Neoplasms

All Conditions

Digestive System Diseases

Gland and Hormone Related Diseases

Rare Diseases

Adenocarcinoma

Pancreatic Neoplasms

Carcinoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Pancreatic Cancer

Antineoplastic Agents

All Drugs and Chemicals

Gastrointestinal Agents

Gemcitabine

Pancrelipase

Pancreatin

Antimetabolites

Subjects will receive pimasertib capsule orally once daily (qd) doses of 15, 30, 45, 68, 90, and 120 milligram (mg) on Day 1, 2, 3, 4, 5, 8, 9, 10, 11, 12, 15,16, 17, 18, 19, 22, 23, 24, 25, 26 and gemcitabine 1000 milligram per square meter (mg/m\^2) intravenous (IV) infusion for 30 minutes on Days 1, 8, 15, 22, 29, 36, and 43 followed by a 1-week rest (1 Cycle = 8 weeks).

Subjects will receive pimasertib capsule orally twice daily (bid) doses of 60 and 75 mg continuously for a 28-day cycle and gemcitabine 1000 mg/m\^2 intravenous (IV) infusion for 30 minutes on Days 1, 8, 15, 22, 29, 36, and 43 followed by a 1-week rest (1 Cycle = 8 weeks) (bid - continuous regimen).

Subjects will receive gemcitabine 1000 mg/m\^2 IV infusion on for 30 minutes on Day 1, 8, 15, 22, 29, 36, and 43 followed by a 1-week rest (Cycle 1) then on Days 1, 8, and 15 of a 28-day cycle and placebo matched to pimasertib orally bid - continuous regimen.

Subjects will receive gemcitabine 1000 mg/m\^2 IV infusion for 30 minutes on Day 1, 8, 15, 22, 29, 36, and 43 followed by a 1-week rest (Cycle 1) then on Days 1, 8, and 15 of a 28-day cycle and pimasertib capsule orally bid - continuous regimen.

Pimasertib

Placebo

Medical Responsible

The research trial is testing the experimental treatment MSC1936369B in combination with Gemcitabine, in subjects with metastatic pancreatic adenocarcinoma. The study will be run in two parts:

Safety Run-In: Will determine the Maximum Tolerated Dose (MTD) and the recommended Phase II dose of MSC1936369B, when combined with gemcitabine, in subjects with metastatic pancreatic adenocarcinoma.

Phase II: Will assess the anti-tumor activity of MSC1936369B combined with gemcitabine compared to gemcitabine alone as first line treatment in subjects with metastatic pancreatic adenocarcinoma.

Trial of Gemcitabine With or Without MSC1936369B in Pancreatic Cancer

Phase II Randomized Trial of MEK Inhibitor MSC1936369B or Placebo Combined With Gemcitabine in Metastatic Pancreas Cancer Subjects

DLT using the National Cancer Institute Common Terminology Criteria for Adverse Events(CTCAE) v3.0,was defined as any of the following toxicities at any dose level and judged to be possibly or probably related to trial medication by the Investigator and/or the Sponsor and relevant for the combination treatment: Grade 3/more non-hematological toxicity excluding: Subjects with liver involvement: Grade 4 asymptomatic increases in liver function tests and subject without liver involvement: Grade 3 asymptomatic increases in liver function tests reversible within 7 days. Grade 3 vomiting encountered despite adequate therapy. Grade 3 diarrhea encountered despite adequate anti diarrhea therapy. Grade 4 neutropenia greater (\>) 5 days duration or febrile neutropenia lasting for more than 1 day. Grade 4 thrombocytopenia \> 1 day/Grade 3 with bleeding. Grade 4 anemia: Any treatment delay \> 2 weeks due to drug-related adverse effects.

PFS was defined as the time from randomization to the first documentation of objective tumor progression (Complete Response (CR): Disappearance of all target lesions, Partial Response (PR): At least 30% decrease in the sum of the longest diameter of target lesions, taking as reference the sum of the longest diameter at baseline, Progressive Disease (PD): At least 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum of the longest diameter recorded since treatment started, or the appearance of 1 or more new lesions and stable disease: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of the longest diameter since treatment started) or to death due to any cause, whichever occurred first. PFS calculated as (Months) = Date of first PD or death or censoring date minus date of randomization plus 1) divided by 30.4375.

An adverse event (AE) was any untoward medical occurrence in a subjects who received study drug without regard to possibility of causal relationship. An serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. All AEs (serious and non-serious) except AEs recorded with an onset date prior to the first day of drug administration unless a worsening of the event was recorded after the first dosing date, in which case the event was counted as a TEAE. TEAEs include both SAEs and non-SAEs.

Plasma decay half-life was the time measured for the plasma concentration to decrease by one half.

AUC:0 to infinity was a measure of the serum concentration of the drug over time. It was used to characterize drug absorption.

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

Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes.

Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug.

Apparent volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug.

ERK phosphoprotein in peripheral blood monocytes (PBMCs) was analyzed from blood samples of all subjects in the SAF analysis set (safety-run part) only.

AUC:0 to infinity is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption.

Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.

Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed.

Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug.

An AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. All AEs (serious and non-serious) except AEs recorded with an onset date prior to the first day of drug administration unless a worsening of the event was recorded after the first dosing date, in which case the event was counted as a TEAE. TEAEs include both SAEs and non-SAEs.

Best overall response was defined as the presence of at least one complete response (CR), partial response (PR) or Stable Disease (SD) (using RECIST v1.0) during treatment. CR: Disappearance of all target lesions, PR: At least 30% decrease in the sum of the longest diameter of target lesions, taking as reference the sum of the longest diameter at baseline and SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of the longest diameter since treatment started.

Clinical Benefit was defined as the presence of at least one CR, PR or Stable Disease (SD) (using RECIST v1.0) during treatment. CR: Disappearance of all target lesions, PR: At least 30% decrease in the sum of the longest diameter of target lesions, taking as reference the sum of the longest diameter at baseline and SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of the longest diameter since treatment started.

Time to progression (TTP) is defined as the time (in months) from the randomization date to the date of progression prior to the start of any subsequent therapy for the primary disease, as reported and documented by the Investigator (i.e. radiological progression per RECIST).

Overall survival (OS) time is defined as the time (in months) from randomization to death.

Merck KGaA, Darmstadt, Germany

EMD Serono

Adverse Events were collected for SAF. SAF for safety run-in part included all subjects who had received at least 1 administration of trial medication (pimasertib or gemcitabine). SAF for Phase II included all subjects who had received at least 1 administration of trial medication Gemcitabine or Placebo if subject is in gemcitabine + Placebo arm (Arm 1) or at least 1 administration of trial medication MSC1936369B or gemcitabine if subject is in MSC1936369B + gemcitabine arm (Arm 2).

Subjects received pimasertib capsule orally once daily (qd) doses of 15, 30, 45, 68, 90, and 120 milligram (mg) on Day 1, 2, 3, 4, 5, 8, 9, 10, 11, 12, 15,16, 17, 18, 19, 22, 23, 24, 25, 26 and gemcitabine 1000 milligram per square meter (mg/m\^2) intravenous (IV) infusion for 30 minutes on Days 1, 8, 15, 22, 29, 36, and 43 followed by a 1-week rest (1 Cycle = 8 weeks).

Safety Run-in Part: Regimen 1

Subjects received pimasertib capsule orally twice daily (bid) doses of 60 and 75 mg continuously for a 28-day cycle and gemcitabine 1000 mg/m\^2 intravenous (IV) infusion for 30 minutes on Days 1, 8, 15, 22, 29, 36, and 43 followed by a 1-week rest (1 Cycle = 8 weeks).

Safety Run-in Part: Regimen 2

Subjects received gemcitabine 1000 mg/m\^2 for 30 minutes IV infusion on Days 1, 8, 15, 22, 29, 36, and 43 followed by a 1-week rest (Cycle 1) then on Days 1, 8, and 15 of a 28-day cycle and placebo orally bid - continuous regimen. Subjects with disease progression in Arm 1 were allowed crossover to receive pimasertib orally 60 mg bid - continuous regimen.

Phase II: Arm 1

Subjects received gemcitabine 1000 mg/m\^2 for 30 minutes IV infusion on Days 1, 8, 15, 22, 29, 36, and 43 followed by a 1-week rest (Cycle 1) then on Days 1, 8, and 15 of a 28-day cycle and pimasertib orally 60 mg bid - continuous regimen.

Phase II: Arm 2

Subjects received gemcitabine 1000 mg/m\^2 IV infusion on for 30 minutes on Day 1, 8, 15, 22, 29, 36, and 43 followed by a 1-week rest (Cycle 1) then on Days 1, 8, and 15 of a 28-day cycle and placebo matched to pimasertib orally bid - continuous regimen. Subjects with disease progression in Arm 1 were allowed crossover to receive pimasertib capsule orally 60 mg bid - continuous regimen.

Phase II: Arm 1 (Gemcitabine + Placebo)

Subjects received gemcitabine 1000 mg/m\^2 IV infusion on for 30 minutes on Day 1, 8, 15, 22, 29, 36, and 43 followed by a 1-week rest (Cycle 1) then on Days 1, 8, and 15 of a 28-day cycle and pimasertib capsule orally 60 mg bid - continuous regimen.

Phase II: Arm 2 (Gemcitabine + Pimasertib)

Total

Age, Categorical

Sex: Female, Male

The safety analysis set (SAF) analysis set for the safety run-in part included subjects who received at least 1 (non-zero) administration of trial medication (pimasertib or gemcitabine). For Phase II: Intention-to-treat (ITT) set included subjects who were randomized, as per Interactive Voice Response System (IVRS).

Merck KGaA Communication Center

Subjects received pimasertib capsule orally once daily (qd) doses of 15, mg on Day 1, 2, 3, 4, 5, 8, 9, 10, 11, 12, 15,16, 17, 18, 19, 22, 23, 24, 25, 26 and gemcitabine 1000 milligram per square meter (mg/m\^2) intravenous (IV) infusion for 30 minutes on Days 1, 8, 15, 22, 29, 36, and 43 followed by a 1-week rest (1 Cycle = 8 weeks).

Safety Run-in Part Regimen 1: 15 mg

Subjects received pimasertib capsule orally once daily (qd) doses of 30, mg on Day 1, 2, 3, 4, 5, 8, 9, 10, 11, 12, 15,16, 17, 18, 19, 22, 23, 24, 25, 26 and gemcitabine 1000 milligram per square meter (mg/m\^2) intravenous (IV) infusion for 30 minutes on Days 1, 8, 15, 22, 29, 36, and 43 followed by a 1-week rest (1 Cycle = 8 weeks).

Safety Run-in Part Regimen 1: 30 mg

Subjects received pimasertib capsule orally once daily (qd) doses of 45, mg on Day 1, 2, 3, 4, 5, 8, 9, 10, 11, 12, 15,16, 17, 18, 19, 22, 23, 24, 25, 26 and gemcitabine 1000 milligram per square meter (mg/m\^2) intravenous (IV) infusion for 30 minutes on Days 1, 8, 15, 22, 29, 36, and 43 followed by a 1-week rest (1 Cycle = 8 weeks).

Safety Run-in Part Regimen 1: 45 mg

Subjects received pimasertib capsule orally once daily (qd) doses of 68, mg on Day 1, 2, 3, 4, 5, 8, 9, 10, 11, 12, 15,16, 17, 18, 19, 22, 23, 24, 25, 26 and gemcitabine 1000 milligram per square meter (mg/m\^2) intravenous (IV) infusion for 30 minutes on Days 1, 8, 15, 22, 29, 36, and 43 followed by a 1-week rest (1 Cycle = 8 weeks).

Safety Run-in Part Regimen 1: 68 mg

Subjects received pimasertib capsule orally once daily (qd) doses of 90 mg on Day 1, 2, 3, 4, 5, 8, 9, 10, 11, 12, 15,16, 17, 18, 19, 22, 23, 24, 25, 26 and gemcitabine 1000 milligram per square meter (mg/m\^2) intravenous (IV) infusion for 30 minutes on Days 1, 8, 15, 22, 29, 36, and 43 followed by a 1-week rest (1 Cycle = 8 weeks).

Safety Run-in Part Regimen 1: 90 mg

Subjects received pimasertib capsule orally once daily (qd) doses of 120 mg on Day 1, 2, 3, 4, 5, 8, 9, 10, 11, 12, 15,16, 17, 18, 19, 22, 23, 24, 25, 26 and gemcitabine 1000 milligram per square meter (mg/m\^2) intravenous (IV) infusion for 30 minutes on Days 1, 8, 15, 22, 29, 36, and 43 followed by a 1-week rest (1 Cycle = 8 weeks).

Safety Run-in Part Regimen 1: 120 mg

Subject received pimasertib capsule orally twice daily (bid) continuously for a 28-day cycle (60 mg bid - continuous regimen) and gemcitabine 1000 mg/m\^2 intravenous (IV) infusion for 30 minutes on Days 1, 8, 15, 22, 29, 36, and 43 followed by a 1-week rest (Cycle 1 = 8 weeks).

Safety Run-in Part Regimen 2: 60 mg

Subject received pimasertib capsule orally twice daily (bid) continuously for a 28-day cycle (75 mg bid - continuous regimen) and gemcitabine 1000 mg/m\^2 intravenous (IV) infusion for 30 minutes on Days 1, 8, 15, 22, 29, 36, and 43 followed by a 1-week rest (Cycle 1 = 8 weeks).

Safety Run-in Part Regimen 2: 75 mg

DLT analysis set included all subjects of safety run-in part who received any dose of pimasertib on at least 18 out of 20/25 out of 28 of the planned days on pimasertib \& least 3 gemcitabine weekly infusions during first 28 days of treatment or experienced DLT during the 28 first days of treatment regardless of the amount of each drug received.

Safety Run-In Part: Number of Subjects With Dose Limiting Toxicities (DLTs)

Subjects received gemcitabine 1000 mg/m\^2 IV infusion on for 30 minutes on Day 1, 8, 15, 22, 29, 36, and 43 followed by a 1-week rest (Cycle 1) then on Days 1, 8, and 15 of a 28-day cycle and placebo orally bid - continuous regimen. Subjects with disease progression in Arm 1 were allowed crossover to receive pimasertib capsule orally 60 mg bid - continuous regimen.

Intent to Treat (ITT) analysis set included all subjects who had been randomized for the phase II part, as per the interactive voice response system (IVRS).

Phase II: Progression-Free Survival (PFS) Time

TEAEs

Serious TEAEs

Permanent treatment discontinuation of pimasertib

Permanent treatment discontinuation of gemcitabine

Safety analysis set (SAF) for the safety run-in part included all subjects who had received at least 1 administration of the trial medication (pimasertib or gemcitabine).

Safety Run-In Part: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Permanent Treatment Discontinuation

MSC1936369B on Days 1 (n=4,3,3,3,3,11)

MSC1936369B on Days 22 (n= 3,3,3,2,3,10)

Gemcitabine (dFdC) on Day 1 (n=4,3,3,3,3,11)

Gemcitabine (dFdC) on Day 22 (n= 2,3,3,2,3,9)

Metabolite (dFdU) on Day 1 (n= 4,3,3,3,3,11)

Metabolite (dFdU) on Day 22 (n= 2,3,3,2,3,10)

Regimen 1: 15 mg

Regimen 1: 30 mg

Regimen 1: 45 mg

Regimen 1: 68 mg

Regimen 1: 90 mg

Regimen 1: 120 mg

Pharmacokinetic set (PKS) of the safety run in part included subjects who had received at least the first dose of both drugs (i.e., gemcitabine and pimasertib), and provided PK samples as per the protocol for at least 24 hours following first dosing on Day1. Here "n" signifies number of subjects evaluable for each category at specified time point.

Safety Run-In Part: Maximum Concentration (Cmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU) for Regimen 1

Tmax: MSC1936369B on Day 1 (n= 4,3,3,3,3,11)

Tmax: MSC1936369B on Day 22 (n= 3,3,3 2,3,10)

Tmax: Gemcitabine (dFdC) on Day 1 (n=4,3,3,3,3,11)

Tmax: Gemcitabine (dFdC) on Day 22 (n=2,3,3,2,3,9)

Tmax: Metabolite (dFdU) on Day 1 (n=4,3,3,3,3,11)

Tmax: Metabolite (dFdU) on Day 22 (n=2,3,3,2,3,10

Subjects received pimasertib capsule orally once daily (qd) doses of 15 mg on Day 1, 2, 3, 4, 5, 8, 9, 10, 11, 12, 15,16, 17, 18, 19, 22, 23, 24, 25, 26 and gemcitabine 1000 milligram per square meter (mg/m\^2) intravenous (IV) infusion for 30 minutes on Days 1, 8, 15, 22, 29, 36, and 43 followed by a 1-week rest (1 Cycle = 8 weeks).

Subjects received pimasertib orally once daily (qd) 5-days-on / 2-days-off, continuously (Days 1 to 5, 8 to 12, 15 to 19, 22 to 26, and so on) dose of 68 mg and gemcitabine 1000 milligram per square meter (mg/m\^2) 30 minutes intravenous (IV) infusion on Days 1, 8, 15, 22, 29, 36, and 43 followed by a 1-week rest (Cycle 1 = 8 weeks) then on Days 1, 8, and 15 of a 28-day cycle.

Subjects received pimasertib orally once daily (qd) 5-days-on / 2-days-off, continuously (Days 1 to 5, 8 to 12, 15 to 19, 22 to 26, and so on) dose of 90 mg and gemcitabine 1000 milligram per square meter (mg/m\^2) 30 minutes intravenous (IV) infusion on Days 1, 8, 15, 22, 29, 36, and 43 followed by a 1-week rest (Cycle 1 = 8 weeks) then on Days 1, 8, and 15 of a 28-day cycle.

Subjects received pimasertib orally once daily (qd) 5-days-on / 2-days-off, continuously (Days 1 to 5, 8 to 12, 15 to 19, 22 to 26, and so on) dose of 120 mg and gemcitabine 1000 milligram per square meter (mg/m\^2) 30 minutes intravenous (IV) infusion on Days 1, 8, 15, 22, 29, 36, and 43 followed by a 1-week rest (Cycle 1 = 8 weeks) then on Days 1, 8, and 15 of a 28-day cycle.

PKS set of the safety run in part included subjects who had received at least the first dose of both drugs (i.e., gemcitabine and pimasertib), and provided PK samples as per the protocol for at least 24 hours following first dosing on Day 1. Here "n" signifies number of subjects evaluable for each category at specified time point.

Safety Run-In Part: Time to Reach Maximum Concentration (Tmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1

t1/2: MSC1936369B on Day 1 (n=4,3,3,2,3,11)

t1/2: MSC1936369B on Day 22 (n=2,2,3,2,3,8)

t1/2: Gemcitabine (dFdC) on Day 1 (n=4,3,3,3,3,11)

t1/2: Gemcitabine (dFdC) on Day 22 (n=2,2,1,2,2,9)

t1/2: Metabolite (dFdU) on Day 1 (n=4,3,3,3,3,11)

t1/2: Metabolite (dFdU) on Day 22(n=2,2,2,2,2,10)

Subjects received pimasertib capsule orally once daily (qd) doses of 30 mg on Day 1, 2, 3, 4, 5, 8, 9, 10, 11, 12, 15,16, 17, 18, 19, 22, 23, 24, 25, 26 and gemcitabine 1000 milligram per square meter (mg/m\^2) intravenous (IV) infusion for 30 minutes on Days 1, 8, 15, 22, 29, 36, and 43 followed by a 1-week rest (1 Cycle = 8 weeks).

Subjects received pimasertib capsule orally once daily (qd) doses of 45 mg on Day 1, 2, 3, 4, 5, 8, 9, 10, 11, 12, 15,16, 17, 18, 19, 22, 23, 24, 25, 26 and gemcitabine 1000 milligram per square meter (mg/m\^2) intravenous (IV) infusion for 30 minutes on Days 1, 8, 15, 22, 29, 36, and 43 followed by a 1-week rest (1 Cycle = 8 weeks).

Subjects received pimasertib capsule orally once daily (qd) doses of 68 mg on Day 1, 2, 3, 4, 5, 8, 9, 10, 11, 12, 15,16, 17, 18, 19, 22, 23, 24, 25, 26 and gemcitabine 1000 milligram per square meter (mg/m\^2) intravenous (IV) infusion for 30 minutes on Days 1, 8, 15, 22, 29, 36, and 43 followed by a 1-week rest (1 Cycle = 8 weeks).

Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1

AUC: MSC1936369B on Day 1 (n=4,3,3,3,3,11)

AUC: Gemcitabine (dFdC) on Day 1(n=4,3,3,3,3,11)

AUC: Gemcitabine (dFdC) on Day 22(n=2,2,1,2,2,9)

AUC: Metabolite (dFdU) on Day 1 (n=4,3,3,3,3,11)

AUC: Metabolite (dFdU) on Day 22 (n=2,2,2,2,2,10)

Regimen 1:15 mg

Regimen1: 120 mg

PKS of the safety run in part included subjects who had received at least the first dose of both drugs (i.e., gemcitabine and pimasertib), and provided PK samples as per the protocol for at least 24 hours following first dosing on Day 1. Here "n" signifies number of subjects evaluable for each category at specified time point.

Safety Run-In Part: Area Under Curve (AUC: 0 to Infinity) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 1

CL/f: MSC1936369B on Day 1 (n=4,3,3,2,3,11)

CL/f: MSC1936369B on Day 22 (n=2,2,3,2,3,9)

Safety Run-In Part: Apparent Oral Clearance (CL/f) of Pimasertib (MSC1936369B): Regimen 1

CL: Gemcitabine on Day 1 (n=4,3,3,3,3,11)

CL: Gemcitabine on Day 22 (n=2,2,1,2,2,9)

PKS set of the safety run in part included subjects who had received at least the first dose of both drugs (i.e., gemcitabine and pimasertib), and provided PK samples as per the protocol for at least 24 hours following first dosing on Day 1. Here "n" signifies those subjects who were evaluable at the specified time point.

Safety Run-In Part: Total Clearance (CL) of Gemcitabine: Regimen 1

V/f: MSC1936369B on Day 1 (n=4,3,3,2,3,11)

V/f: MSC1936369B on Day 22 (n=2,2,3,2,3,8)

Safety Run-In Part: Oral Volume of Distribution (V/f) of Pimasertib (MSC1936369B): Regimen 1

V: Gemcitabine (dFdC) on Day 1 (n= 4,3,3,3,3,11)

V: Gemcitabine (dFdC) on Day 22 (n=2,2,1,2,2,9)

Safety Run-In Part: Apparent Volume of Distribution (V) of Gemcitabine: Regimen 1

Cycle 1 Day 1 Pre-dose (n=3,2,2,3,3,7)

Cycle 1 Day 1 Post-dose (n=3,2,2,3,2,6)

Cycle 1 Day 2 Pre-dose (n=3,2,1,2,2,6)

Cycle 1 Day 22 Pre-dose (n=2,1,2,1,3,5)

Cycle 1 Day 22 Post-dose (n=0,0,0,0,2)

Pharmacodynamic population included SAF analysis set for the safety run-in part include all subjects who received at least 1 (non-zero) administration of the trial medication (pimasertib or gemcitabine). Here "n" signifies those subjects who were evaluable at the specified time point for each arm, respectively.

Safety Run-In Part: Levels of Pharmacodynamic (Pd) Markers (Phosphorylated- Extracellular Signal-Regulated Kinase (ERK) in Peripheral Blood Mononuclear Cells [PBMCs]): Regimen 1

MSC1936369B on Day 1 (n= 12,13)

MSC1936369B on Day 22 (n=10,9)

Gemcitabine (dFdC) on Day 1 (n=11,14)

Gemcitabine (dFdC) on Day 22 (n=9,4)

Gemcitabine Metabolite (dFdU) on Day 1 (n=11, 10)

Gemcitabine Metabolite (dFdU) on Day 22 (n=10,5)

Regimen 2: 60 mg

Regimen 2: 75 mg

Safety Run-In Part: Maximum Concentration (Cmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 2

AUC: MSC1936369B on Day 1 (n= 10, 11)

AUC: Gemcitabine (dFdC) on Day 1 (n= 11, 14)

AUC: Gemcitabine (dFdC) on Day 22 (n= 9, 4)

AUC: Metabolite (dFdU) on Day 1 (n= 11, 13)

AUC: Metabolite (dFdU) on Day 22 (n= 10, 5)

Regimen 1: 75 mg

Safety Run-In Part: Area Under Curve (AUC:0 to Infinity) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU) Regimen 2

Tmax: MSC1936369B on Day 1 (n=12,13)

Tmax: MSC1936369B on Day 22 (n=10,9)

Tmax: Gemcitabine (dFdC) on Day 1 (n=11,14)

Tmax: Gemcitabine (dFdC) on Day 22 (n=9,4)

Tmax: Metabolite (dFdU) on Day 1 (n=11,13)

Tmax: Metabolite (dFdU) on Day 22 (n=10,5)

PKS set of the safety run in part included subjects who had received at least the first dose of both drugs (i.e., gemcitabine and pimasertib), and provided PK samples as per the protocol for at least 24 hours following first dosing on Day 1.Here "n" signifies number of subjects evaluable for each category at specified time point.

Safety Run-In Part: Time to Reach Maximum Concentration (Tmax) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 2

t1/2: MSC1936369B on Day 1 (n=10,11)

t1/2: MSC1936369B on Day 22 (n=8,5)

t1/2: Gemcitabine (dFdC) on Day 1 (n=11,14)

t1/2: Gemcitabine (dFdC) on Day 22 (n=9,4)

t1/2: Metabolite (dFdU) on Day 1 (n=11,13)

t1/2: Metabolite (dFdU) on Day 22 (n=10,5)

Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of Pimasertib (MSC1936369B), Gemcitabine (dFdC), and Gemcitabine Inactive Metabolite 2',2'-Difluorodeoxyuridine (dFdU): Regimen 2

CL/f: MSC1936369B on Day 1 (n=10,11)

CL/f: MSC1936369B on Day 22 (n=8,5)

Safety Run-In Part: Apparent Oral Clearance (CL/f) of Pimasertib (MSC1936369B): Regimen 2

CL: Gemcitabine on Day 1 (n=11, 14)

CL: Gemcitabine on Day 22 (n=9, 4)

Subjects received pimasertib orally twice daily (bid) continuously without a break for a 28-day cycle (60 mg bid - continuous regimen) and gemcitabine 1000 milligram per square meter (mg/m\^2) 30 minutes intravenous (IV) infusion on Days 1, 8, 15, 22, 29, 36, and 43 followed by a 1-week rest (Cycle 1 = 8 weeks) then on Days 1, 8, and 15 of a 28-day cycle.

Subjects received pimasertib orally twice daily (bid) continuously without a break for a 28-day cycle (75 mg bid - continuous regimen) and gemcitabine 1000 milligram per square meter (mg/m\^2) 30 minutes intravenous (IV) infusion on Days 1, 8, 15, 22, 29, 36, and 43 followed by a 1-week rest (Cycle 1 = 8 weeks) then on Days 1, 8, and 15 of a 28-day cycle.

Spots Global Cancer Trial Database for Trial of Gemcitabine With or Without MSC1936369B in Pancreatic Cancer

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