib and Its Metabolite M-11 Refametinib	549.7 μg/L Geometric Coefficient of Variation 58	273.3 μg/L Geometric Coefficient of Variation 82	253.0 μg/L Geometric Coefficient of Variation 38
Maximum Drug Concentration in Plasma After Single (First) Dose (Cmax) for Refametinib and Its Metabolite M-11 Metabolite M-11	58.7 μg/L Geometric Coefficient of Variation 10	37.0 μg/L Geometric Coefficient of Variation 83	35.7 μg/L Geometric Coefficient of Variation 42

SECONDARY outcome

Timeframe: Cycle 1 Day 1 at 0 (pre-dose), 0.5, 1, 2, 4 and 8 hours post-dose

Population: PK analysis set for single dose.

Time to reach maximum drug concentration in plasma after single (first) dose for Refametinib and its metabolite M-11. Median and full range were reported.

Outcome measures

Measure	Ph1b-Refametinib/Regorafenib Cohort 0 n=2 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort 0: Refametinib 30mg twice daily (b.i.d) + Regorafenib 80mg once daily (q.d), 3 weeks on/1 week off.	Ph1b-Refametinib/Regorafenib Cohort -1 n=7 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort -1: Refametinib 20mg b.i.d + Regorafenib 80mg q.d, 3 weeks on/1 week off.	Ph1b-Refametinib/Regorafenib Cohort -1a n=11 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort -1a: Refametinib 20mg b.i.d + Regorafenib 120mg q.d, 3 weeks on/1 week off.
Time to Reach Maximum Drug Concentration in Plasma After Single (First) Dose (Tmax) for Refametinib and Its Metabolite M-11 Refametinib	2.5 h Interval 1.0 to 4.02	1.0 h Interval 0.77 to 7.5	4.0 h Interval 0.97 to 8.0
Time to Reach Maximum Drug Concentration in Plasma After Single (First) Dose (Tmax) for Refametinib and Its Metabolite M-11 Metabolite M-11	6.0 h Interval 4.02 to 8.0	4.0 h Interval 1.8 to 7.5	4.0 h Interval 1.93 to 8.0

SECONDARY outcome

Timeframe: Cycle 1 Day 1 at 0 (pre-dose), 0.5, 1, 2, 4 and 8 hours post-dose

Population: PK analysis set for single dose.

Area under the plasma concentration-time curve from 0 to 8 h after single (first) dose for Refametinib and its metabolite M-11. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.

Outcome measures

Measure	Ph1b-Refametinib/Regorafenib Cohort 0 n=2 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort 0: Refametinib 30mg twice daily (b.i.d) + Regorafenib 80mg once daily (q.d), 3 weeks on/1 week off.	Ph1b-Refametinib/Regorafenib Cohort -1 n=7 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort -1: Refametinib 20mg b.i.d + Regorafenib 80mg q.d, 3 weeks on/1 week off.	Ph1b-Refametinib/Regorafenib Cohort -1a n=10 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort -1a: Refametinib 20mg b.i.d + Regorafenib 120mg q.d, 3 weeks on/1 week off.
Area Under the Plasma Concentration-time Curve From 0 to 8 h (AUC(0-8)) After Single (First) Dose for Refametinib and Its Metabolite M-11 Refametinib	2377.1 μg*h/L Geometric Coefficient of Variation 63	1267.9 μg*h/L Geometric Coefficient of Variation 60	1314.6 μg*h/L Geometric Coefficient of Variation 26
Area Under the Plasma Concentration-time Curve From 0 to 8 h (AUC(0-8)) After Single (First) Dose for Refametinib and Its Metabolite M-11 Metabolite M-11	411 μg*h/L Geometric Coefficient of Variation NA Summary statistic was not performed due to only one valid patient.	212.6 μg*h/L Geometric Coefficient of Variation 82	206.8 μg*h/L Geometric Coefficient of Variation 48

SECONDARY outcome

Timeframe: Cycle 1 Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8 and 12 hours post-dose

Population: PK analysis set for multiple dose. On Day 21, one patient in Cohort 0 was dose reduced and the other patient was not dosed. Therefore no patient was evaluable.

Time to reach maximum drug concentration in plasma after multiple dose for Refametinib and its metabolite M-11. Median and full range were reported.

Outcome measures

Measure	Ph1b-Refametinib/Regorafenib Cohort 0 Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort 0: Refametinib 30mg twice daily (b.i.d) + Regorafenib 80mg once daily (q.d), 3 weeks on/1 week off.	Ph1b-Refametinib/Regorafenib Cohort -1 n=2 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort -1: Refametinib 20mg b.i.d + Regorafenib 80mg q.d, 3 weeks on/1 week off.	Ph1b-Refametinib/Regorafenib Cohort -1a n=9 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort -1a: Refametinib 20mg b.i.d + Regorafenib 120mg q.d, 3 weeks on/1 week off.
Time to Reach Maximum Drug Concentration in Plasma After Multiple Dose (Tmax,md) for Refametinib and Its Metabolite M-11 Refametinib	—	1.6 h Interval 1.2 to 2.0	4.0 h Interval 1.0 to 4.0
Time to Reach Maximum Drug Concentration in Plasma After Multiple Dose (Tmax,md) for Refametinib and Its Metabolite M-11 Metabolite M-11	—	3.0 h Interval 2.1 to 4.0	4.0 h Interval 0.0 to 4.03

SECONDARY outcome

Timeframe: Cycle 1 Day 1 at 0 (pre-dose), 0.5, 1, 2, 4, 8 and 24 hours post-dose

Population: PK analysis set for single dose.

Maximum drug concentration in plasma after single (first) dose for Regorafenib and its metabolites M-2 and M-5. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.

Outcome measures

Measure	Ph1b-Refametinib/Regorafenib Cohort 0 n=2 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort 0: Refametinib 30mg twice daily (b.i.d) + Regorafenib 80mg once daily (q.d), 3 weeks on/1 week off.	Ph1b-Refametinib/Regorafenib Cohort -1 n=6 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort -1: Refametinib 20mg b.i.d + Regorafenib 80mg q.d, 3 weeks on/1 week off.	Ph1b-Refametinib/Regorafenib Cohort -1a n=11 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort -1a: Refametinib 20mg b.i.d + Regorafenib 120mg q.d, 3 weeks on/1 week off.
Maximum Drug Concentration in Plasma After Single (First) Dose (Cmax) for Regorafenib and Its Metabolites M-2 and M-5 Regorafenib	952.0 μg/L Geometric Coefficient of Variation 34	794.2 μg/L Geometric Coefficient of Variation 128	1194.6 μg/L Geometric Coefficient of Variation 56
Maximum Drug Concentration in Plasma After Single (First) Dose (Cmax) for Regorafenib and Its Metabolites M-2 and M-5 Metabolite M-2	234.4 μg/L Geometric Coefficient of Variation 101	194.4 μg/L Geometric Coefficient of Variation 438	367.2 μg/L Geometric Coefficient of Variation 166
Maximum Drug Concentration in Plasma After Single (First) Dose (Cmax) for Regorafenib and Its Metabolites M-2 and M-5 Metabolite M-5	22.1 μg/L Geometric Coefficient of Variation 138	41.8 μg/L Geometric Coefficient of Variation 58	35.1 μg/L Geometric Coefficient of Variation 244

SECONDARY outcome

Timeframe: Cycle 1 Day 1 at 0 (pre-dose), 0.5, 1, 2, 4, 8 and 24 hours post-dose

Population: PK analysis set for single dose.

Time to reach maximum drug concentration in plasma after single (first) dose for Regorafenib and its metabolites M-2 and M-5. Median and full range were reported.

Outcome measures

Measure	Ph1b-Refametinib/Regorafenib Cohort 0 n=2 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort 0: Refametinib 30mg twice daily (b.i.d) + Regorafenib 80mg once daily (q.d), 3 weeks on/1 week off.	Ph1b-Refametinib/Regorafenib Cohort -1 n=6 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort -1: Refametinib 20mg b.i.d + Regorafenib 80mg q.d, 3 weeks on/1 week off.	Ph1b-Refametinib/Regorafenib Cohort -1a n=11 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort -1a: Refametinib 20mg b.i.d + Regorafenib 120mg q.d, 3 weeks on/1 week off.
Time to Reach Maximum Drug Concentration in Plasma After Single (First) Dose (Tmax) for Regorafenib and Its Metabolites M-2 and M-5 Regorafenib	23.9 h Interval 23.75 to 23.98	8.0 h Interval 2.0 to 24.12	7.6 h Interval 2.0 to 23.95
Time to Reach Maximum Drug Concentration in Plasma After Single (First) Dose (Tmax) for Regorafenib and Its Metabolites M-2 and M-5 Metabolite M-2	23.9 h Interval 23.75 to 23.98	8.0 h Interval 3.88 to 24.12	7.6 h Interval 3.97 to 25.25
Time to Reach Maximum Drug Concentration in Plasma After Single (First) Dose (Tmax) for Regorafenib and Its Metabolites M-2 and M-5 Metabolite M-5	23.9 h Interval 23.75 to 23.98	23.6 h Interval 8.0 to 24.12	23.8 h Interval 23.52 to 24.17

SECONDARY outcome

Timeframe: Cycle 1 Day 1 at 0 (pre-dose), 0.5, 1, 2, 4, 8 and 24 hours post-dose

Population: PK analysis set for single dose.

Area under the plasma concentration-time curve from 0 to 24 h after single (first) dose for Regorafenib and its metabolites M-2 and M-5. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.

Outcome measures

Measure	Ph1b-Refametinib/Regorafenib Cohort 0 n=2 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort 0: Refametinib 30mg twice daily (b.i.d) + Regorafenib 80mg once daily (q.d), 3 weeks on/1 week off.	Ph1b-Refametinib/Regorafenib Cohort -1 n=6 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort -1: Refametinib 20mg b.i.d + Regorafenib 80mg q.d, 3 weeks on/1 week off.	Ph1b-Refametinib/Regorafenib Cohort -1a n=11 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort -1a: Refametinib 20mg b.i.d + Regorafenib 120mg q.d, 3 weeks on/1 week off.
Area Under the Plasma Concentration-time Curve From 0 to 24 h (AUC(0-24)) After Single (First) Dose for Regorafenib and Its Metabolites M-2 and M-5 Regorafenib	14642.6 μg*h/L Geometric Coefficient of Variation 32	13524.8 μg*h/L Geometric Coefficient of Variation 142	17475.7 μg*h/L Geometric Coefficient of Variation 46
Area Under the Plasma Concentration-time Curve From 0 to 24 h (AUC(0-24)) After Single (First) Dose for Regorafenib and Its Metabolites M-2 and M-5 Metabolite M-2	3964.2 μg*h/L Geometric Coefficient of Variation 97	3306.6 μg*h/L Geometric Coefficient of Variation 452	6743.1 μg*h/L Geometric Coefficient of Variation 102
Area Under the Plasma Concentration-time Curve From 0 to 24 h (AUC(0-24)) After Single (First) Dose for Regorafenib and Its Metabolites M-2 and M-5 Metabolite M-5	499 μg*h/L Geometric Coefficient of Variation NA Summary statistic was not performed due to only one valid patient.	654.4 μg*h/L Geometric Coefficient of Variation 91	794.2 μg*h/L Geometric Coefficient of Variation 95

SECONDARY outcome

Timeframe: Cycle 1 Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose

Population: PK analysis set for multiple dose. On Day 21, one patient in Cohort 0 was dose reduced and the other patient was not dosed. Therefore no patient was evaluable.

Time to reach maximum drug concentration in plasma after multiple dose for Regorafenib and its metabolites M-2 and M-5. Median and full range were reported.

Outcome measures

Measure	Ph1b-Refametinib/Regorafenib Cohort 0 Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort 0: Refametinib 30mg twice daily (b.i.d) + Regorafenib 80mg once daily (q.d), 3 weeks on/1 week off.	Ph1b-Refametinib/Regorafenib Cohort -1 n=2 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort -1: Refametinib 20mg b.i.d + Regorafenib 80mg q.d, 3 weeks on/1 week off.	Ph1b-Refametinib/Regorafenib Cohort -1a n=8 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort -1a: Refametinib 20mg b.i.d + Regorafenib 120mg q.d, 3 weeks on/1 week off.
Time to Reach Maximum Drug Concentration in Plasma After Multiple Dose (Tmax,md) for Regorafenib and Its Metabolites M-2 and M-5 Regorafenib	—	6.0 h Interval 0.0 to 12.0	6.0 h Interval 0.0 to 24.38
Time to Reach Maximum Drug Concentration in Plasma After Multiple Dose (Tmax,md) for Regorafenib and Its Metabolites M-2 and M-5 Metabolite M-2	—	11.5 h Interval 10.93 to 12.0	9.4 h Interval 0.0 to 24.38
Time to Reach Maximum Drug Concentration in Plasma After Multiple Dose (Tmax,md) for Regorafenib and Its Metabolites M-2 and M-5 Metabolite M-5	—	12.0 h Interval 0.0 to 24.08	9.4 h Interval 0.0 to 24.38

SECONDARY outcome

Timeframe: From start of treatment until progression is documented

Population: Full analysis set

Tumor Response was defined as the best tumor response (Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progressive Disease (PD)) observed during trial period assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST). CR was defined as disappearance of all target and non-target tumor lesions, PR was defined as a decrease of at least 30% in the sum of diameters of target lesions, SD was defined neither sufficient shrinkage for PR nor sufficient increase for PD, PD was defined as an increase of at least 20% in the sum of diameters of target lesions.

Outcome measures

Measure	Ph1b-Refametinib/Regorafenib Cohort 0 n=1 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort 0: Refametinib 30mg twice daily (b.i.d) + Regorafenib 80mg once daily (q.d), 3 weeks on/1 week off.	Ph1b-Refametinib/Regorafenib Cohort -1 n=7 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort -1: Refametinib 20mg b.i.d + Regorafenib 80mg q.d, 3 weeks on/1 week off.	Ph1b-Refametinib/Regorafenib Cohort -1a n=11 Participants Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort -1a: Refametinib 20mg b.i.d + Regorafenib 120mg q.d, 3 weeks on/1 week off.
Tumor Response During Phase 1b as Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 Stable Disease	1 Participants	2 Participants	5 Participants
Tumor Response During Phase 1b as Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 Progressive Disease	0 Participants	5 Participants	6 Participants

SECONDARY outcome

Timeframe: Up to 12 months after last patient first visit

Population: Phase 2 part was not conducted.

Overall survival (OS) was defined as the time (days) from the treatment start date to the date of death due to any cause. For participants who were still alive or who were lost to follow-up as of the database cutoff date for the primary completion, OS was censored at the last known alive date on or prior to the database cutoff date.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: From start of treatment until progression is documented

Population: Phase 2 part was not conducted.

Time to progression was defined as the time (days) from the treatment start date to the disease progression on or following the start date. Participants not experiencing progression at the database cutoff date for primary completion were censored at the last assessment.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: From start of treatment until progression is documented

Population: Phase 2 part was not conducted.

Progression-free survival was defined as the time from date of treatment assignment to date of first observed disease progression or death due to any cause, if death occurred while the participant was in the study and before progression was observed.

Outcome measures

Outcome data not reported

Adverse Events

Ph1b - Refametinib/Regorafenib Cohort 0

Serious events: 0 serious events

Other events: 2 other events

Deaths: 0 deaths

Ph1b - Refametinib/Regorafenib Cohort -1

Serious events: 4 serious events

Other events: 7 other events

Deaths: 0 deaths

Ph1b - Refametinib/Regorafenib Cohort -1a

Serious events: 5 serious events

Other events: 11 other events

Deaths: 0 deaths

Serious adverse events

Measure	Ph1b - Refametinib/Regorafenib Cohort 0 n=2 participants at risk Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort 0: Refametinib 30mg twice daily (b.i.d) + Regorafenib 80mg once daily (q.d), 3 weeks on/1 week off.	Ph1b - Refametinib/Regorafenib Cohort -1 n=7 participants at risk Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort -1: Refametinib 20mg b.i.d + Regorafenib 80mg q.d, 3 weeks on/1 week off.	Ph1b - Refametinib/Regorafenib Cohort -1a n=11 participants at risk Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort -1a: Refametinib 20mg b.i.d + Regorafenib 120mg q.d, 3 weeks on/1 week off.
Hepatobiliary disorders Cholangitis	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	14.3% 1/7 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/11 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Infections and infestations Urinary tract infection	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	14.3% 1/7 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/11 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Infections and infestations Wound infection	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	9.1% 1/11 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Investigations Blood creatine phosphokinase increased	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	18.2% 2/11 • Number of events 2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Investigations Troponin increased	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	14.3% 1/7 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/11 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Metabolism and nutrition disorders Dehydration	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	14.3% 1/7 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/11 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Metabolism and nutrition disorders Hypokalaemia	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	9.1% 1/11 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Pancreatic carcinoma	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	9.1% 1/11 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Renal and urinary disorders Acute kidney injury	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	9.1% 1/11 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	9.1% 1/11 • Number of events 2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Vascular disorders Hypertension	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	14.3% 1/7 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/11 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Vascular disorders Embolism	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	9.1% 1/11 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.

Other adverse events

Measure	Ph1b - Refametinib/Regorafenib Cohort 0 n=2 participants at risk Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort 0: Refametinib 30mg twice daily (b.i.d) + Regorafenib 80mg once daily (q.d), 3 weeks on/1 week off.	Ph1b - Refametinib/Regorafenib Cohort -1 n=7 participants at risk Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort -1: Refametinib 20mg b.i.d + Regorafenib 80mg q.d, 3 weeks on/1 week off.	Ph1b - Refametinib/Regorafenib Cohort -1a n=11 participants at risk Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort -1a: Refametinib 20mg b.i.d + Regorafenib 120mg q.d, 3 weeks on/1 week off.
Blood and lymphatic system disorders Anaemia	50.0% 1/2 • Number of events 3 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	42.9% 3/7 • Number of events 7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	36.4% 4/11 • Number of events 7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Blood and lymphatic system disorders Leukocytosis	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	14.3% 1/7 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/11 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Blood and lymphatic system disorders Leukopenia	50.0% 1/2 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/11 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Blood and lymphatic system disorders Lymphopenia	50.0% 1/2 • Number of events 2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/11 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Blood and lymphatic system disorders Neutropenia	50.0% 1/2 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/11 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Blood and lymphatic system disorders Thrombocytopenia	100.0% 2/2 • Number of events 4 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	9.1% 1/11 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Endocrine disorders Hypothyroidism	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	18.2% 2/11 • Number of events 3 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Eye disorders Dry eye	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	28.6% 2/7 • Number of events 2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/11 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Eye disorders Eye pain	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	14.3% 1/7 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/11 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Eye disorders Iridocyclitis	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	14.3% 1/7 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/11 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Eye disorders Photopsia	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	9.1% 1/11 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Eye disorders Vision blurred	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	14.3% 1/7 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	9.1% 1/11 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Eye disorders Visual impairment	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	9.1% 1/11 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Gastrointestinal disorders Abdominal pain	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	57.1% 4/7 • Number of events 8 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	9.1% 1/11 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Gastrointestinal disorders Constipation	50.0% 1/2 • Number of events 2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	42.9% 3/7 • Number of events 3 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	27.3% 3/11 • Number of events 4 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Gastrointestinal disorders Diarrhoea	100.0% 2/2 • Number of events 9 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	57.1% 4/7 • Number of events 4 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	81.8% 9/11 • Number of events 29 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Gastrointestinal disorders Dry mouth	50.0% 1/2 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	14.3% 1/7 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	18.2% 2/11 • Number of events 2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Gastrointestinal disorders Dyspepsia	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	9.1% 1/11 • Number of events 3 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Gastrointestinal disorders Faecal incontinence	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	9.1% 1/11 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Gastrointestinal disorders Flatulence	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	14.3% 1/7 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/11 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Gastrointestinal disorders Gastrooesophageal reflux disease	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	18.2% 2/11 • Number of events 2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Gastrointestinal disorders Nausea	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	28.6% 2/7 • Number of events 3 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	36.4% 4/11 • Number of events 8 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Gastrointestinal disorders Oral pain	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	14.3% 1/7 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/11 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Gastrointestinal disorders Rectal haemorrhage	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	9.1% 1/11 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Gastrointestinal disorders Stomatitis	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	14.3% 1/7 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	9.1% 1/11 • Number of events 2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Gastrointestinal disorders Vomiting	50.0% 1/2 • Number of events 3 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	28.6% 2/7 • Number of events 2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	18.2% 2/11 • Number of events 2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Gastrointestinal disorders Lip disorder	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	14.3% 1/7 • Number of events 2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/11 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Gastrointestinal disorders Haemorrhoidal haemorrhage	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	9.1% 1/11 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Gastrointestinal disorders Hypoaesthesia oral	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	9.1% 1/11 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Gastrointestinal disorders Paraesthesia oral	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	14.3% 1/7 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/11 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
General disorders Chills	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	28.6% 2/7 • Number of events 2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	9.1% 1/11 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
General disorders Fatigue	100.0% 2/2 • Number of events 9 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	57.1% 4/7 • Number of events 6 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	72.7% 8/11 • Number of events 24 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
General disorders Malaise	50.0% 1/2 • Number of events 2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/11 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
General disorders Mucosal inflammation	50.0% 1/2 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	18.2% 2/11 • Number of events 2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
General disorders Oedema peripheral	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	18.2% 2/11 • Number of events 5 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
General disorders Pain	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	9.1% 1/11 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
General disorders Pyrexia	50.0% 1/2 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	14.3% 1/7 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	27.3% 3/11 • Number of events 3 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
General disorders Localised oedema	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	9.1% 1/11 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Hepatobiliary disorders Hyperbilirubinaemia	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	9.1% 1/11 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Infections and infestations Bacteraemia	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	14.3% 1/7 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/11 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Infections and infestations Cystitis	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	9.1% 1/11 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Infections and infestations Fungal skin infection	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	9.1% 1/11 • Number of events 2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Infections and infestations Herpes zoster	50.0% 1/2 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/11 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Infections and infestations Otitis externa	50.0% 1/2 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/11 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Infections and infestations Urinary tract infection	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	28.6% 2/7 • Number of events 2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	36.4% 4/11 • Number of events 4 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Infections and infestations Groin infection	50.0% 1/2 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/11 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Infections and infestations Mastitis fungal	50.0% 1/2 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/11 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Injury, poisoning and procedural complications Wound complication	50.0% 1/2 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/11 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Injury, poisoning and procedural complications Post procedural contusion	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	14.3% 1/7 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/11 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Investigations Activated partial thromboplastin time prolonged	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	9.1% 1/11 • Number of events 2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Investigations Alanine aminotransferase increased	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	18.2% 2/11 • Number of events 2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Investigations Amylase increased	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	14.3% 1/7 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/11 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Investigations Aspartate aminotransferase increased	100.0% 2/2 • Number of events 4 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	54.5% 6/11 • Number of events 11 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Investigations Blood bilirubin increased	50.0% 1/2 • Number of events 7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/11 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Investigations Blood creatine phosphokinase increased	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	28.6% 2/7 • Number of events 3 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	45.5% 5/11 • Number of events 12 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Investigations Blood creatinine increased	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	14.3% 1/7 • Number of events 3 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	27.3% 3/11 • Number of events 5 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Investigations Blood lactate dehydrogenase increased	50.0% 1/2 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/11 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Investigations Blood thyroid stimulating hormone increased	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	9.1% 1/11 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Investigations Electrocardiogram QT prolonged	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	9.1% 1/11 • Number of events 2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Investigations Lipase increased	50.0% 1/2 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	14.3% 1/7 • Number of events 4 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	27.3% 3/11 • Number of events 3 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Investigations Platelet count decreased	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	14.3% 1/7 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/11 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Investigations Weight decreased	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	42.9% 3/7 • Number of events 3 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	9.1% 1/11 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Investigations Ejection fraction decreased	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	14.3% 1/7 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	9.1% 1/11 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Investigations Urine leukocyte esterase positive	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	9.1% 1/11 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Investigations Electrocardiogram PR prolongation	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	9.1% 1/11 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Investigations Blood alkaline phosphatase increased	100.0% 2/2 • Number of events 2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	18.2% 2/11 • Number of events 2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Metabolism and nutrition disorders Dehydration	50.0% 1/2 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	27.3% 3/11 • Number of events 4 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Metabolism and nutrition disorders Hypercalcaemia	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	14.3% 1/7 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/11 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Metabolism and nutrition disorders Hyperkalaemia	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	14.3% 1/7 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	9.1% 1/11 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Metabolism and nutrition disorders Hypermagnesaemia	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	9.1% 1/11 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Metabolism and nutrition disorders Hypoalbuminaemia	100.0% 2/2 • Number of events 4 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	45.5% 5/11 • Number of events 6 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Metabolism and nutrition disorders Hypokalaemia	100.0% 2/2 • Number of events 3 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	14.3% 1/7 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/11 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Metabolism and nutrition disorders Hypomagnesaemia	100.0% 2/2 • Number of events 2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	14.3% 1/7 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	27.3% 3/11 • Number of events 5 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Metabolism and nutrition disorders Hyponatraemia	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	28.6% 2/7 • Number of events 2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/11 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Metabolism and nutrition disorders Hypophosphataemia	100.0% 2/2 • Number of events 4 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/11 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Metabolism and nutrition disorders Decreased appetite	50.0% 1/2 • Number of events 3 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	14.3% 1/7 • Number of events 2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	45.5% 5/11 • Number of events 5 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Musculoskeletal and connective tissue disorders Back pain	50.0% 1/2 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	28.6% 2/7 • Number of events 3 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	18.2% 2/11 • Number of events 5 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Musculoskeletal and connective tissue disorders Flank pain	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	9.1% 1/11 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Musculoskeletal and connective tissue disorders Muscle spasms	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	42.9% 3/7 • Number of events 4 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/11 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Musculoskeletal and connective tissue disorders Muscular weakness	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	14.3% 1/7 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/11 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	14.3% 1/7 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/11 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Musculoskeletal and connective tissue disorders Myalgia	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	14.3% 1/7 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	9.1% 1/11 • Number of events 4 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Musculoskeletal and connective tissue disorders Pain in jaw	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	14.3% 1/7 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/11 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	14.3% 1/7 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/11 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Nervous system disorders Burning sensation	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	9.1% 1/11 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Nervous system disorders Dysgeusia	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	9.1% 1/11 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Nervous system disorders Headache	50.0% 1/2 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	14.3% 1/7 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	9.1% 1/11 • Number of events 2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Nervous system disorders Hypoaesthesia	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	9.1% 1/11 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Nervous system disorders Memory impairment	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	14.3% 1/7 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/11 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Nervous system disorders Mental impairment	50.0% 1/2 • Number of events 2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/11 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Nervous system disorders Peripheral sensory neuropathy	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	14.3% 1/7 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/11 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Nervous system disorders Presyncope	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	28.6% 2/7 • Number of events 2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/11 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Nervous system disorders Somnolence	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	14.3% 1/7 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	9.1% 1/11 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Psychiatric disorders Anxiety	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	14.3% 1/7 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	9.1% 1/11 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Psychiatric disorders Depression	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	14.3% 1/7 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/11 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Psychiatric disorders Insomnia	50.0% 1/2 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	9.1% 1/11 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Psychiatric disorders Mental status changes	50.0% 1/2 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/11 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Renal and urinary disorders Dysuria	50.0% 1/2 • Number of events 2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/11 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Renal and urinary disorders Micturition urgency	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	9.1% 1/11 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Renal and urinary disorders Pollakiuria	50.0% 1/2 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	9.1% 1/11 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Renal and urinary disorders Urinary tract pain	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	9.1% 1/11 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Renal and urinary disorders Renal impairment	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	14.3% 1/7 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/11 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Renal and urinary disorders Acute kidney injury	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	9.1% 1/11 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Reproductive system and breast disorders Pelvic pain	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	14.3% 1/7 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/11 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Reproductive system and breast disorders Penile pain	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	9.1% 1/11 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Reproductive system and breast disorders Genital burning sensation	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	9.1% 1/11 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Respiratory, thoracic and mediastinal disorders Cough	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	14.3% 1/7 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/11 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	28.6% 2/7 • Number of events 2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	9.1% 1/11 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Respiratory, thoracic and mediastinal disorders Dyspnoea exertional	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	18.2% 2/11 • Number of events 5 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Skin and subcutaneous tissue disorders Alopecia	50.0% 1/2 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	18.2% 2/11 • Number of events 2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Skin and subcutaneous tissue disorders Decubitus ulcer	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	9.1% 1/11 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Skin and subcutaneous tissue disorders Dermatitis acneiform	100.0% 2/2 • Number of events 4 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	28.6% 2/7 • Number of events 2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	27.3% 3/11 • Number of events 5 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Skin and subcutaneous tissue disorders Dry skin	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	14.3% 1/7 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/11 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Skin and subcutaneous tissue disorders Nail discolouration	50.0% 1/2 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/11 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Skin and subcutaneous tissue disorders Pain of skin	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	9.1% 1/11 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Skin and subcutaneous tissue disorders Palmar-plantar erythrodysaesthesia syndrome	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	18.2% 2/11 • Number of events 2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Skin and subcutaneous tissue disorders Photosensitivity reaction	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	9.1% 1/11 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Skin and subcutaneous tissue disorders Pruritus	50.0% 1/2 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	9.1% 1/11 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Skin and subcutaneous tissue disorders Rash	50.0% 1/2 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	14.3% 1/7 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	45.5% 5/11 • Number of events 8 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Skin and subcutaneous tissue disorders Rash papular	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	9.1% 1/11 • Number of events 2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Skin and subcutaneous tissue disorders Skin ulcer	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	9.1% 1/11 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Skin and subcutaneous tissue disorders Pruritus generalised	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	14.3% 1/7 • Number of events 1 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/11 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Vascular disorders Hypertension	50.0% 1/2 • Number of events 2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	28.6% 2/7 • Number of events 3 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	27.3% 3/11 • Number of events 10 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.
Vascular disorders Hot flush	0.00% 0/2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	0.00% 0/7 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.	9.1% 1/11 • Number of events 2 • From the start of study treatment until 30 days after last dose of study drug treatment. One subject had an Adverse Event which resulted in death, which was judged as unrelated to both study drugs.

Additional Information

Therapeutic Area Head

BAYER

Email: clinical-trials-contact@bayer.com

Results disclosure agreements

• Principal investigator is a sponsor employee Written consent must be obtained from Bayer prior to any information being submitted for publication. Material proposed for publication or presentation must be provided to Bayer at least 60 days prior to submission.
• Publication restrictions are in place

Restriction type: OTHER