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Clinical Trial Results:
Phase II randomized trial of MEK inhibitor MSC1936369B or placebo combined with gemcitabine in metastatic pancreas cancer subjects.

Due to the EudraCT – Results system being out of service between 31 July 2015 and 12 January 2016, these results have been published in compliance with revised timelines.

Summary
EudraCT number	2009-011992-61
Trial protocol	ES BE FR DE GB
Global end of trial date	19 Feb 2015

Results information
Results version number	v1(current)
This version publication date	28 Jul 2016
First version publication date	28 Jul 2016
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

EMR200066_003

ISRCTN number

US NCT number

NCT01016483

WHO universal trial number (UTN)

Sponsor organisation name

Merck KGaA

Sponsor organisation address

Frankfurter Strasse 250,, Darmstadt, Germany, 64293

Public contact

Merck KGaA, Communication Centre Merck KGaA, Merck Serono, +49 6151725200, service@merckgroup.com

Scientific contact

Merck KGaA, Communication Centre Merck KGaA, Merck KGaA, +49 6151725200, service@merckgroup.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

30 Dec 2013

Is this the analysis of the primary completion data?

Yes

Primary completion date

01 Dec 2013

Global end of trial reached?

Yes

Global end of trial date

19 Feb 2015

Was the trial ended prematurely?

Main objective of the trial

To determine the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D) of MSC1936369B (pimasertib) when combined with gemcitabine in subjects with metastatic pancreatic adenocarcinoma for each of the 2 treatment regimens.

Protection of trial subjects

Subject protection was ensured by following high medical and ethical standards in accordance with the principles laid down in the Declaration of Helsinki, and that are consistent with Good Clinical Practice and applicable regulations.

Background therapy

Evidence for comparator

Actual start date of recruitment

01 Nov 2009

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Spain: 28

Country: Number of subjects enrolled

United Kingdom: 5

Country: Number of subjects enrolled

United States: 4

Country: Number of subjects enrolled

Belgium: 34

Country: Number of subjects enrolled

France: 16

Country: Number of subjects enrolled

Germany: 3

Country: Number of subjects enrolled

Italy: 10

Country: Number of subjects enrolled

Russian Federation: 17

Country: Number of subjects enrolled

Serbia: 24

Worldwide total number of subjects

141

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

First/last subject (informed consent): Nov 2009/Jul 2013. Clinical data cut off: Dec 2013, Study completion date: April 2015

Screening details

Safety Run-In Part: Total of 68 subjects were enrolled out of which 53 subject were treated (27 Subject in Regimen 1 and 26 Subject in Regimen 2). Phase II: Total 104 subjects were screened. 88 subjects were randomized: 44 subjects each in Arm 1 and Arm 2 respectively.

Period 1 title

Safety Run-in Part

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Carer, Assessor

Are arms mutually exclusive

Yes

Safety Run-in Part: Regimen 1

Arm description

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).

Arm type

Experimental

Investigational medicinal product name

Pimasertib

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Pimasertib was administered as 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.

Investigational medicinal product name

Gemcitabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Gemcitabine was administered as 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 2

Arm description

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).

Arm type

Experimental

Investigational medicinal product name

Pimasertib

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Pimasertib capsule was administered orally twice daily (bid) doses of 60 and 75 mg continuously for a 28-day cycle.

Investigational medicinal product name

Gemcitabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Gemcitabine was administered as 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).

Part II: Arm 1

Arm description

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.

Arm type

Active comparator

Investigational medicinal product name

Pimasertib

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Pimasertib capsule was administered orally twice daily (bid) doses of 60 - continuous regimen.

Investigational medicinal product name

Gemcitabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Gemcitabine was administered as 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) then on Days 1, 8, and 15 of a 28-day cycle and placebo orally bid - continuous regimen.

Part II: Arm 2

Arm description

Arm type

Active comparator

Investigational medicinal product name

Pimasertib

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Pimasertib capsule was administered orally twice daily (bid) doses of 60 mg - continuous regimen.

Investigational medicinal product name

Gemcitabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Gemcitabine was administered as 1000 mg/m^2 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) then on Days 1, 8, and 15 of a 28-day cycle.

Number of subjects in period 1	Safety Run-in Part: Regimen 1	Safety Run-in Part: Regimen 2	Part II: Arm 1	Part II: Arm 2
Started	27	26	44	44
Completed	27	26	44	44

Period 2 title

Phase II

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Carer, Assessor

Are arms mutually exclusive

Yes

Safety Run-in Part: Regimen 1

Arm description

Arm type

Experimental

Investigational medicinal product name

Pimasertib

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Pimasertib was administered as 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.

Investigational medicinal product name

Gemcitabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Gemcitabine was administered as 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 2

Arm description

Arm type

Experimental

Investigational medicinal product name

Pimasertib

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Pimasertib was administered as capsule orally twice daily (bid) doses of 60 and 75 mg continuously for a 28-day cycle and gemcitabine 1000 mg/m^2 .

Part II: Arm 1

Arm description

Arm type

Experimental

Investigational medicinal product name

Gemcitabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Gemcitabine was administered as 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).

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Subjects received matching placebo as Gemcitabine orally as continuous regimen.

Part II: Arm 2

Arm description

Arm type

Experimental

Investigational medicinal product name

Pimasertib

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Pimasertib capsule was administered orally twice daily (bid) doses of 60 mg - continuous regimen.

Investigational medicinal product name

Gemcitabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Gemcitabine was administered as 1000 mg/m^2 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) then on Days 1, 8, and 15 of a 28-day cycle.

Number of subjects in period 2	Safety Run-in Part: Regimen 1	Safety Run-in Part: Regimen 2	Part II: Arm 1	Part II: Arm 2
Started	27	26	44	44
Completed	27	26	44	44

Baseline characteristics

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Reporting group title

Safety Run-in Part: Regimen 1

Reporting group description

Reporting group title

Safety Run-in Part: Regimen 2

Reporting group description

Reporting group title

Part II: Arm 1

Reporting group description

Reporting group title

Part II: Arm 2

Reporting group description

Reporting group values	Safety Run-in Part: Regimen 1	Safety Run-in Part: Regimen 2	Part II: Arm 1	Part II: Arm 2	Total
Number of subjects	27	26	44	44	141
Age categorical
Units: Subjects
Between 18 and 65 years	16	19	25	28	88
>=65 years	11	7	19	16	53
Gender, Male/Female
Units: subjects
Female	9	8	22	17	56
Male	18	18	22	27	85

End points

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Reporting group title

Safety Run-in Part: Regimen 1

Reporting group description

Reporting group title

Safety Run-in Part: Regimen 2

Reporting group description

Reporting group title

Part II: Arm 1

Reporting group description

Reporting group title

Part II: Arm 2

Reporting group description

Reporting group title

Safety Run-in Part: Regimen 1

Reporting group description

Reporting group title

Safety Run-in Part: Regimen 2

Reporting group description

Reporting group title

Part II: Arm 1

Reporting group description

Reporting group title

Part II: Arm 2

Reporting group description

Subject analysis set title

Regimen 1: 15 mg

Subject analysis set type

Full analysis

Subject analysis set description

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).

Subject analysis set title

Regimen 1: 30 mg

Subject analysis set type

Full analysis

Subject analysis set description

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).

Subject analysis set title

Regimen 1: 45 mg

Subject analysis set type

Full analysis

Subject analysis set description

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).

Subject analysis set title

Regimen 1: 68 mg

Subject analysis set type

Full analysis

Subject analysis set description

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).

Subject analysis set title

Regimen 1: 90 mg

Subject analysis set type

Full analysis

Subject analysis set description

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).

Subject analysis set title

Regimen 1: 120 mg

Subject analysis set type

Full analysis

Subject analysis set description

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).

Subject analysis set title

Regimen 1: 15 mg

Subject analysis set type

Full analysis

Subject analysis set description

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).

Subject analysis set title

Regimen 1: 68 mg

Subject analysis set type

Full analysis

Subject analysis set description

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.

Subject analysis set title

Regimen 1: 90 mg

Subject analysis set type

Full analysis

Subject analysis set description

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.

Subject analysis set title

Regimen 1: 120 mg

Subject analysis set type

Full analysis

Subject analysis set description

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.

Subject analysis set title

Regimen 1: 30 mg

Subject analysis set type

Full analysis

Subject analysis set description

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).

Subject analysis set title

Regimen 1: 45 mg

Subject analysis set type

Full analysis

Subject analysis set description

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).

Subject analysis set title

Regimen 1: 68 mg

Subject analysis set type

Full analysis

Subject analysis set description

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).

Subject analysis set title

Regimen 1:15 mg

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Regimen1: 120 mg

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Regimen 1:15 mg

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Regimen 1: 30 mg

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Regimen 1: 45 mg

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Regimen1: 120 mg

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Regimen 2: 60 mg

Subject analysis set type

Full analysis

Subject analysis set description

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).

Subject analysis set title

Regimen 2: 75 mg

Subject analysis set type

Full analysis

Subject analysis set description

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).

Subject analysis set title

Regimen 1: 75 mg

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Regimen 2: 60 mg

Subject analysis set type

Full analysis

Subject analysis set description

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.

Subject analysis set title

Regimen 2: 75 mg

Subject analysis set type

Full analysis

Subject analysis set description

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.

Subject analysis set title

Regimen 2: 60 mg

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Regimen 2: 75 mg

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Regimen 2: 60 mg

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Regimen 2: 75 mg

Subject analysis set type

Full analysis

Subject analysis set description

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

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End point title

Safety Run-In Part: Number of Subjects With Dose Limiting Toxicities (DLTs) ^[1] ^[2]

End point description

DLT using NCI- CTCAE v3.0, defined as toxicities at any dose level, judged to be possibly related to trial medication by Investigator/ Sponsor relevant for combination treatment:Grade 3/more non- hematological toxicity excluding:Subjects with liver involvement:Grade 4 asymptomatic increases liver function tests (LFT) or without liver involvement:Grade 3 asymptomatic increases LFT reversible within 7 days.Grade 3 vomiting encountered despite adequate therapy.Grade 3 diarrhoea encountered despite anti diarrhoea therapy.Grade 4 neutropenia >5 days duration/febrile neutropenia lasting for more than 1 day.Grade 4 thrombocytopenia >1 day/Grade 3 with bleeding.Grade 4 anaemia:treatment delay >2 weeks due to drug-related adverse effects.DLT population: all subjects of safety run-in part received any dose of pimasertib:least 18 out of 20/25 of 28 planned days on pimasertib & least 3 gemcitabine weekly IV during first 28 days of treatment:experienced DLT during 28 first days of treatment.

End point type

Primary

End point timeframe

Day 1, 2, 8, 15, 22, 29 of Cycle 1

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No inferential statistics were performed for this endpoint, only descriptive statistics was reported for this endpoint.
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Subject analysis set has been created for various dose regimen to capture the data.

End point values	Safety Run-in Part: Regimen 1	Safety Run-in Part: Regimen 2
Number of subjects analysed	20	19
Units: subjects
number (not applicable)	0	3

No statistical analyses for this end point

Primary: Phase II: Progression-Free Survival (PFS) time

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End point title

Phase II: Progression-Free Survival (PFS) time ^[3] ^[4]

End point description

PFS: Defined as time from randomization to first documentation of objective tumor progression (Complete Response (CR): Disappearance of all target lesions, Partial Response (PR): At least 30% decrease in sum of the longest diameter of target lesions, taking as reference sum of longest diameter at baseline, Progressive Disease (PD): At least 20% increase in sum of longest diameter of target lesions, taking as reference smallest sum of longest diameter recorded since treatment started, or appearance of 1 or more new lesions and SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of longest diameter since treatment started)/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 +1) divided by 30.4375. ITT analysis set included all subjects who had been randomized for the phase II part, as per the IVRS

End point type

Primary

End point timeframe

From the time of randomization to every 8 weeks up to end of treatment (EOT) (6 years)

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No inferential statistics were performed for this endpoint, only descriptive statistics was reported for this endpoint.
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Subject analysis set has been created for various dose regimen to capture the data.

End point values	Part II: Arm 1	Part II: Arm 2
Number of subjects analysed	44	44
Units: months
median (confidence interval 95%)	2.83 (1.77 to 3.88)	3.75 (2.63 to 5.09)

No statistical analyses for this end point

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

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End point title

Safety Run-In Part: Number of Subjects with Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Permanent Treatment Discontinuation ^[5]

End point description

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. 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).

End point type

Secondary

End point timeframe

Baseline up to post treatment follow-up period (28 days after last trial drug administration)

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Subject analysis set has been created for various dose regimen to capture the data.

End point values	Safety Run-in Part: Regimen 1	Safety Run-in Part: Regimen 2
Number of subjects analysed	27	26
Units: subjects
number (not applicable)
TEAEs	27	26
Serious TEAEs	18	20
Permanent treatment discontinuation of pimasertib	12	16
Permanent treatment discontinuation of gemcitabine	14	15

No statistical analyses for this end point

Secondary: Safety Run-In Part: Maximum Concentration (Cmax) of MSC1936369B, gemcitabine, its inactive metabolite 2',2'-difluorodeoxyuridine (dFdU), and its main active metabolite 2',2'-difluorodeoxycytidine 5'-triphosphate (dFdCTP) for Regimen 1

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End point title

Safety Run-In Part: Maximum Concentration (Cmax) of MSC1936369B, gemcitabine, its inactive metabolite 2',2'-difluorodeoxyuridine (dFdU), and its main active metabolite 2',2'-difluorodeoxycytidine 5'-triphosphate (dFdCTP) for Regimen 1

End point description

Maximum observed plasma concentration (Cmax) was calculated for MSC1936369B, gemcitabine, its inactive metabolite 2',2'-difluorodeoxyuridine (dFdU), and its main active metabolite 2',2'-difluorodeoxycytidine 5'. 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.

End point type

Secondary

End point timeframe

0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1

End point values	Regimen 1: 15 mg	Regimen 1: 30 mg	Regimen 1: 45 mg	Regimen 1: 68 mg	Regimen 1: 90 mg	Regimen 1: 120 mg
Number of subjects analysed	4	3	3	3	3	11
Units: nanogram per milliliter (ng/mL)
geometric mean (geometric coefficient of variation)
MSC1936369B on Days 1 (n=4,3,3,3,3,11)	32.3 ( 107.5 )	131 ( 32.9 )	205.8 ( 30 )	151.3 ( 40.1 )	485.3 ( 58.7 )	484.3 ( 39.8 )
MSC1936369B on Days 22 (n= 3,3,3,2,3,10)	29.6 ( 39.8 )	174.2 ( 29.6 )	261.8 ( 52 )	212.5 ( 16.9 )	409.1 ( 44.1 )	252.9 ( 477 )
Gemcitabine (dFdC) on Day 1 (n=4,3,3,3,3,11)	69540.5 ( 1729.4 )	21207.3 ( 21 )	17759.9 ( 34.1 )	29762.1 ( 76.7 )	15606.3 ( 23.1 )	23880.7 ( 83.8 )
Gemcitabine (dFdC) on Day 22 (n= 2,3,3,2,3,9)	24115.8 ( 71.9 )	11799.7 ( 167.7 )	181.9 ( 39158542.7 )	163196.2 ( 3183.3 )	669.5 ( 3278825923 )	23207.2 ( 99.5 )
Gemcitabine (dFdU) on Day 1 (n= 4,3,3,3,3,11)	29359.8 ( 8.5 )	33171.6 ( 21.2 )	34868.9 ( 12.8 )	33804.4 ( 16.7 )	37786.4 ( 13.6 )	34038.7 ( 29.7 )
Gemcitabine (dFdU) on Day 22 (n= 2,3,3,2,3,10)	29677.6 ( 3 )	38265.2 ( 54.3 )	10569.2 ( 449.2 )	32869.2 ( 8.7 )	17135 ( 227.5 )	21077.5 ( 179.5 )

No statistical analyses for this end point

Secondary: Safety Run-In Part: Time to Reach Maximum Concentration (tmax) of MSC1936369B, gemcitabine, and its inactive metabolite 2',2'-difluorodeoxyuridine (dFdU): Regimen 1

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End point title

Safety Run-In Part: Time to Reach Maximum Concentration (tmax) of MSC1936369B, gemcitabine, and its inactive metabolite 2',2'-difluorodeoxyuridine (dFdU): Regimen 1

End point description

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.

End point type

Secondary

End point timeframe

0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1

End point values	Regimen 1: 15 mg	Regimen 1: 30 mg	Regimen 1: 45 mg	Regimen 1: 68 mg	Regimen 1: 90 mg	Regimen 1: 120 mg
Number of subjects analysed	4	3	3	3	3	11
Units: hours
median (full range (min-max))
Tmax: MSC1936369B on Day 1 (n= 4,3,3,3,3,11)	1.25 (1 to 1.5)	1 (1 to 2.5)	1.533 (1 to 2)	2 (0.67 to 8)	1.083 (1 to 2)	1.5 (0.5 to 4)
Tmax: MSC1936369B on Day 22 (n= 3,3,3 2,3,10)	2.017 (1.28 to 4)	1 (0.5 to 2.5)	1 (0.5 to 1.58)	1.75 (1 to 2.5)	1.5 (1 to 1.75)	2 (0.83 to 8)
Tmax: Gemcitabine (dFdC) on Day 1 (n=4,3,3,3,3,11)	0.38 (0.25 to 0.5)	0.5 (0.25 to 0.5)	0.25 (0.25 to 0.5)	0.25 (0.25 to 1.17)	0.25 (0.25 to 0.38)	0.27 (0.25 to 0.75)
Tmax: Gemcitabine (dFdC) on Day 22 (n=2,3,3,2,3,9)	0.42 (0.33 to 0.5)	0.5 (0.5 to 1.58)	0.53 (0.25 to 2)	1.04 (1 to 1.08)	0.25 (0.23 to 24)	0.5 (0.25 to 0.75)
Tmax: Gemcitabine (dFdU) on Day 1 (n=4,3,3,3,3,11)	0.64 (0.5 to 1)	0.5 (0.5 to 0.75)	0.5 (0.5 to 0.77)	0.75 (0.67 to 1)	0.5 (0.38 to 0.5)	0.5 (0.25 to 0.75)
Tmax: Gemcitabine (dFdU) on Day 22 (n=2,3,3,2,3,10	0.54 (0.33 to 0.75)	0.75 (0.5 to 1.58)	1 (0.73 to 2)	0.67 (0.33 to 1)	0.75 (0.5 to 24)	0.75 (0 to 1)

No statistical analyses for this end point

Secondary: Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of MSC1936369B, gemcitabine, and its inactive metabolite 2',2'-difluorodeoxyuridine (dFdU): Regimen 1

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End point title

Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of MSC1936369B, gemcitabine, and its inactive metabolite 2',2'-difluorodeoxyuridine (dFdU): Regimen 1

End point description

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

End point type

Secondary

End point timeframe

0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1

End point values	Regimen 1: 15 mg	Regimen 1: 30 mg	Regimen 1: 45 mg	Regimen 1: 68 mg	Regimen 1: 90 mg	Regimen 1: 120 mg
Number of subjects analysed	4	3	3	3	3	11
Units: hours
median (full range (min-max))
t1/2: MSC1936369B on Day 1 (n=4,3,3,2,3,11)	4.008 (2.539 to 6.131)	3.807 (3.373 to 6.648)	3.833 (3.612 to 6.477)	4.232 (3.382 to 5.083)	5.036 (4.361 to 5.12)	4.58 (3.394 to 6.938)
t1/2: MSC1936369B on Day 22 (n=2,2,3,2,3,8)	8.66 (4.709 to 12.61)	6.1 (4.878 to 7.322)	3.254 (3.048 to 6.999)	5.744 (3.829 to 7.658)	3.162 (2.903 to 6.341)	4.825 (2.829 to 8.642)
t1/2: Gemcitabine (dFdC) on Day 1 (n=4,3,3,3,3,11)	4.274 (2.1 to 7.519)	2.461 (1.239 to 6.821)	2.421 (0.707 to 5.709)	5.327 (5.148 to 5.338)	8.94 (5.565 to 9.982)	6.242 (0.8913 to 11.9)
t1/2: Gemcitabine (dFdC) on Day 22 (n=2,2,1,2,2,9)	7.449 (6.032 to 8.866)	4.553 (2.403 to 6.702)	0.9152 (0.9152 to 0.9152)	4.493 (2.721 to 6.266)	8.213 (6.665 to 9.762)	4.68 (0.8685 to 8.49)
t1/2: Gemcitabine (dFdU) on Day 1 (n=4,3,3,3,3,11)	8.956 (8.129 to 14.68)	10.49 (4.336 to 10.7)	9.836 (9.383 to 14.69)	11.52 (9.344 to 12.36)	8.349 (7.191 to 9.551)	10.93 (8.802 to 15.48)
t1/2: Gemcitabine (dFdU) on Day 22(n=2,2,2,2,210)	7.731 (6.978 to 8.483)	8.925 (8.299 to 9.552)	8.843 (5.427 to 12.26)	11.14 (9.119 to 13.17)	10.21 (6.782 to 13.64)	12.17 (3.468 to 211.2)

No statistical analyses for this end point

Secondary: Safety Run-In Part: Area Under Curve (AUC: 0 to Infinity) of MSC1936369B, gemcitabine, and its inactive metabolite 2',2'-difluorodeoxyuridine (dFdU)

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End point title

Safety Run-In Part: Area Under Curve (AUC: 0 to Infinity) of MSC1936369B, gemcitabine, and its inactive metabolite 2',2'-difluorodeoxyuridine (dFdU)

End point description

AUC: 0 to Infinity was a measure of the serum concentration of the drug over time. It was used to characterize drug absorption. 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 and "99999" signifies Geometric Mean and Geometric Coefficient of Variation was not estimable as no subject was analyzed.

End point type

Secondary

End point timeframe

0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1

End point values	Regimen 1: 30 mg	Regimen 1: 45 mg	Regimen 1: 68 mg	Regimen 1: 90 mg	Regimen 1:15 mg	Regimen1: 120 mg
Number of subjects analysed	4	3	3	3	3	11
Units: hournanogram per milliliter (hng/mL)
geometric mean (geometric coefficient of variation)
AUC: MSC1936369B on Day 1	162.8 ( 25.3 )	516.3 ( 30.1 )	881.1 ( 37.1 )	774.8 ( 58.9 )	1729.9 ( 32.3 )	2175.1 ( 53 )
AUC: MSC1936369B on Day 22	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )
AUC: Gemcitabine metabolite (dFdU) on Day 1	245795.5 ( 10.8 )	228032.9 ( 27.6 )	276968.3 ( 28.9 )	259816.2 ( 9.2 )	239902.9 ( 27.1 )	240293.8 ( 15 )
AUC: Gemcitabine metabolite (dFdU) on Day 22	190952.6 ( 9.3 )	376280.5 ( 13 )	217930.8 ( 70.4 )	327424.8 ( 2 )	248496.4 ( 5.2 )	247430.7 ( 29.2 )

No statistical analyses for this end point

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

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End point title

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

End point description

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. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. 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.

End point type

Secondary

End point timeframe

0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1

End point values	Regimen 1: 30 mg	Regimen 1: 45 mg	Regimen 1: 68 mg	Regimen 1: 90 mg	Regimen 1: 120 mg	Regimen 1:15 mg
Number of subjects analysed	3	3	3	3	11	4
Units: Liter per hour (L/h)
geometric mean (geometric coefficient of variation)
CL/f: MSC1936369B on Day 1 (n=4,3,3,2,3,11)	58.104 ( 32.9 )	51.072 ( 37.1 )	87.765 ( 58.9 )	52.025 ( 32.3 )	55.171 ( 53 )	92.152 ( 25.3 )
CL/f: MSC1936369B on Day 22 (n=2,2,3,2,3,9)	42.484 ( 31.2 )	44.579 ( 23.1 )	56.502 ( 7.5 )	50.873 ( 59.6 )	55.723 ( 57.8 )	74.143 ( 43.6 )

No statistical analyses for this end point

Secondary: Safety Run-In Part: Oral volume of distribution (V/f) of MSC1936369B: Regimen 1

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End point title

Safety Run-In Part: Oral volume of distribution (V/f) of MSC1936369B: Regimen 1

End point description

End point type

Secondary

End point timeframe

0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1

End point values	Regimen 1: 15 mg	Regimen 1: 30 mg	Regimen 1: 45 mg	Regimen 1: 68 mg	Regimen 1: 90 mg	Regimen 1: 120 mg
Number of subjects analysed	4	3	3	3	3	11
Units: liter
geometric mean (geometric coefficient of variation)
V/f: MSC1936369B of Day 1 (n=4,3,3,2,3,11)	528.62 ( 63.1 )	369.12 ( 5 )	329.8 ( 28.4 )	524.96 ( 26.2 )	362.29 ( 34 )	367.25 ( 50.5 )
V/f: MSC1936369B of Day 22 (n=2,2,3,2,3,8)	824.33 ( 156.8 )	366.3 ( 1.8 )	264.31 ( 43.8 )	441.4 ( 43.4 )	284.42 ( 35.1 )	414.38 ( 66.8 )

No statistical analyses for this end point

Secondary: Safety Run-In Part: Apparent volume of distribution (V) of gemcitabine: Regimen 1

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End point title

Safety Run-In Part: Apparent volume of distribution (V) of gemcitabine: Regimen 1

End point description

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. Apparent volume of distribution after oral dose (Vz/F) was influenced by the fraction absorbed. 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 and "99999" signifies Geometric Coefficient of Variation was not estimable as data for only 1 subject was collected.

End point type

Secondary

End point timeframe

0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1

End point values	Regimen 1: 15 mg	Regimen 1: 30 mg	Regimen 1: 45 mg	Regimen 1: 68 mg	Regimen 1: 90 mg	Regimen 1: 120 mg
Number of subjects analysed	4	3	3	3	3	11
Units: liter
geometric mean (geometric coefficient of variation)
V: Gemcitabine (dFdC) of Day 1 (n= 4,3,3,3,3,11)	359.55 ( 635.6 )	531.23 ( 64.7 )	587.64 ( 206.3 )	729.65 ( 46.3 )	2402.1 ( 59.5 )	1270.1 ( 82 )
V: Gemcitabine (dFdC) of Day 22 (n=2,2,1,2,2,9)	1723.6 ( 55.9 )	908.5 ( 56.5 )	251.79 ( 99999 )	149.65 ( 1453.7 )	2140.8 ( 15.5 )	805.15 ( 138 )

No statistical analyses for this end point

Secondary: Safety Run-In Part: Total Clearance (CL) of MSC1936369B and Gemcitabine: Regimen 1

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End point title

Safety Run-In Part: Total Clearance (CL) of MSC1936369B and Gemcitabine: Regimen 1

End point description

Clearance was described as a quantitative measure of the rate at which a drug substance is removed from the body. 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 "99999" signifies Geometric Coefficient of Variation was not estimable as data for only 1 subject was collected.

End point type

Secondary

End point timeframe

0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1

End point values	Regimen 1: 15 mg	Regimen 1: 30 mg	Regimen 1: 45 mg	Regimen 1: 68 mg	Regimen 1: 90 mg	Regimen 1: 120 mg
Number of subjects analysed	4	3	3	3	3	11
Units: liter/hour
geometric mean (geometric coefficient of variation)
CL: MSC1936369B of Day 1	92.152 ( 25.3 )	58.104 ( 32.9 )	51.072 ( 37.1 )	87.765 ( 58.9 )	52.025 ( 32.3 )	55.171 ( 53 )
CL: MSC1936369B of Day 22	74.143 ( 43.6 )	42.484 ( 31.2 )	44.579 ( 23.1 )	56.502 ( 7.5 )	50.873 ( 59.6 )	55.723 ( 57.8 )
CL: Gemcitabine of Day 1	60.537 ( 483.4 )	133.88 ( 45.1 )	190.52 ( 26 )	95.96 ( 47.7 )	210.25 ( 27.9 )	151.93 ( 54.7 )
CL: Gemcitabine of Day 22	163.37 ( 93.7 )	156.93 ( 20.1 )	190.69 ( 99999 )	25.123 ( 431.2 )	183.97 ( 11.6 )	164.6 ( 71.7 )

No statistical analyses for this end point

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

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End point title

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

End point description

ERK phosphoprotein in peripheral blood monocytes (PBMCs) was analyzed from blood samples of all subjects in the SAF analysis set (safety-run part) only. 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"9999" signifies data for standard deviation was not estimable as only one patient analyzed, No subjects were evaluable hence the mean ad standard deviation was not analyzed and "n" signifies number of subjects evaluable for each category at specified time point.

End point type

Secondary

End point timeframe

Days 1, 2, and 22 of Cycle 1

End point values	Regimen 1: 68 mg	Regimen 1: 90 mg	Regimen 1:15 mg	Regimen 1: 30 mg	Regimen 1: 45 mg	Regimen1: 120 mg
Number of subjects analysed	3	3	3	2	2	7
Units: Fluorescence Intensity
arithmetic mean (standard deviation)
Cycle 1 Day 1 Pre−dose (n=3,2,2,3,3,7)	6.509 ( 2.24 )	4.608 ( 0.197 )	5.389 ( 0.797 )	6.476 ( 0.997 )	4.767 ( 0.114 )	4.229 ( 1.719 )
Cycle 1 Day 1 Post−dose (n=3,2,2,3,2,6)	3.881 ( 5.387 )	1.059 ( 0.042 )	1.611 ( 0.537 )	2.061 ( 0.825 )	0.837 ( 0.149 )	0.946 ( 0.248 )
Cycle 1 Day 2 Pre−dose (n=3,2,1,2,2,6)	2.768 ( 0.33 )	4.874 ( 2.119 )	4.818 ( 0.808 )	6.719 ( 2.835 )	3.902 ( 9999 )	3.636 ( 1.755 )
Cycle 1 Day 22 Pre−dose (n=2,1,2,1,3,5)	8.653 ( 9999 )	4.252 ( 1.259 )	5.242 ( 0.21 )	6 ( 9999 )	1.978 ( 2.539 )	3.453 ( 0.86 )
Cycle 1 Day 22 Post-dose (n=0,0,0,0,2)	9999 ( 9999 )	9999 ( 9999 )	9999 ( 9999 )	9999 ( 9999 )	9999 ( 9999 )	4.13 ( 1.772 )

No statistical analyses for this end point

Secondary: Safety Run-In Part: Maximum Concentration (Cmax) of MSC1936369B, gemcitabine, its inactive metabolite 2',2'-difluorodeoxyuridine (dFdU), and its main active metabolite 2',2'-difluorodeoxycytidine 5'-triphosphate (dFdCTP) for Regimen 2

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End point title

End point description

Maximum observed plasma concentration (Cmax) was calculated for MSC1936369B, gemcitabine, its inactive metabolite 2',2'-difluorodeoxyuridine (dFdU), and its main active metabolite 2',2'-difluorodeoxycytidine 5'. 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.

End point type

Secondary

End point timeframe

0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1

End point values	Regimen 2: 60 mg	Regimen 2: 75 mg
Number of subjects analysed	12	14
Units: nanogram per milliliter (ng/mL)
geometric mean (geometric coefficient of variation)
MSC1936369B on Days 1 (n= 12,13)	175.7 ( 65 )	345.5 ( 52.8 )
MSC1936369B on Days 22 (n=10,9)	228.2 ( 59 )	244.8 ( 31.9 )
Gemcitabine (dFdC) on Day 1 (n=11,14)	27849.2 ( 344 )	17663.9 ( 173.3 )
Gemcitabine (dFdC) on Day 22 (n=9,4)	21589.7 ( 118.8 )	18733.4 ( 88.6 )
Gemcitabine (dFdU) on Day 1 (n=11, 10)	33033.3 ( 11.8 )	31623.9 ( 25.4 )
Gemcitabine (dFdU) on Day 22 (n=10,5)	13455.5 ( 546 )	18298.7 ( 247.7 )

No statistical analyses for this end point

Secondary: Safety Run-In Part: Area Under Curve (AUC: 0 to Infinity) of MSC1936369B, gemcitabine, and its inactive metabolite 2',2'-difluorodeoxyuridine (dFdU) Regimen 2

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End point title

Safety Run-In Part: Area Under Curve (AUC: 0 to Infinity) of MSC1936369B, gemcitabine, and its inactive metabolite 2',2'-difluorodeoxyuridine (dFdU) Regimen 2

End point description

AUC: 0 to Infinity is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption. 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 and "99999" signifies Geometric Mean and Geometric Coefficient of Variation was not estimable as no subject was analyzed.

End point type

Secondary

End point timeframe

0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1

End point values	Regimen 2: 60 mg	Regimen 2: 75 mg
Number of subjects analysed	12	14
Units: hournanogram per milliliter (hng/mL)
geometric mean (geometric coefficient of variation)
AUC: MSC1936369B on Day 1	704.3 ( 69.4 )	1427 ( 30 )
AUC: MSC1936369B on Day 22	99999 ( 99999 )	99999 ( 99999 )
AUC: Gemcitabine metabolite (dFdU) on Day 1	189007 ( 40.6 )	234934.8 ( 29.9 )
AUC: Gemcitabine metabolite (dFdU) on Day 22	177504.5 ( 171.5 )	256714.9 ( 37.3 )

No statistical analyses for this end point

Secondary: Safety Run-In Part: Time to Reach Maximum Concentration (tmax) of MSC1936369B, gemcitabine, and its inactive metabolite 2',2'-difluorodeoxyuridine (dFdU): Regimen 2

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End point title

Safety Run-In Part: Time to Reach Maximum Concentration (tmax) of MSC1936369B, gemcitabine, and its inactive metabolite 2',2'-difluorodeoxyuridine (dFdU): Regimen 2

End point description

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.

End point type

Secondary

End point timeframe

0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1

End point values	Regimen 2: 60 mg	Regimen 2: 75 mg
Number of subjects analysed	12	14
Units: hours
median (full range (min-max))
Tmax: MSC1936369B on Day 1 (n=12,13)	2 (0.5 to 3.98)	1.583 (0.5 to 7.98)
Tmax: MSC1936369B on Day 22 (n=10,9)	1.5 (0.25 to 4.4)	2 (0.58 to 4)
Tmax: Gemcitabine (dFdC) on Day 1 (n=11,14)	0.5 (0.25 to 0.73)	0.38 (0.25 to 0.75)
Tmax: Gemcitabine (dFdC) on Day 22 (n=9,4)	0.25 (0 to 0.5)	0.25 (0.25 to 0.5)
Tmax: Gemcitabine (dFdU) on Day 1 (n=11,13)	0.67 (0.5 to 0.75)	0.67 (0.25 to 1)
Tmax: Gemcitabine (dFdU) on Day 22 (n=10,5)	0.5 (0 to 2)	0.5 (0.5 to 0.75)

No statistical analyses for this end point

Secondary: Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of MSC1936369B, gemcitabine, and its inactive metabolite 2',2'-difluorodeoxyuridine (dFdU): Regimen 2

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End point title

Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of MSC1936369B, gemcitabine, and its inactive metabolite 2',2'-difluorodeoxyuridine (dFdU): Regimen 2

End point description

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

End point type

Secondary

End point timeframe

0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1

End point values	Regimen 2: 60 mg	Regimen 2: 75 mg
Number of subjects analysed	12	14
Units: hours
median (full range (min-max))
t1/2: MSC1936369B on Day 1 (n=10,11)	2.757 (2.183 to 3.557)	2.603 (1.775 to 4.91)
t1/2: MSC1936369B on Day 22 (n=8,5)	3.425 (2.584 to 10.6)	3.188 (2.296 to 4.617)
t1/2: Gemcitabine (dFdC) on Day 1 (n=11,14)	5.258 (0.796 to 8.757)	5.376 (0.6681 to 11.64)
t1/2: Gemcitabine (dFdC) on Day 22 (n=9,4)	5.522 (3.759 to 11.45)	5.249 (0.3198 to 9.505)
t1/2: Gemcitabine (dFdU) on Day 1 (n=11,13)	9.471 (6.559 to 13.1)	10.26 (7.123 to 12.92)
t1/2: Gemcitabine (dFdU) on Day 22 (n=10,5)	10.68 (6.543 to 441.9)	13.58 (7.575 to 17.535)

No statistical analyses for this end point

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

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End point title

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

End point description

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. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. 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.

End point type

Secondary

End point timeframe

0 hour (pre-dose), 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 24 (post-dose) on Day 1, 22 of Cycle 1

End point values	Regimen 2: 60 mg	Regimen 2: 75 mg
Number of subjects analysed	12	14
Units: Liter per hour (L/H)
geometric mean (geometric coefficient of variation)
CL/f: MSC1936369B on Day 1 (n=10,11)	85.186 ( 69.4 )	52.558 ( 30 )
CL/f: MSC1936369B on Day 22 (n=8,5)	70.163 ( 63.2 )	68.312 ( 24.9 )

No statistical analyses for this end point

Secondary: Safety Run-In Part: Apparent volume of distribution (V) of gemcitabine: Regimen 2

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End point title

Safety Run-In Part: Apparent volume of distribution (V) of gemcitabine: Regimen 2

End point description

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. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed. 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.

End point type

Secondary

End point timeframe

Days 1 and 22 of Cycle 1

End point values	Regimen 2: 60 mg	Regimen 2: 75 mg
Number of subjects analysed	12	14
Units: liter
geometric mean (geometric coefficient of variation)
V: Gemcitabine of Day 1 (n=11,14)	716.12 ( 343.3 )	1059 ( 196.6 )
V: Gemcitabine of Day 22 (n=9,4)	1590.8 ( 120.5 )	801.9 ( 130.3 )

No statistical analyses for this end point

Secondary: Safety Run-In Part: Oral Volume of Distribution (V/f) of MSC1936369B: Regimen 2

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End point title

Safety Run-In Part: Oral Volume of Distribution (V/f) of MSC1936369B: Regimen 2

End point description

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

End point type

Secondary

End point timeframe

Days 1 and 22 of Cycle 1

End point values	Regimen 2: 60 mg	Regimen 2: 75 mg
Number of subjects analysed	12	14
Units: liter
geometric mean (geometric coefficient of variation)
V/f: MSC1936369B of Day 1 (n= 10,11)	335.56 ( 66.3 )	213.24 ( 37.7 )
V/f: MSC1936369B of Day 22 (n=8,5)	389.56 ( 47.1 )	319.02 ( 35.5 )

No statistical analyses for this end point

Secondary: Safety Run-In Part: Levels of Pharmacodynamic (Pd) Markers (Phosphorylated- Extracellular Signal-Regulated Kinase (ERK) in Peripheral Blood Mononuclear Cells [PBMCs]) Regimen 2

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End point title

Safety Run-In Part: Levels of Pharmacodynamic (Pd) Markers (Phosphorylated- Extracellular Signal-Regulated Kinase (ERK) in Peripheral Blood Mononuclear Cells [PBMCs]) Regimen 2

End point description

ERK phosphoprotein in peripheral blood monocytes (PBMCs) was analyzed from blood samples of all subjects in the SAF analysis set (safety-run part) only. 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"9999" signifies data for standard deviation was not estimable as only one patient analyzed and'n' signifies number of subjects evaluable for each category at specified time point.

End point type

Secondary

End point timeframe

Days 1, 2, and 22 of Cycle 1

End point values	Regimen 2: 60 mg	Regimen 2: 75 mg
Number of subjects analysed	7	4
Units: Fluorescence Intensity
arithmetic mean (standard deviation)
Cycle 1 Day 1 Pre−dose (n=7,4)	6.081 ( 0.827 )	5.874 ( 2.239 )
Cycle 1 Day 1 Post−dose (n=5,3)	1.52 ( 0.109 )	1.048 ( 0.155 )
Cycle 1 Day 2 Pre−dose (n=7,3)	3.877 ( 2.099 )	2.263 ( 0.593 )
Cycle 1 Day 22 Pre−dose (n=6,2)	2.728 ( 0.818 )	2.295 ( 0.51 )
Cycle 1 Day 22 Post-dose (n=3,1)	1.443 ( 0.458 )	1.111 ( 9999 )

No statistical analyses for this end point

Secondary: Safety Run-In Part: Total Clearance (CL) of MSC1936369B and Gemcitabine: Regimen 2

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End point title

Safety Run-In Part: Total Clearance (CL) of MSC1936369B and Gemcitabine: Regimen 2

End point description

CL is a quantitative measure of the rate at which a drug substance is removed from the body. 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.

End point type

Secondary

End point timeframe

Days 1 and 22 of Cycle

End point values	Regimen 2: 60 mg	Regimen 2: 75 mg
Number of subjects analysed	10	11
Units: liter/hour
geometric mean (geometric coefficient of variation)
CL: MSC1936369B of Day 1	85.186 ( 69.4 )	52.558 ( 30 )
CL: MSC1936369B of Day 22	70.163 ( 63.2 )	68.312 ( 24.9 )
CL: Gemcitabine of Day 1	145.65 ( 363.2 )	221.46 ( 186 )
CL: Gemcitabine of Day 22	164.68 ( 81.4 )	183.85 ( 73.5 )

No statistical analyses for this end point

Secondary: Part 2: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Permanent Treatment Discontinuation

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End point title

Part 2: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Permanent Treatment Discontinuation ^[6]

End point description

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. SAF for the Part II included all subjects who had received at least 1 administration of the trial medication .Gemcitabine or Placebo if the subject is in the gemcitabine + Placebo treatment arm (Arm 1) and MSC1936369B or gemcitabine in the MSC1936369B + gemcitabine treatment arm (Arm 2)

End point type

Secondary

End point timeframe

Baseline up to post treatment follow-up period (28 days after last trial drug administration)

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Subject analysis set has been created for various dose regimen to capture the data.

End point values	Part II: Arm 1	Part II: Arm 2
Number of subjects analysed	42	44
Units: subjects
number (not applicable)
TEAEs	40	44
Serious TEAEs	27	34
TEAEs Leading to Treatment Discontinuation	10	21

No statistical analyses for this end point

Secondary: Part 2: Percentage of Subjects With Best Overall Response (BOR)

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End point title

Part 2: Percentage of Subjects With Best Overall Response (BOR) ^[7]

End point description

Best overall response was defined as the presence oof 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 and non evaluable (NE) subjects. ITT analysis set included all subjects who had been randomized for the phase II part, as per the interactive voice response system (IVRS).

End point type

Secondary

End point timeframe

Baseline, every 8 weeks up to end of treatment (EOT i.e. 6 years)

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Subject analysis set has been created for various dose regimen to capture the data.

End point values	Part II: Arm 1	Part II: Arm 2
Number of subjects analysed	44	44
Units: percentage of subjects
number (not applicable)
CR	0	0
PR	9.1	9.1
SD	36.4	50
PD	29.5	20.5
NE	25	20.5

No statistical analyses for this end point

Secondary: Part 2: Percentage of Subjects With Clinical Benefit

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End point title

Part 2: Percentage of Subjects With Clinical Benefit ^[8]

End point description

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

End point type

Secondary

End point timeframe

Baseline, every 8 weeks up to end of treatment (EOT i.e. 6 years)

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Subject analysis set has been created for various dose regimen to capture the data.

End point values	Part II: Arm 1	Part II: Arm 2
Number of subjects analysed	44	44
Units: percentage of subjects
number (not applicable)	45.5	59.1

No statistical analyses for this end point

Secondary: Part 2: Time to progression (TTP)

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End point title

Part 2: Time to progression (TTP) ^[9]

End point description

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

End point type

Secondary

End point timeframe

From randomization every 8 weeks up to EOT (6 years)

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Subject analysis set has been created for various dose regimen to capture the data.

End point values	Part II: Arm 1	Part II: Arm 2
Number of subjects analysed	44	44
Units: months
median (confidence interval 95%)	3.78 (1.87 to 5.55)	5.09 (3.75 to 6.47)

No statistical analyses for this end point

Secondary: Part 2: Overall Survival (OS) Time

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End point title

Part 2: Overall Survival (OS) Time ^[10]

End point description

Overall survival (OS) time is defined as the time (in months) from randomization to death. ITT analysis set included all subjects who had been randomized for the phase II part, as per the interactive voice response system (IVRS). Here "99999" signifies data not evaluated as upper limit of 95% Confidence Interval (CI) not estimable.

End point type

Secondary

End point timeframe

Baseline, every 8 weeks up to EOT (6 years)

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Subject analysis set has been created for various dose regimen to capture the data.

End point values	Part II: Arm 1	Part II: Arm 2
Number of subjects analysed	44	44
Units: months
median (confidence interval 95%)	6.64 (5.06 to 99999)	9.33 (3.71 to 99999)

No statistical analyses for this end point

Secondary: Part 2: Absorption rate constant (ka) of MSC1936369B

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End point title

Part 2: Absorption rate constant (ka) of MSC1936369B ^[11]

End point description

Due to change in planned analysis “ Reduction of PK investigations for the phase II part of the trial: Removal of PK sampling for gemcitabine and its metabolites and replacement of intense sampling with a sparse sampling scheme for pimasertib”. outcome measure was not analyzed.

End point type

Secondary

End point timeframe

Baseline, every 8 weeks up to EOT (6 years)

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Subject analysis set has been created for various dose regimen to capture the data.

End point values	Part II: Arm 1	Part II: Arm 2
Number of subjects analysed	0 ^[12]	0 ^[13]
Units: days
number (not applicable)

Notes
[12] - MANDATORY COMMENT
[13] - MANDATORY COMMENT

No statistical analyses for this end point

Secondary: Part 2: Clearance from central compartment (CL/f) and Intercompartmental Clearance (Q/f) of MSC1936369B

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End point title

Part 2: Clearance from central compartment (CL/f) and Intercompartmental Clearance (Q/f) of MSC1936369B ^[14]

End point description

Clearance is a quantitative measure of the rate at which a drug substance is removed from the body. Due to change in planned analysis “ Reduction of PK investigations for the phase II part of the trial: Removal of PK sampling for gemcitabine and its metabolites and replacement of intense sampling with a sparse sampling scheme for pimasertib”. outcome measure was not analyzed.

End point type

Secondary

End point timeframe

Baseline, every 8 weeks up to EOT (6 years)

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Subject analysis set has been created for various dose regimen to capture the data.

End point values	Part II: Arm 1	Part II: Arm 2
Number of subjects analysed	0 ^[15]	0 ^[16]
Units: milliliter per minute (mL/min)
geometric mean (standard deviation)	( )	( )

Notes
[15] - MANDATORY COMMENT
[16] - MANDATORY COMMENT

No statistical analyses for this end point

Secondary: Part 2: Volume of central compartment (V1/f) volume of peripheral compartment (V2/f) of MSC1936369B

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End point title

Part 2: Volume of central compartment (V1/f) volume of peripheral compartment (V2/f) of MSC1936369B ^[17]

End point description

End point type

Secondary

End point timeframe

Baseline, every 8 weeks up to EOT (6 years)

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Subject analysis set has been created for various dose regimen to capture the data.

End point values	Part II: Arm 1	Part II: Arm 2
Number of subjects analysed	0 ^[18]	0 ^[19]
Units: liter
geometric mean (standard deviation)	( )	( )

Notes
[18] - MANDATORY COMMENT
[19] - MANDATORY COMMENT

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From the first dose of study drug administration until EOT (6 years)

Adverse event reporting additional description

SAF for the Part II included all subjects who had received at least 1 administration of the trial medication .Gemcitabine or Placebo if the subject is in the gemcitabine + Placebo treatment arm (Arm 1) and MSC1936369B or gemcitabine in the MSC1936369B + gemcitabine treatment arm (Arm 2)

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

16.1

Reporting group title

Part II: Arm 2

Reporting group description

Reporting group title

Part II: Arm 1

Reporting group description

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.

Serious adverse events	Part II: Arm 2	Part II: Arm 1
Total subjects affected by serious adverse events
subjects affected / exposed	34 / 45 (75.56%)	27 / 42 (64.29%)
number of deaths (all causes)	4	2
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Infected neoplasm
subjects affected / exposed	0 / 45 (0.00%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Circulatory collapse
alternative assessment type: Systematic
subjects affected / exposed	1 / 45 (2.22%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypertension
alternative assessment type: Systematic
subjects affected / exposed	0 / 45 (0.00%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Orthostatic hypotension
alternative assessment type: Systematic
subjects affected / exposed	1 / 45 (2.22%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	5 / 45 (11.11%)	5 / 42 (11.90%)
occurrences causally related to treatment / all	0 / 5	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Disease progression
subjects affected / exposed	4 / 45 (8.89%)	5 / 42 (11.90%)
occurrences causally related to treatment / all	0 / 4	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	3 / 45 (6.67%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Chills
alternative assessment type: Systematic
subjects affected / exposed	2 / 45 (4.44%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Asthenia
alternative assessment type: Systematic
subjects affected / exposed	1 / 45 (2.22%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Fatigue
alternative assessment type: Systematic
subjects affected / exposed	2 / 45 (4.44%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Malaise
alternative assessment type: Systematic
subjects affected / exposed	0 / 45 (0.00%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Non-cardiac chest pain
alternative assessment type: Systematic
subjects affected / exposed	1 / 45 (2.22%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Reproductive system and breast disorders
Endometriosis
alternative assessment type: Systematic
subjects affected / exposed	1 / 45 (2.22%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism
alternative dictionary used: MedDRA 15.0
subjects affected / exposed	2 / 45 (4.44%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Dyspnoea
alternative assessment type: Systematic
subjects affected / exposed	1 / 45 (2.22%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Epistaxis
alternative assessment type: Systematic
subjects affected / exposed	1 / 45 (2.22%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Interstitial lung disease
alternative assessment type: Systematic
subjects affected / exposed	1 / 45 (2.22%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary artery thrombosis
alternative assessment type: Systematic
subjects affected / exposed	1 / 45 (2.22%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Depression
subjects affected / exposed	1 / 45 (2.22%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
Blood bilirubin increased
alternative assessment type: Systematic
subjects affected / exposed	0 / 45 (0.00%)	4 / 42 (9.52%)
occurrences causally related to treatment / all	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Gamma-glutamyltransferase increased
alternative assessment type: Systematic
subjects affected / exposed	1 / 45 (2.22%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Amylase increased
alternative assessment type: Systematic
subjects affected / exposed	0 / 45 (0.00%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Alanine aminotransferase increased
subjects affected / exposed	1 / 45 (2.22%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Aspartate aminotransferase increased
alternative assessment type: Systematic
subjects affected / exposed	1 / 45 (2.22%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood potassium decreased
alternative assessment type: Systematic
subjects affected / exposed	1 / 45 (2.22%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lipase increased
alternative assessment type: Systematic
subjects affected / exposed	0 / 45 (0.00%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Platelet count decreased
alternative assessment type: Systematic
subjects affected / exposed	1 / 45 (2.22%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Overdose
alternative assessment type: Systematic
subjects affected / exposed	5 / 45 (11.11%)	3 / 42 (7.14%)
occurrences causally related to treatment / all	0 / 5	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Myocardial infarction
subjects affected / exposed	1 / 45 (2.22%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorder
alternative assessment type: Systematic
subjects affected / exposed	0 / 45 (0.00%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Left ventricular dysfunction
alternative assessment type: Systematic
subjects affected / exposed	0 / 45 (0.00%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Syncope
alternative assessment type: Systematic
subjects affected / exposed	2 / 45 (4.44%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebrovascular accident
alternative assessment type: Systematic
subjects affected / exposed	1 / 45 (2.22%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Coma
alternative assessment type: Systematic
subjects affected / exposed	1 / 45 (2.22%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Epilepsy
alternative assessment type: Systematic
subjects affected / exposed	1 / 45 (2.22%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Headache
alternative assessment type: Systematic
subjects affected / exposed	1 / 45 (2.22%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ischaemic cerebral infarction
alternative assessment type: Systematic
subjects affected / exposed	1 / 45 (2.22%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Neutropenia
subjects affected / exposed	3 / 45 (6.67%)	3 / 42 (7.14%)
occurrences causally related to treatment / all	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	3 / 45 (6.67%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombocytopenia
alternative assessment type: Systematic
subjects affected / exposed	4 / 45 (8.89%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Anaemia
alternative assessment type: Systematic
subjects affected / exposed	1 / 45 (2.22%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Leukaemoid reaction
alternative assessment type: Systematic
subjects affected / exposed	0 / 45 (0.00%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Leukopenia
alternative assessment type: Systematic
subjects affected / exposed	1 / 45 (2.22%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Normochromic normocytic anaemia
alternative assessment type: Systematic
subjects affected / exposed	0 / 45 (0.00%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ear and labyrinth disorders
Vertigo
alternative assessment type: Systematic
subjects affected / exposed	1 / 45 (2.22%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Eye disorders
Retinal detachment
subjects affected / exposed	1 / 45 (2.22%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Macular detachment
alternative assessment type: Systematic
subjects affected / exposed	1 / 45 (2.22%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Vomiting
subjects affected / exposed	4 / 45 (8.89%)	4 / 42 (9.52%)
occurrences causally related to treatment / all	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Stomatitis
alternative assessment type: Systematic
subjects affected / exposed	3 / 45 (6.67%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal pain
alternative assessment type: Systematic
subjects affected / exposed	2 / 45 (4.44%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Aphthous stomatitis
alternative assessment type: Systematic
subjects affected / exposed	1 / 45 (2.22%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diarrhoea
alternative assessment type: Systematic
subjects affected / exposed	0 / 45 (0.00%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal haemorrhage
alternative assessment type: Systematic
subjects affected / exposed	0 / 45 (0.00%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gingival bleeding
alternative assessment type: Systematic
subjects affected / exposed	1 / 45 (2.22%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Intestinal obstruction
alternative assessment type: Systematic
subjects affected / exposed	1 / 45 (2.22%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nausea
alternative assessment type: Systematic
subjects affected / exposed	1 / 45 (2.22%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophagitis
alternative assessment type: Systematic
subjects affected / exposed	1 / 45 (2.22%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Small intestinal obstruction
alternative assessment type: Systematic
subjects affected / exposed	1 / 45 (2.22%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Small intestinal perforation
alternative assessment type: Systematic
subjects affected / exposed	1 / 45 (2.22%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
alternative assessment type: Systematic
subjects affected / exposed	0 / 45 (0.00%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Cholangitis
subjects affected / exposed	2 / 45 (4.44%)	2 / 42 (4.76%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Cholecystitis
alternative assessment type: Systematic
subjects affected / exposed	1 / 45 (2.22%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Jaundice cholestatic
alternative assessment type: Systematic
subjects affected / exposed	1 / 45 (2.22%)	3 / 42 (7.14%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Bile duct obstruction
alternative assessment type: Systematic
subjects affected / exposed	1 / 45 (2.22%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic failure
alternative assessment type: Systematic
subjects affected / exposed	0 / 45 (0.00%)	2 / 42 (4.76%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatotoxicity
alternative assessment type: Systematic
subjects affected / exposed	1 / 45 (2.22%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperbilirubinaemia
subjects affected / exposed	1 / 45 (2.22%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Jaundice extrahepatic obstructive
alternative assessment type: Systematic
subjects affected / exposed	0 / 45 (0.00%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Jaundice
alternative assessment type: Systematic
subjects affected / exposed	0 / 45 (0.00%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Skin toxicity
alternative assessment type: Systematic
subjects affected / exposed	1 / 45 (2.22%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Dysuria
alternative assessment type: Systematic
subjects affected / exposed	0 / 45 (0.00%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 45 (0.00%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Flank pain
alternative assessment type: Systematic
subjects affected / exposed	1 / 45 (2.22%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Muscular weakness
alternative assessment type: Systematic
subjects affected / exposed	1 / 45 (2.22%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Neck pain
alternative assessment type: Systematic
subjects affected / exposed	1 / 45 (2.22%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Pneumonia
subjects affected / exposed	2 / 45 (4.44%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	1 / 45 (2.22%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bacteraemia
subjects affected / exposed	1 / 45 (2.22%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bacterial infection
subjects affected / exposed	0 / 45 (0.00%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Biliary tract infection
alternative assessment type: Systematic
subjects affected / exposed	0 / 45 (0.00%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchitis
alternative assessment type: Systematic
subjects affected / exposed	0 / 45 (0.00%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Enterobacter sepsis
alternative assessment type: Systematic
subjects affected / exposed	1 / 45 (2.22%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic infection
alternative assessment type: Systematic
subjects affected / exposed	0 / 45 (0.00%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pharyngitis
alternative assessment type: Systematic
subjects affected / exposed	1 / 45 (2.22%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Sepsis
alternative assessment type: Systematic
subjects affected / exposed	1 / 45 (2.22%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Viral infection
alternative assessment type: Systematic
subjects affected / exposed	1 / 45 (2.22%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Hypophosphataemia
alternative assessment type: Systematic
subjects affected / exposed	1 / 45 (2.22%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperkalaemia
alternative assessment type: Systematic
subjects affected / exposed	0 / 45 (0.00%)	2 / 42 (4.76%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Decreased appetite
alternative assessment type: Systematic
subjects affected / exposed	1 / 45 (2.22%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Part II: Arm 2	Part II: Arm 1
Total subjects affected by non serious adverse events
subjects affected / exposed	44 / 45 (97.78%)	37 / 42 (88.10%)
Vascular disorders
Hypotension
alternative assessment type: Systematic
subjects affected / exposed	4 / 45 (8.89%)	1 / 42 (2.38%)
occurrences all number	4	1
General disorders and administration site conditions
Fatigue
subjects affected / exposed	16 / 45 (35.56%)	17 / 42 (40.48%)
occurrences all number	16	17
Oedema peripheral
alternative assessment type: Systematic
subjects affected / exposed	21 / 45 (46.67%)	7 / 42 (16.67%)
occurrences all number	21	7
Pyrexia
alternative assessment type: Systematic
subjects affected / exposed	16 / 45 (35.56%)	12 / 42 (28.57%)
occurrences all number	16	12
Asthenia
alternative assessment type: Systematic
subjects affected / exposed	8 / 45 (17.78%)	6 / 42 (14.29%)
occurrences all number	8	6
Respiratory, thoracic and mediastinal disorders
Dyspnoea
alternative assessment type: Systematic
subjects affected / exposed	5 / 45 (11.11%)	3 / 42 (7.14%)
occurrences all number	5	3
Cough
alternative assessment type: Systematic
subjects affected / exposed	3 / 45 (6.67%)	3 / 42 (7.14%)
occurrences all number	3	3
Investigations
Gamma-glutamyltransferase increased
subjects affected / exposed	4 / 45 (8.89%)	7 / 42 (16.67%)
occurrences all number	4	7
Blood creatine phosphokinase increased
alternative assessment type: Systematic
subjects affected / exposed	9 / 45 (20.00%)	1 / 42 (2.38%)
occurrences all number	9	1
Alanine aminotransferase increased
alternative assessment type: Systematic
subjects affected / exposed	4 / 45 (8.89%)	4 / 42 (9.52%)
occurrences all number	4	4
Aspartate aminotransferase increased
alternative assessment type: Systematic
subjects affected / exposed	4 / 45 (8.89%)	3 / 42 (7.14%)
occurrences all number	4	3
Blood bilirubin increased
alternative assessment type: Systematic
subjects affected / exposed	2 / 45 (4.44%)	5 / 42 (11.90%)
occurrences all number	2	5
Blood alkaline phosphatase increased
alternative assessment type: Systematic
subjects affected / exposed	4 / 45 (8.89%)	2 / 42 (4.76%)
occurrences all number	4	2
Platelet count decreased
alternative assessment type: Systematic
subjects affected / exposed	5 / 45 (11.11%)	1 / 42 (2.38%)
occurrences all number	5	1
Weight decreased
alternative assessment type: Systematic
subjects affected / exposed	1 / 45 (2.22%)	4 / 42 (9.52%)
occurrences all number	1	4
Ejection fraction decreased
alternative assessment type: Systematic
subjects affected / exposed	3 / 45 (6.67%)	0 / 42 (0.00%)
occurrences all number	3	0
Nervous system disorders
Dizziness
alternative assessment type: Systematic
subjects affected / exposed	6 / 45 (13.33%)	1 / 42 (2.38%)
occurrences all number	6	1
Blood and lymphatic system disorders
Neutropenia
subjects affected / exposed	17 / 45 (37.78%)	16 / 42 (38.10%)
occurrences all number	17	16
Thrombocytopenia
alternative assessment type: Systematic
subjects affected / exposed	16 / 45 (35.56%)	9 / 42 (21.43%)
occurrences all number	16	9
Anaemia
alternative assessment type: Systematic
subjects affected / exposed	13 / 45 (28.89%)	6 / 42 (14.29%)
occurrences all number	13	6
Leukopenia
alternative assessment type: Systematic
subjects affected / exposed	4 / 45 (8.89%)	6 / 42 (14.29%)
occurrences all number	4	6
Hypochromic anaemia
alternative assessment type: Systematic
subjects affected / exposed	3 / 45 (6.67%)	2 / 42 (4.76%)
occurrences all number	3	2
Eye disorders
Retinal detachment
subjects affected / exposed	10 / 45 (22.22%)	1 / 42 (2.38%)
occurrences all number	10	1
Macular degeneration
alternative assessment type: Systematic
subjects affected / exposed	8 / 45 (17.78%)	0 / 42 (0.00%)
occurrences all number	8	0
Visual acuity reduced
alternative assessment type: Systematic
subjects affected / exposed	4 / 45 (8.89%)	1 / 42 (2.38%)
occurrences all number	4	1
Visual impairment
alternative assessment type: Systematic
subjects affected / exposed	4 / 45 (8.89%)	0 / 42 (0.00%)
occurrences all number	4	0
Eyelid oedema
alternative assessment type: Systematic
subjects affected / exposed	3 / 45 (6.67%)	0 / 42 (0.00%)
occurrences all number	3	0
Vision blurred
alternative assessment type: Systematic
subjects affected / exposed	3 / 45 (6.67%)	0 / 42 (0.00%)
occurrences all number	3	0
Gastrointestinal disorders
Diarrhoea
alternative assessment type: Systematic
subjects affected / exposed	20 / 45 (44.44%)	8 / 42 (19.05%)
occurrences all number	20	8
Abdominal pain
alternative assessment type: Systematic
subjects affected / exposed	7 / 45 (15.56%)	9 / 42 (21.43%)
occurrences all number	7	9
Constipation
alternative assessment type: Systematic
subjects affected / exposed	6 / 45 (13.33%)	8 / 42 (19.05%)
occurrences all number	6	8
Abdominal pain upper
alternative assessment type: Systematic
subjects affected / exposed	4 / 45 (8.89%)	6 / 42 (14.29%)
occurrences all number	4	6
Dry mouth
alternative assessment type: Systematic
subjects affected / exposed	3 / 45 (6.67%)	1 / 42 (2.38%)
occurrences all number	3	1
Nausea
alternative assessment type: Systematic
subjects affected / exposed	23 / 45 (51.11%)	15 / 42 (35.71%)
occurrences all number	23	15
Vomiting
alternative assessment type: Systematic
subjects affected / exposed	21 / 45 (46.67%)	10 / 42 (23.81%)
occurrences all number	21	10
Stomatitis
alternative assessment type: Systematic
subjects affected / exposed	15 / 45 (33.33%)	4 / 42 (9.52%)
occurrences all number	15	4
Dyspepsia
alternative assessment type: Systematic
subjects affected / exposed	3 / 45 (6.67%)	2 / 42 (4.76%)
occurrences all number	3	2
Dysphagia
alternative assessment type: Systematic
subjects affected / exposed	3 / 45 (6.67%)	0 / 42 (0.00%)
occurrences all number	3	0
Hepatobiliary disorders
Hepatotoxicity
alternative assessment type: Systematic
subjects affected / exposed	4 / 45 (8.89%)	0 / 42 (0.00%)
occurrences all number	4	0
Jaundice
alternative assessment type: Systematic
subjects affected / exposed	0 / 45 (0.00%)	3 / 42 (7.14%)
occurrences all number	0	3
Skin and subcutaneous tissue disorders
Rash
alternative assessment type: Systematic
subjects affected / exposed	20 / 45 (44.44%)	4 / 42 (9.52%)
occurrences all number	20	4
Alopecia
alternative assessment type: Systematic
subjects affected / exposed	4 / 45 (8.89%)	2 / 42 (4.76%)
occurrences all number	4	2
Dermatitis acneiform
alternative assessment type: Systematic
subjects affected / exposed	5 / 45 (11.11%)	1 / 42 (2.38%)
occurrences all number	5	1
Dry skin
alternative assessment type: Systematic
subjects affected / exposed	4 / 45 (8.89%)	2 / 42 (4.76%)
occurrences all number	4	2
Pruritus
alternative assessment type: Systematic
subjects affected / exposed	3 / 45 (6.67%)	2 / 42 (4.76%)
occurrences all number	3	2
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	1 / 45 (2.22%)	3 / 42 (7.14%)
occurrences all number	1	3
Arthralgia
alternative assessment type: Systematic
subjects affected / exposed	0 / 45 (0.00%)	3 / 42 (7.14%)
occurrences all number	0	3
Infections and infestations
Urinary tract infection
alternative assessment type: Systematic
subjects affected / exposed	1 / 45 (2.22%)	3 / 42 (7.14%)
occurrences all number	1	3
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	13 / 45 (28.89%)	9 / 42 (21.43%)
occurrences all number	13	9
Hypokalaemia
alternative assessment type: Systematic
subjects affected / exposed	6 / 45 (13.33%)	2 / 42 (4.76%)
occurrences all number	6	2
Hypoalbuminaemia
alternative assessment type: Systematic
subjects affected / exposed	3 / 45 (6.67%)	2 / 42 (4.76%)
occurrences all number	3	2
Hyperglycaemia
subjects affected / exposed	0 / 45 (0.00%)	4 / 42 (9.52%)
occurrences all number	0	4

More information

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Were there any global substantial amendments to the protocol? Yes

27 Apr 2010

1. To update the dose and dose escalation scheme. 2. To introduce a new investigational medical product strength of 30 mg.

27 Jun 2011

1. To explore safety, PK and Pd effects, and activity signals of pimasertib when administered in a new oral dosing regimen: bid as a continuous dosing regimen (bid - continuous regimen).

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: Phase II randomized trial of MEK inhibitor MSC1936369B or placebo combined with gemcitabine in metastatic pancreas cancer subjects.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

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

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

Primary: Phase II: Progression-Free Survival (PFS) time

Primary: Phase II: Progression-Free Survival (PFS) time

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

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

Secondary: Safety Run-In Part: Maximum Concentration (Cmax) of MSC1936369B, gemcitabine, its inactive metabolite 2',2'-difluorodeoxyuridine (dFdU), and its main active metabolite 2',2'-difluorodeoxycytidine 5'-triphosphate (dFdCTP) for Regimen 1

Secondary: Safety Run-In Part: Maximum Concentration (Cmax) of MSC1936369B, gemcitabine, its inactive metabolite 2',2'-difluorodeoxyuridine (dFdU), and its main active metabolite 2',2'-difluorodeoxycytidine 5'-triphosphate (dFdCTP) for Regimen 1

Secondary: Safety Run-In Part: Time to Reach Maximum Concentration (tmax) of MSC1936369B, gemcitabine, and its inactive metabolite 2',2'-difluorodeoxyuridine (dFdU): Regimen 1

Secondary: Safety Run-In Part: Time to Reach Maximum Concentration (tmax) of MSC1936369B, gemcitabine, and its inactive metabolite 2',2'-difluorodeoxyuridine (dFdU): Regimen 1

Secondary: Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of MSC1936369B, gemcitabine, and its inactive metabolite 2',2'-difluorodeoxyuridine (dFdU): Regimen 1

Secondary: Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of MSC1936369B, gemcitabine, and its inactive metabolite 2',2'-difluorodeoxyuridine (dFdU): Regimen 1

Secondary: Safety Run-In Part: Area Under Curve (AUC: 0 to Infinity) of MSC1936369B, gemcitabine, and its inactive metabolite 2',2'-difluorodeoxyuridine (dFdU)

Secondary: Safety Run-In Part: Area Under Curve (AUC: 0 to Infinity) of MSC1936369B, gemcitabine, and its inactive metabolite 2',2'-difluorodeoxyuridine (dFdU)

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

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

Secondary: Safety Run-In Part: Oral volume of distribution (V/f) of MSC1936369B: Regimen 1

Secondary: Safety Run-In Part: Oral volume of distribution (V/f) of MSC1936369B: Regimen 1

Secondary: Safety Run-In Part: Apparent volume of distribution (V) of gemcitabine: Regimen 1

Secondary: Safety Run-In Part: Apparent volume of distribution (V) of gemcitabine: Regimen 1

Secondary: Safety Run-In Part: Total Clearance (CL) of MSC1936369B and Gemcitabine: Regimen 1

Secondary: Safety Run-In Part: Total Clearance (CL) of MSC1936369B and Gemcitabine: Regimen 1

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

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

Secondary: Safety Run-In Part: Maximum Concentration (Cmax) of MSC1936369B, gemcitabine, its inactive metabolite 2',2'-difluorodeoxyuridine (dFdU), and its main active metabolite 2',2'-difluorodeoxycytidine 5'-triphosphate (dFdCTP) for Regimen 2

Secondary: Safety Run-In Part: Maximum Concentration (Cmax) of MSC1936369B, gemcitabine, its inactive metabolite 2',2'-difluorodeoxyuridine (dFdU), and its main active metabolite 2',2'-difluorodeoxycytidine 5'-triphosphate (dFdCTP) for Regimen 2

Secondary: Safety Run-In Part: Area Under Curve (AUC: 0 to Infinity) of MSC1936369B, gemcitabine, and its inactive metabolite 2',2'-difluorodeoxyuridine (dFdU) Regimen 2

Secondary: Safety Run-In Part: Area Under Curve (AUC: 0 to Infinity) of MSC1936369B, gemcitabine, and its inactive metabolite 2',2'-difluorodeoxyuridine (dFdU) Regimen 2

Secondary: Safety Run-In Part: Time to Reach Maximum Concentration (tmax) of MSC1936369B, gemcitabine, and its inactive metabolite 2',2'-difluorodeoxyuridine (dFdU): Regimen 2

Secondary: Safety Run-In Part: Time to Reach Maximum Concentration (tmax) of MSC1936369B, gemcitabine, and its inactive metabolite 2',2'-difluorodeoxyuridine (dFdU): Regimen 2

Secondary: Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of MSC1936369B, gemcitabine, and its inactive metabolite 2',2'-difluorodeoxyuridine (dFdU): Regimen 2

Secondary: Safety Run-In Part: Time to Reach Apparent Terminal Half-Life (t1/2) of MSC1936369B, gemcitabine, and its inactive metabolite 2',2'-difluorodeoxyuridine (dFdU): Regimen 2

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

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

Secondary: Safety Run-In Part: Apparent volume of distribution (V) of gemcitabine: Regimen 2

Secondary: Safety Run-In Part: Apparent volume of distribution (V) of gemcitabine: Regimen 2

Secondary: Safety Run-In Part: Oral Volume of Distribution (V/f) of MSC1936369B: Regimen 2

Secondary: Safety Run-In Part: Oral Volume of Distribution (V/f) of MSC1936369B: Regimen 2

Secondary: Safety Run-In Part: Levels of Pharmacodynamic (Pd) Markers (Phosphorylated- Extracellular Signal-Regulated Kinase (ERK) in Peripheral Blood Mononuclear Cells [PBMCs]) Regimen 2

Secondary: Safety Run-In Part: Levels of Pharmacodynamic (Pd) Markers (Phosphorylated- Extracellular Signal-Regulated Kinase (ERK) in Peripheral Blood Mononuclear Cells [PBMCs]) Regimen 2

Secondary: Safety Run-In Part: Total Clearance (CL) of MSC1936369B and Gemcitabine: Regimen 2

Secondary: Safety Run-In Part: Total Clearance (CL) of MSC1936369B and Gemcitabine: Regimen 2

Secondary: Part 2: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Permanent Treatment Discontinuation

Secondary: Part 2: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Permanent Treatment Discontinuation

Secondary: Part 2: Percentage of Subjects With Best Overall Response (BOR)

Secondary: Part 2: Percentage of Subjects With Best Overall Response (BOR)

Secondary: Part 2: Percentage of Subjects With Clinical Benefit

Secondary: Part 2: Percentage of Subjects With Clinical Benefit

Secondary: Part 2: Time to progression (TTP)

Secondary: Part 2: Time to progression (TTP)

Secondary: Part 2: Overall Survival (OS) Time

Secondary: Part 2: Overall Survival (OS) Time

Secondary: Part 2: Absorption rate constant (ka) of MSC1936369B

Secondary: Part 2: Absorption rate constant (ka) of MSC1936369B

Secondary: Part 2: Clearance from central compartment (CL/f) and Intercompartmental Clearance (Q/f) of MSC1936369B

Secondary: Part 2: Clearance from central compartment (CL/f) and Intercompartmental Clearance (Q/f) of MSC1936369B

Secondary: Part 2: Volume of central compartment (V1/f) volume of peripheral compartment (V2/f) of MSC1936369B

Secondary: Part 2: Volume of central compartment (V1/f) volume of peripheral compartment (V2/f) of MSC1936369B

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
Phase II randomized trial of MEK inhibitor MSC1936369B or placebo combined with gemcitabine in metastatic pancreas cancer subjects.