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Clinical Trial Results:
A multi-center, phase I/II study of BAY86-9766 in combination with gemcitabine in patients with locally advanced inoperable or metastatic pancreatic cancer

Summary
EudraCT number	2010-019588-12
Trial protocol	DE BE GB CZ IT
Global end of trial date	01 Aug 2013

Results information
Results version number	v2(current)
This version publication date	24 Jul 2016
First version publication date	04 Jul 2015
Other versions	v1
Version creation reason	Correction of full data set Justfication needs revision

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

BAY86-9766/14905

ISRCTN number

US NCT number

NCT01251640

WHO universal trial number (UTN)

Sponsor organisation name

Bayer AG

Sponsor organisation address

Kaiser Wilhelm Allee, Leverkusen, Germany, D-51368

Public contact

Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com

Scientific contact

Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.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

01 Aug 2013

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

01 Aug 2013

Was the trial ended prematurely?

Main objective of the trial

Phase I: •Determine the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) of BAY 86-9766 to be investigated in combination with the standard gemcitabine regimen in the subsequent Phase II part of this study Phase II •Determine the efficacy of the combination BAY 86-9766 / gemcitabine in terms of the overall response rate (confirmed complete response + partial response) according to response evaluation criteria in solid tumors (RECIST) Version 1.1

Protection of trial subjects

The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonization guideline E6: Good Clinical Practice. Participating subjects signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.

Background therapy

Gemcitabine was administered on Day 1 at a dose of 1000 milligram per meter square (mg/m^2) of body surface area intravenous (IV) infusion over 30 minutes weekly for 7 out of 8 weeks (cycle 1), thereafter, 3 out of 4 weeks (cycle 2 and subsequent).

Evidence for comparator

Actual start date of recruitment

01 Jan 2011

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Norway: 3

Country: Number of subjects enrolled

Poland: 14

Country: Number of subjects enrolled

United Kingdom: 8

Country: Number of subjects enrolled

Belgium: 14

Country: Number of subjects enrolled

Czech Republic: 5

Country: Number of subjects enrolled

France: 1

Country: Number of subjects enrolled

Germany: 32

Country: Number of subjects enrolled

Italy: 7

Country: Number of subjects enrolled

United States: 6

Worldwide total number of subjects

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

The study was conducted at 22 study centers in 9 countries (8 countries in Europe, and the United States). The first patient’s first visit was on 01 January 2011 and the cut-off date for the final analysis was 01 August 2013, when last patient's last visit occurred.

Screening details

Total of 121 subjects were screened, out of which 31 subjects failed screening. Ninety subjects were assigned to treatment. Subjects assigned to Phase 1 were reported separately from Phase 2. Ten evaluable subjects originally assigned to the 50 milligram (mg) arm of Phase 1 were subsequently reported also under the Phase 2 and so accounted for twic

Period 1 title

Overall Trial (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Refametinib (BAY86-9766), 30 mg twice daily, Phase I

Arm description

Refametinib was administered orally on Day 2 at a dose of 30 mg twice daily during the treatment cycle. Gemcitabine was administered on Day 1 at a dose of 1000 milligram per meter square (mg/m^2) of body surface area intravenous (IV) infusion over 30 minutes weekly for 7 out of 8 weeks (cycle 1), thereafter, 3 out of 4 weeks (cycle 2 and subsequent). The treatment was continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met.

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 1000 mg/m^2 of body surface area IV infusion dose over 30 minutes weekly for 7 out of 8 weeks, thereafter, 3 out of 4 weeks. The treatment was continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met.

Investigational medicinal product name

Refametinib

Investigational medicinal product code

BAY86-9766

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Refametinib was administered orally at a dose of 30 mg twice daily during the treatment cycle.

Refametinib (BAY86-9766), 50 mg twice daily, Phase I

Arm description

Refametinib was administered orally on Day 2 at a dose of 50 mg twice daily during the treatment cycle. Gemcitabine was administered on Day 1 at a dose of 1000 mg/m^2 of body surface area IV infusion over 30 minutes weekly for 7 out of 8 weeks (cycle 1), thereafter, 3 out of 4 weeks (cycle 2 and subsequent). The treatment was continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met.

Arm type

Experimental

Investigational medicinal product name

Refametinib

Investigational medicinal product code

BAY86-9766

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Refametinib was administered orally at a dose of 50 mg twice daily during the treatment cycle.

Investigational medicinal product name

Gemcitabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Refametinib (BAY86-9766), 50 mg twice daily, Phase II

Arm description

Refametinib was administered orally on Day 1 at a dose of 50 mg twice daily during the treatment cycle. Gemcitabine was administered on Day 1 at a dose of 1000 mg/m^2 of body surface area IV infusion dose over 30 minutes weekly for 7 out of 8 weeks (cycle 1), thereafter, 3 out of 4 weeks (cycle 2 and subsequent). The treatment was continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met. Ten evaluable subjects originally assigned to the 50 mg arm of Phase I were subsequently reported also under the Phase II and so accounted for twice.

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

Investigational medicinal product name

Refametinib

Investigational medicinal product code

BAY86-9766

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Refametinib was administered orally at a dose of 50 mg twice daily during the treatment cycle.

Number of subjects in period 1	Refametinib (BAY86-9766), 30 mg twice daily, Phase I	Refametinib (BAY86-9766), 50 mg twice daily, Phase I	Refametinib (BAY86-9766), 50 mg twice daily, Phase II
Started	10	10	80
Treated	10	10	80
Survival follow up	9	9	64
Safety follow up	10	10	74
Terminated treatment	10	10	80
Completed	0	0	0
Not completed	10	10	80
Progressive disease – radiological progression	5	2	26
AE associated with clinical disease progression	1	-	4
Consent withdrawn by subject	-	1	8
Physician decision	-	-	2
Death	-	-	6
Switching to another therapy	-	-	1
AE unassociated with clinical disease progression	3	7	31
Progressive disease – clinical progression	1	-	2

Baseline characteristics

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Reporting group title

Refametinib (BAY86-9766), 30 mg twice daily, Phase I

Reporting group description

Reporting group title

Refametinib (BAY86-9766), 50 mg twice daily, Phase I

Reporting group description

Reporting group title

Refametinib (BAY86-9766), 50 mg twice daily, Phase II

Reporting group description

Reporting group values	Refametinib (BAY86-9766), 30 mg twice daily, Phase I	Refametinib (BAY86-9766), 50 mg twice daily, Phase I	Refametinib (BAY86-9766), 50 mg twice daily, Phase II	Total
Number of subjects	10	10	80	90
Age categorical
Units: Subjects
Age 18 to less than or equal to 65 years	5	5	50	52
Age more than 65 years	5	5	30	38
Age continuous
Units: years
arithmetic mean (standard deviation)	59.9 ± 13.9	64.2 ± 8.8	62.7 ± 9.4	-
Gender categorical
Units: Subjects
Female	4	3	36	40
Male	6	7	44	50
Tumor node metastases (TNM) Classification at study entry
TNM was based on size of tumor, if cancer cells had spread to nearby lymph nodes (LN), or distant (to other parts of the body) metastasis had occurred. Stages included: stage 0(no evidence of cancer cells), stage 1(T1N0M0), stage IIA(T0N1M0, T1N1M0, T2N0M0), stage IIB(T2N1M0, T3N0M0), stage III(any TN3M0), stage IV(anyT anyNM1), where T0=early form of tumor, T1= <2 centimeter(cm), T2=2-5 cm, T3= >2 cm, T4=large sized tumor, N0=not spread to LN, N1=spread to 1 to 3, N2=spread to 4 to 9, N3=spread >10 axillary LN, M0=no metastasis, M1= Metastasis.
Units: Subjects
Stage IIA	0	0	1	1
Stage IIB	1	0	1	2
Stage III	1	2	10	11
Stage IV	8	8	68	76

End points

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Reporting group title

Refametinib (BAY86-9766), 30 mg twice daily, Phase I

Reporting group description

Reporting group title

Refametinib (BAY86-9766), 50 mg twice daily, Phase I

Reporting group description

Reporting group title

Refametinib (BAY86-9766), 50 mg twice daily, Phase II

Reporting group description

Subject analysis set title

Safety analysis set (SAF) population: Phase I

Subject analysis set type

Safety analysis

Subject analysis set description

SAF population included all subjects who was assigned to study treatment with at least one intake of study drug.

Subject analysis set title

Maximum tolerated dose (MTD) population: Phase I

Subject analysis set type

Sub-group analysis

Subject analysis set description

MTD population included all SAF subjects fully evaluable for occurence of dose limiting toxicities (DLTs).

Subject analysis set title

Refametinib (BAY86-9766),dose escalation 30 mg, 50 mg, Phase I

Subject analysis set type

Sub-group analysis

Subject analysis set description

All subjects who received refametinib 30 mg twice daily during the treatment cycle and 50 mg twice daily during the treatment cycle.

Subject analysis set title

Per protocol set (PPS) population: Phase II

Subject analysis set type

Per protocol

Subject analysis set description

PPS population included all subjects who was assigned to treatment with no major protocol deviations for whom the primary efficacy variable was assessable.

Primary: Number of Subjects With Dose Limiting Toxicities (DLT): Phase I

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End point title

Number of Subjects With Dose Limiting Toxicities (DLT): Phase I ^[1] ^[2]

End point description

DLT were defined using National Cancer Institute Common Toxicity Criteria (CTC) Adverse Event (NCI CTCAE) version4.0 as, Hematologic Toxicity: Grade 4 anemia, Grade 4 neutropenia lasting greater than (>) 10 days, Grade 3/4 neutropenia with fever >101 degree Fahrenheit , thrombocytopenia/Grade 3/4 thrombocytopenia with serious bleeding, or signs of serious bleeding and/or International Normalized Ratio >2.5 upper limit of normal (ULN) and/or partial thromboplastin time elevation of >2.5 ULN; Non-hematological toxicity: greater than or equal to (>=) Grade 3 toxicity, diarrhea only if refractory to maximal antidiarrheal therapy, skin toxicity Grade 3 for >2 weeks and Grade 4, missing >14 consecutive daily doses of BAY86-9766 due to drug-related toxicity, aspartate/alanine aminotransferase increase from Grade 1 to Grade 2-4, or from Grade 2 (in subjects with liver metastases) to Grade 3-4 in case of: 2nd occurrence after a 1st recovery to baseline level taking >14 days; or 3rd occurrence.

End point type

Primary

End point timeframe

From randomization up to the first 8 weeks of therapy

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: All planned continuous and ordinal categorical variables were analyzed by descriptive statistics only.
[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: This endpoint was related to Phase I arms only, hence not reporting statistics for all the arms in the baseline period.

End point values	Refametinib (BAY86-9766), 30 mg twice daily, Phase I	Refametinib (BAY86-9766), 50 mg twice daily, Phase I
Number of subjects analysed	6 ^[3]	6 ^[4]
Units: subjects
No	5	5
Yes	1	1

Notes
[3] - MTD analysis set included all safety analysis set subjects fully evaluable for occurence of DLTs.
[4] - MTD analysis set included all safety analysis set subjects fully evaluable for occurence of DLTs.

No statistical analyses for this end point

Primary: Tumor Response (Adjudicated Blinded Read Assessment): Phase II

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End point title

Tumor Response (Adjudicated Blinded Read Assessment): Phase II ^[5] ^[6]

End point description

Tumor Response (= Best Overall Response) of a subject was defined as the best tumor response [Complete Response (CR), Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD)] observed during trial period assessed according to the RECIST v 1.1 criteria. The subject's best overall response assignment was depended on the findings of both target and non-target disease and also on the appearance of new lesions. CR was defined as disappearance of tumor lesions, PR was defined as a decrease of at least 30% in the sum of tumor lesion sizes, SD was defined as steady state of disease, PD was defined as an increase of at least 20% in the sum of tumor lesions sizes. The blinded readers who were board certified, experienced and independent radiologists with broad expertise in oncology, radiology performed image evaluation independent from the conduct of the clinical part of the study.

End point type

Primary

End point timeframe

From start of treatment until 134 weeks assessed every 8 weeks

Notes
[5] - 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: All planned continuous and ordinal categorical variables were analyzed by descriptive statistics only.
[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: The statistical analysis was performed for each arm and reported under different endpoints. Hence not all the arms in the baseline period were reporting statistics in this endpoint.

End point values	Refametinib (BAY86-9766), 50 mg twice daily, Phase II
Number of subjects analysed	60 ^[7]
Units: percentage of subjects
number (confidence interval 75%)
Partial response	23.3 (16.89 to 30.99)
Stable disease	38.3 (30.63 to 46.57)
Unconfirmed Partial response	11.7 (7 to 18.15)
Progressive disease	10 (5.69 to 16.23)
Missing	16.7 (11.12 to 23.76)

Notes
[7] - Primary analysis set (PAS) included the first 60 per protocol set (PPS) subjects.

No statistical analyses for this end point

Secondary: Tumor Response: Investigator Assessment: Phase I

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End point title

Tumor Response: Investigator Assessment: Phase I ^[8]

End point description

Tumor Response (= Best Overall Response) of a subject was defined as the best tumor response [CR, PR, SD, or PD] observed during trial period assessed according to the RECIST v 1.1 criteria. The subject's best overall response assignment was depended on the findings of both target and non-target disease and also on the appearance of new lesions. CR was defined as disappearance of tumor lesions, PR was defined as a decrease of at least 30% in the sum of tumor lesion sizes, SD was defined as steady state of disease, PD was defined as an increase of at least 20% in the sum of tumor lesions sizes. '99999' in the reported data indicates that there were no subjects with those responses.

End point type

Secondary

End point timeframe

From start of treatment until 134 weeks assessed every 8 weeks

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: The statistical analysis was performed for each arm and reported under different endpoints. Hence not all the arms in the baseline period were reporting statistics in this endpoint.

End point values	Refametinib (BAY86-9766), 30 mg twice daily, Phase I	Refametinib (BAY86-9766), 50 mg twice daily, Phase I
Number of subjects analysed	10 ^[9]	10 ^[10]
Units: percentage of subjects
number (confidence interval 75%)
Partial response	20 (6.22 to 42.9)	20 (6.22 to 42.9)
Stable disease	50 (28.45 to 71.55)	40 (20.23 to 62.68)
Unconfirmed Partial response	20 (6.22 to 42.9)	10 (1.33 to 31.67)
Unconfirmed Stable disease	10 (1.33 to 31.67)	0 (0 to 0)
Progressive disease	0 (0 to 0)	10 (1.33 to 31.67)
Missing	0 (0 to 0)	20 (6.22 to 42.9)

Notes
[9] - Safety analysis set (SAF) included all subjects with at least one drug dose.
[10] - SAF included all subjects with at least one drug dose.

No statistical analyses for this end point

Secondary: Disease Control (DC): Phase I

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End point title

Disease Control (DC): Phase I ^[11]

End point description

Disease control rate (DCR) was defined as the proportion of subjects who have a best response rating over the whole duration of the study of CR, PR, or SD according to RECIST (Version 1.1). SD had to be maintained for at least six weeks from the first demonstration of that rating. Confirmed DCR included unconfirmed CR or PR which is more than 6 weeks from the first dosing date and unconfirmed DCR included unconfirmed CR or PR which is less than 6 weeks from the first dosing date.

End point type

Secondary

End point timeframe

From start of treatment until 134 weeks assessed every 8 weeks

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: This endpoint was related to Phase II arms only, hence not reporting statistics for all the arms in the baseline period.

End point values	Refametinib (BAY86-9766), 30 mg twice daily, Phase I	Refametinib (BAY86-9766), 50 mg twice daily, Phase I
Number of subjects analysed	10 ^[12]	10 ^[13]
Units: percentage of subjects
number (confidence interval 75%)
Confirmed DCR	90 (68.33 to 98.67)	70 (46.85 to 87.25)
Unconfirmed DCR	10 (1.33 to 31.67)	0 (0 to 0)

Notes
[12] - SAF included all subjects with at least one drug dose.
[13] - SAF included all subjects with at least one drug dose.

No statistical analyses for this end point

Secondary: Disease Control (DC): Phase II

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End point title

Disease Control (DC): Phase II ^[14]

End point description

DCR was defined as the proportion of subjects who have a best response rating over the whole duration of the study of CR, PR, or SD according to RECIST (Version 1.1). SD had to be maintained for at least six weeks from the first demonstration of that rating. Confirmed DCR included unconfirmed CR or PR which is more than 6 weeks from the first dosing date and unconfirmed DCR included unconfirmed CR or PR which is less than 6 weeks from the first dosing date.

End point type

Secondary

End point timeframe

From start of treatment until 134 weeks assessed every 8 weeks

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: This endpoint was related to Phase II arms only, hence not reporting statistics for all the arms in the baseline period.

End point values	Refametinib (BAY86-9766), 50 mg twice daily, Phase II
Number of subjects analysed	60 ^[15]
Units: percentage of subjects
number (confidence interval 75%)
Confirmed DCR	73.3 (65.47 to 80.13)

Notes
[15] - PAS included the first 60 PPS subjects.

No statistical analyses for this end point

Secondary: Duration of Response (DOR): Phase I

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End point title

Duration of Response (DOR): Phase I ^[16]

End point description

DOR defined as the time from first observed tumor response (CR or PR) until disease progression or until death caused by disease progression. Only confirmed responses were considered. '99999' in the reported data indicates there were too few subjects in the data set, hence the data were not summarized.

End point type

Secondary

End point timeframe

From start of treatment until 134 weeks assessed every 8 weeks

Notes
[16] - 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: This endpoint was related to Phase I arms only, hence not reporting statistics for all the arms in the baseline period.

End point values	Refametinib (BAY86-9766), 30 mg twice daily, Phase I	Refametinib (BAY86-9766), 50 mg twice daily, Phase I
Number of subjects analysed	10 ^[17]	10 ^[18]
Units: days
median (confidence interval 95%)	99999 (99999 to 99999)	99999 (99999 to 99999)

Notes
[17] - SAF included all subjects with at least one drug dose.
[18] - SAF included all subjects with at least one drug dose.

No statistical analyses for this end point

Secondary: Duration of Response: Phase II

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End point title

Duration of Response: Phase II ^[19]

End point description

DOR defined as the time from first observed tumor response (CR or PR) until disease progression or until death caused by disease progression. Only confirmed responses were considered.

End point type

Secondary

End point timeframe

From start of treatment until 134 weeks assessed every 8 weeks

Notes
[19] - 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: This endpoint was related to Phase II arms only, hence not reporting statistics for all the arms in the baseline period.

End point values	Refametinib (BAY86-9766), 50 mg twice daily, Phase II
Number of subjects analysed	10 ^[20]
Units: days
median (confidence interval 95%)	112 (84 to 265)

Notes
[20] - PAS included the first 60 PPS subjects.

No statistical analyses for this end point

Secondary: Time to Progression (TTP): Phase I

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End point title

Time to Progression (TTP): Phase I ^[21]

End point description

TTP defined as the time from randomization (in this study randomization refers to the date of treatment assignment) to the first observation of progressive disease (PD, RECIST Version 1.1) or to the last date of a definite assessment (not status Unknown), if the subject was progression-free until that assessment. Subjects without progression at the time of analysis were censored at their last date of tumor evaluation.

End point type

Secondary

End point timeframe

From start of treatment until 134 weeks assessed every 8 weeks

Notes
[21] - 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: This endpoint was related to Phase I arms only, hence not reporting statistics for all the arms in the baseline period.

End point values	Refametinib (BAY86-9766), 30 mg twice daily, Phase I	Refametinib (BAY86-9766), 50 mg twice daily, Phase I
Number of subjects analysed	10 ^[22]	10 ^[23]
Units: days
median (confidence interval 95%)	275 (107 to 392)	168 (20 to 168)

Notes
[22] - SAF included all subjects with at least one drug dose.
[23] - SAF included all subjects with at least one drug dose.

No statistical analyses for this end point

Secondary: Progression-Free Survival (PFS): Phase I

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End point title

Progression-Free Survival (PFS): Phase I ^[24]

End point description

PFS defined as the time from randomization (Randomization referred to the date of treatment assignment) to disease progression (radiological or clinical, whichever was earlier) or death (if death occurred before progression was documented). Subjects without progression or death at the time of analysis were censored at their last date of tumor evaluation.

End point type

Secondary

End point timeframe

From start of treatment until 134 weeks assessed every 8 weeks

Notes
[24] - 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: This endpoint was related to Phase I arms only, hence not reporting statistics for all the arms in the baseline period.

End point values	Refametinib (BAY86-9766), 30 mg twice daily, Phase I	Refametinib (BAY86-9766), 50 mg twice daily, Phase I
Number of subjects analysed	10 ^[25]	10 ^[26]
Units: days
median (confidence interval 95%)	163 (65 to 275)	267 (20 to 322)

Notes
[25] - SAF included all subjects with at least one drug dose.
[26] - SAF included all subjects with at least one drug dose.

No statistical analyses for this end point

Secondary: Time to Progression (TTP): Phase II

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End point title

Time to Progression (TTP): Phase II ^[27]

End point description

TTP defined as the time from randomization (in this study randomization referred to the date of treatment assignment) to the first observation of progressive disease (PD, RECIST Version 1.1) or to the last date of a definite assessment (not status Unknown), if the subject was progression-free until that assessment. Subjects without progression at the time of analysis were censored at their last date of tumor evaluation.

End point type

Secondary

End point timeframe

From start of treatment until 134 weeks assessed every 8 weeks

Notes
[27] - 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: This endpoint was related to Phase II arms only, hence not reporting statistics for all the arms in the baseline period.

End point values	Refametinib (BAY86-9766), 50 mg twice daily, Phase II
Number of subjects analysed	60 ^[28]
Units: days
median (confidence interval 95%)	217 (140 to 278)

Notes
[28] - PAS included the first 60 PPS subjects.

No statistical analyses for this end point

Secondary: Progression-Free Survival (PFS): Phase II

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End point title

Progression-Free Survival (PFS): Phase II ^[29]

End point description

End point type

Secondary

End point timeframe

From start of treatment until 134 weeks assessed every 8 weeks

Notes
[29] - 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: This endpoint was related to Phase II arms only, hence not reporting statistics for all the arms in the baseline period.

End point values	Refametinib (BAY86-9766), 50 mg twice daily, Phase II
Number of subjects analysed	60 ^[30]
Units: days
median (confidence interval 95%)	168 (115 to 225)

Notes
[30] - PAS included the first 60 PPS subjects.

No statistical analyses for this end point

Secondary: Overall Survival (OS): Phase I

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End point title

Overall Survival (OS): Phase I ^[31]

End point description

Overall survival defined as the time from randomization (in this study randomization referred to the date of treatment assignment) until death from any cause or until the last date the subject was known to be alive. Subjects who were still alive at the time of analysis were censored at their last date of last contact.

End point type

Secondary

End point timeframe

From start of treatment until 134 weeks assessed every 8 weeks

Notes
[31] - 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: This endpoint was related to Phase I arms only, hence not reporting statistics for all the arms in the baseline period.

End point values	Refametinib (BAY86-9766), 30 mg twice daily, Phase I	Refametinib (BAY86-9766), 50 mg twice daily, Phase I
Number of subjects analysed	10 ^[32]	10 ^[33]
Units: days
median (confidence interval 95%)	355 (65 to 574)	270 (140 to 553)

Notes
[32] - SAF included all subjects with at least one drug dose.
[33] - SAF included all subjects with at least one drug dose.

No statistical analyses for this end point

Secondary: Overall Survival (OS): Phase II

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End point title

Overall Survival (OS): Phase II ^[34]

End point description

End point type

Secondary

End point timeframe

From start of treatment until 134 weeks assessed every 8 weeks

Notes
[34] - 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: This endpoint was related to Phase II arms only, hence not reporting statistics for all the arms in the baseline period.

End point values	Refametinib (BAY86-9766), 50 mg twice daily, Phase II
Number of subjects analysed	60 ^[35]
Units: days
median (confidence interval 95%)	270 (200 to 355)

Notes
[35] - PAS included the first 60 PPS subjects.

No statistical analyses for this end point

Other pre-specified: Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose: Phase I

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End point title

Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose: Phase I

End point description

MTD was determined by testing increasing doses up to 50 mg twice daily on dose escalation cohorts 1 to 2 with 3 subjects each. MTD reflects highest dose of drug that did not cause an unacceptable side effect (= DLT in more than 30% of subjects). The MTD was the dose at which at most, one in six subjects in Cycle 1 had a DLT. RP2D was depended on the results of the Phase I part of this study.

End point type

Other pre-specified

End point timeframe

From start of the treatment upto the first eight weeks of therapy

End point values	Refametinib (BAY86-9766),dose escalation 30 mg, 50 mg, Phase I
Number of subjects analysed	12 ^[36]
Units: milligram(s)
number (not applicable)
MTD	50
RP2D	50

Notes
[36] - MTD analysis set included all safety analysis set subjects fully evaluable for occurence of DLTs.

No statistical analyses for this end point

Other pre-specified: Maximum Observed Drug Concentration in Plasma (Cmax) of Refametinib and Metabolite

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End point title

Maximum Observed Drug Concentration in Plasma (Cmax) of Refametinib and Metabolite ^[37]

End point description

Cmax refers to the highest measured drug concentration which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. Data for this outcome included subjects who received refametinib without gemcitabine at C1D21 and refametinib with gemcitabine at C1D22.

End point type

Other pre-specified

End point timeframe

Cycle (C) 1 Day (D) 21 (C1D21), C1D22

Notes
[37] - 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: This endpoint was related to Phase I arms only, hence not reporting statistics for all the arms in the baseline period.

End point values	Refametinib (BAY86-9766), 30 mg twice daily, Phase I	Refametinib (BAY86-9766), 50 mg twice daily, Phase I
Number of subjects analysed	10 ^[38]	10 ^[39]
Units: microgram per liter
geometric mean (geometric coefficient of variation)
Refametinib: C1D21 (N= 8, 6)	489 ± 66	1046 ± 37
Metabolite M-17: C1D21 (N= 8, 6)	82.9 ± 31	175 ± 75
Refametinib: C1D22 (N= 8, 6)	511 ± 79	900 ± 67
Metabolite M-17: C1D22 (N= 8, 6)	100 ± 30	164 ± 108

Notes
[38] - In the listed categories, 'N' signifies those subjects who were evaluable for this measure.
[39] - In the listed categories, 'N' signifies those subjects who were evaluable for this measure.

No statistical analyses for this end point

Other pre-specified: Maximum Observed Drug Concentration in Plasma (Cmax) of Gemcitabine and its Metabolite

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End point title

Maximum Observed Drug Concentration in Plasma (Cmax) of Gemcitabine and its Metabolite ^[40]

End point description

Cmax refers to the highest measured drug concentration which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. Data for this outcome included subjects who received gemcitabine without refametinib at C1D1 and gemcitabine with refametinib at C1D22.

End point type

Other pre-specified

End point timeframe

C1D1, C1D22

Notes
[40] - 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: This endpoint was related to Phase I arms only, hence not reporting statistics for all the arms in the baseline period.

End point values	Refametinib (BAY86-9766), 30 mg twice daily, Phase I	Refametinib (BAY86-9766), 50 mg twice daily, Phase I
Number of subjects analysed	10 ^[41]	10 ^[42]
Units: milligram per liter
geometric mean (geometric coefficient of variation)
Gemcitabine: C1D1 (N=10, 10)	2.49 ± 163	2.74 ± 197
Metabolite dFdU: C1D1 (N=10, 10)	28 ± 22	26.6 ± 25
Gemcitabine: C1D22 (N=7, 5)	6.06 ± 88	3.5 ± 248
Metabolite dFdU: C1D22 (N=7, 5)	26.2 ± 19	21.5 ± 46

Notes
[41] - In the listed categories, 'N' signifies those subjects who were evaluable for this measure.
[42] - In the listed categories, 'N' signifies those subjects who were evaluable for this measure.

No statistical analyses for this end point

Other pre-specified: Time to Reach Maximum Drug Concentration in Plasma (Tmax) of Refametinib and Metabolite

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End point title

Time to Reach Maximum Drug Concentration in Plasma (Tmax) of Refametinib and Metabolite ^[43]

End point description

Tmax refers to the time after dosing when a drug attains its highest measurable concentration (Cmax). It is obtained by collecting a series of blood samples at various times after dosing, and measuring them for drug content. Data for this outcome included subjects who received refametinib without gemcitabine at C1D21 and refametinib with gemcitabine at C1D22.

End point type

Other pre-specified

End point timeframe

C1D21, C1D22

Notes
[43] - 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: This endpoint was related to Phase I arms only, hence not reporting statistics for all the arms in the baseline period.

End point values	Refametinib (BAY86-9766), 30 mg twice daily, Phase I	Refametinib (BAY86-9766), 50 mg twice daily, Phase I
Number of subjects analysed	10 ^[44]	10 ^[45]
Units: hours
median (full range (min-max))
Refametinib: C1D21 (N= 8, 6)	3.5 (2 to 4)	2 (1 to 4)
Metabolite M-17: C1D21 (N= 8, 6)	4 (2 to 4)	2 (1 to 4)
Refametinib: C1D22 (N= 8, 6)	2.8 (2 to 4.5)	1.8 (1 to 4.5)
Metabolite M-17: C1D22 (N= 8, 6)	2.5 (2 to 4.5)	2 (1.6 to 8.5)

Notes
[44] - In the listed categories, 'N' signifies those subjects who were evaluable for this measure.
[45] - In the listed categories, 'N' signifies those subjects who were evaluable for this measure.

No statistical analyses for this end point

Other pre-specified: Time to Reach Maximum Drug Concentration in Plasma (Tmax) of Gemcitabine and its Metabolite

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End point title

Time to Reach Maximum Drug Concentration in Plasma (Tmax) of Gemcitabine and its Metabolite ^[46]

End point description

Tmax refers to the time after dosing when a drug attains its highest measurable concentration (Cmax). It is obtained by collecting a series of blood samples at various times after dosing, and measuring them for drug content. Data for this outcome included subjects who received gemcitabine without refametinib at C1D1 and gemcitabine with refametinib at C1D22.

End point type

Other pre-specified

End point timeframe

C1D1, C1D22

Notes
[46] - 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: This endpoint was related to Phase I arms only, hence not reporting statistics for all the arms in the baseline period.

End point values	Refametinib (BAY86-9766), 30 mg twice daily, Phase I	Refametinib (BAY86-9766), 50 mg twice daily, Phase I
Number of subjects analysed	10 ^[47]	10 ^[48]
Units: hours
median (full range (min-max))
Gemcitabine: C1D1 (N=10, 10)	0.8 (0.5 to 1)	1 (0.4 to 1.5)
Metabolite dFdU: C1D1 (N=10, 10)	1 (0.5 to 2)	1.2 (0.7 to 2.2)
Gemcitabine: C1D22 (N=7, 5)	1 (0.5 to 1)	1 (0.5 to 1.2)
Metabolite dFdU: C1D22 (N=7, 5)	1 (1 to 2)	1.2 (0.5 to 1.5)

Notes
[47] - In the listed categories, 'N' signifies those subjects who were evaluable for this measure.
[48] - In the listed categories, 'N' signifies those subjects who were evaluable for this measure.

No statistical analyses for this end point

Other pre-specified: Area Under the Curve From Time Zero to Last Quantifiable Concentration AUC (0-tlast) of Refametinib and Metabolite

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End point title

Area Under the Curve From Time Zero to Last Quantifiable Concentration AUC (0-tlast) of Refametinib and Metabolite ^[49]

End point description

AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. AUC(0-tlast) is defined as AUC from time zero to the last data point above the lower limit of quantification (2.00 microgram per liter). Data for this outcome included subjects who received refametinib without gemcitabine at C1D21 and refametinib with gemcitabine at C1D22.

End point type

Other pre-specified

End point timeframe

C1D21, C1D22

Notes
[49] - 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: This endpoint was related to Phase I arms only, hence not reporting statistics for all the arms in the baseline period.

End point values	Refametinib (BAY86-9766), 30 mg twice daily, Phase I	Refametinib (BAY86-9766), 50 mg twice daily, Phase I
Number of subjects analysed	10 ^[50]	10 ^[51]
Units: microgram*hour per liter
geometric mean (geometric coefficient of variation)
Refametinib: C1D21 (N= 8, 6)	2844 ± 80	5186 ± 58
Metabolite M-17: C1D21 (N= 8, 6)	498 ± 28	907 ± 68
Refametinib: C1D22 (N= 8, 6)	2979 ± 85	4629 ± 65
Metabolite M-17: C1D22 (N= 8, 6)	595 ± 37	850 ± 96

Notes
[50] - In the listed categories, 'N' signifies those subjects who were evaluable for this measure.
[51] - In the listed categories, 'N' signifies those subjects who were evaluable for this measure.

No statistical analyses for this end point

Other pre-specified: Area Under the Curve From Time Zero to Last Quantifiable Concentration AUC (0-tlast) of Gemcitabine and its Metabolite

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End point title

Area Under the Curve From Time Zero to Last Quantifiable Concentration AUC (0-tlast) of Gemcitabine and its Metabolite ^[52]

End point description

AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. AUC(0-tlast) is defined as AUC from time zero to the last data point above the lower limit of quantification (5.00 microgram per liter). Data for this outcome included subjects who received gemcitabine without refametinib at C1D1 and gemcitabine with refametinib at C1D22.

End point type

Other pre-specified

End point timeframe

C1D1, C1D22

Notes
[52] - 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: This endpoint was related to Phase I arms only, hence not reporting statistics for all the arms in the baseline period.

End point values	Refametinib (BAY86-9766), 30 mg twice daily, Phase I	Refametinib (BAY86-9766), 50 mg twice daily, Phase I
Number of subjects analysed	10 ^[53]	10 ^[54]
Units: milligram*hour per liter
geometric mean (geometric coefficient of variation)
Gemcitabine: C1D1 (N=10, 10)	2.4 ± 117	2.39 ± 132
Metabolite dFdU: C1D1 (N=10, 10)	198 ± 38	143 ± 26
Gemcitabine: C1D22 (N=7, 5)	4.93 ± 81	2.83 ± 177
Metabolite dFdU: C1D22 (N=7, 5)	212 ± 45	146 ± 41

Notes
[53] - In the listed categories, 'N' signifies those subjects who were evaluable for this measure.
[54] - In the listed categories, 'N' signifies those subjects who were evaluable for this measure.

No statistical analyses for this end point

Other pre-specified: Area Under the Curve From Time Zero to 8 hours [AUC (0 -8)] of Refametinib and Metabolite

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End point title

Area Under the Curve From Time Zero to 8 hours [AUC (0 -8)] of Refametinib and Metabolite ^[55]

End point description

AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. AUC(0-8) is defined as area under the concentration from time zero to 8 hours. Data for this outcome included subjects who received refametinib without gemcitabine at C1D21 and refametinib with gemcitabine at C1D22.

End point type

Other pre-specified

End point timeframe

C1D21, C1D22

Notes
[55] - 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: This endpoint was related to Phase I arms only, hence not reporting statistics for all the arms in the baseline period.

End point values	Refametinib (BAY86-9766), 30 mg twice daily, Phase I	Refametinib (BAY86-9766), 50 mg twice daily, Phase I
Number of subjects analysed	10 ^[56]	10 ^[57]
Units: microgram*hour per liter
geometric mean (geometric coefficient of variation)
Refametinib: C1D21 (N= 8, 6)	2857 ± 80	5193 ± 58
Metabolite M-17: C1D21 (N= 8, 6)	499 ± 30	909 ± 67
Refametinib: C1D22 (N= 8, 6)	2838 ± 85	4457 ± 61
Metabolite M-17: C1D22 (N= 8, 6)	563 ± 31	814 ± 87

Notes
[56] - In the listed categories, 'N' signifies those subjects who were evaluable for this measure.
[57] - In the listed categories, 'N' signifies those subjects who were evaluable for this measure.

No statistical analyses for this end point

Other pre-specified: Area under the Concentration-Time Curve (AUC) of Gemcitabine and its Metabolite

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End point title

Area under the Concentration-Time Curve (AUC) of Gemcitabine and its Metabolite ^[58]

End point description

AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. Data for this outcome included subjects who received gemcitabine without refametinib at C1D1 and gemcitabine with refametinib at C1D22. '99999' in the reported data indicates data for AUC was not calculated due to insufficient number of data points in the terminal phase.

End point type

Other pre-specified

End point timeframe

C1D1, C1D22

Notes
[58] - 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: This endpoint was related to Phase I arms only, hence not reporting statistics for all the arms in the baseline period.

End point values	Refametinib (BAY86-9766), 30 mg twice daily, Phase I	Refametinib (BAY86-9766), 50 mg twice daily, Phase I
Number of subjects analysed	10 ^[59]	10 ^[60]
Units: milligram*hour per liter
geometric mean (geometric coefficient of variation)
Gemcitabine: C1D1 (N=1, 0)	99999 ± 99999	99999 ± 99999
Metabolite dFdU: C1D1 (N=0, 1)	99999 ± 99999	99999 ± 99999
Gemcitabine: C1D22 (N=1, 2)	99999 ± 99999	9.344 ± 11.88
Metabolite dFdU: C1D22 (N=0, 0)	99999 ± 99999	99999 ± 99999

Notes
[59] - In the listed categories, 'N' signifies those subjects who were evaluable for this measure.
[60] - In the listed categories, 'N' signifies those subjects who were evaluable for this measure.

No statistical analyses for this end point

Other pre-specified: Half Life Associated With Terminal Slope (t1/2) of Refametinib and Metabolite

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End point title

Half Life Associated With Terminal Slope (t1/2) of Refametinib and Metabolite ^[61]

End point description

T1/2 refers to the elimination of the drug. It is the time taken for the blood plasma concentration to reach half the concentration in the terminal phase of elimination. It is expressed in hours (h) and derived from the terminal slope of the concentration versus time curve. Data for this outcome included subjects who received refametinib without gemcitabine at C1D21 and refametinib with gemcitabine at C1D22. '99999' in the reported data indicates data for t1/2 was not calculated due to insufficient number of data points in the terminal phase.

End point type

Other pre-specified

End point timeframe

C1D21, C1D22

Notes
[61] - 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: This endpoint was related to Phase I arms only, hence not reporting statistics for all the arms in the baseline period.

End point values	Refametinib (BAY86-9766), 30 mg twice daily, Phase I	Refametinib (BAY86-9766), 50 mg twice daily, Phase I
Number of subjects analysed	10 ^[62]	10 ^[63]
Units: hour
geometric mean (geometric coefficient of variation)
Refametinib: C1D21 (N= 8, 6)	99999 ± 99999	99999 ± 99999
Metabolite M-17: C1D21 (N= 8, 6)	99999 ± 99999	99999 ± 99999
Refametinib: C1D22 (N= 8, 6)	99999 ± 99999	99999 ± 99999
Metabolite M-17: C1D22 (N= 8, 6)	99999 ± 99999	99999 ± 99999

Notes
[62] - In the listed categories, 'N' signifies those subjects who were evaluable for this measure.
[63] - In the listed categories, 'N' signifies those subjects who were evaluable for this measure.

No statistical analyses for this end point

Other pre-specified: Half Life Associated With Terminal Slope (t1/2) of Gemcitabine and its Metabolite

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End point title

Half Life Associated With Terminal Slope (t1/2) of Gemcitabine and its Metabolite ^[64]

End point description

T1/2 refers to the elimination of the drug. It is the time taken for the blood plasma concentration to reach half the concentration in the terminal phase of elimination. It is expressed in hours (h) and derived from the terminal slope of the concentration versus time curve. Data for this outcome included subjects who received gemcitabine without refametinib at C1D1 and gemcitabine with refametinib at C1D22. '99999' in the reported data indicates data for t1/2 was not calculated due to insufficient number of data points in the terminal phase.

End point type

Other pre-specified

End point timeframe

C1D1, C1D22

Notes
[64] - 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: This endpoint was related to Phase I arms only, hence not reporting statistics for all the arms in the baseline period.

End point values	Refametinib (BAY86-9766), 30 mg twice daily, Phase I	Refametinib (BAY86-9766), 50 mg twice daily, Phase I
Number of subjects analysed	10 ^[65]	10 ^[66]
Units: hour
geometric mean (geometric coefficient of variation)
Gemcitabine: C1D1 (N=10, 10)	99999 ± 99999	99999 ± 99999
Metabolite dFdU: C1D1 (N=10, 10)	99999 ± 99999	99999 ± 99999
Gemcitabine: C1D22 (N=7, 5)	99999 ± 99999	99999 ± 99999
Metabolite dFdU: C1D22 (N=7, 5)	99999 ± 99999	99999 ± 99999

Notes
[65] - In the listed categories, 'N' signifies those subjects who were evaluable for this measure.
[66] - In the listed categories, 'N' signifies those subjects who were evaluable for this measure.

No statistical analyses for this end point

Other pre-specified: Number of Subjects With Improvement or Deterioration in Worst Pain: Phase I

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End point title

Number of Subjects With Improvement or Deterioration in Worst Pain: Phase I ^[67]

End point description

A minimally important difference (MID) for the ‘worst’ pain item of BPI-SF scale (11 point scale; range 0 [no pain] to 10 [worst pain]), had been estimated as a 2-point change. The proportions of subjects who have improved [a decrease of greater than or equal to (>=) 2-points from baseline], remained stable (not reached a MID), deteriorated (an increase of >=2-points from baseline) scored by the ‘worst’ pain item were summarized at each time point.

End point type

Other pre-specified

End point timeframe

C1D29, C2D1, C3D1, C4D1, C5D1, C6D1, C7D1, C8D1, C9D1, C10D1, C11D1, C12D1, C13D1, End of treatment visit

Notes
[67] - 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: This endpoint was related to Phase I arms only, hence not reporting statistics for all the arms in the baseline period.

End point values	Refametinib (BAY86-9766), 30 mg twice daily, Phase I	Refametinib (BAY86-9766), 50 mg twice daily, Phase I
Number of subjects analysed	10 ^[68]	10 ^[69]
Units: subjects
C1D29: Improved (N=7, 5)	4	2
C1D29: Stable (N=7, 5)	3	3
C1D29: Deteriorated (N=7, 5)	0	0
C2D1: Improved (N=9, 6)	4	3
C2D1: Stable (N=9, 6)	5	2
C2D1: Deteriorated (N=9, 6)	0	1
C3D1: Improved (N=5, 5)	2	3
C3D1: Stable (N=5, 5)	3	1
C3D1: Deteriorated (N=5, 5)	0	1
C4D1: Improved (N=4, 3)	2	1
C4D1: Stable (N=4, 3)	2	2
C4D1: Deteriorated (N=4, 3)	0	0
C5D1: Improved (N=4, 1)	2	0
C5D1: Stable (N=4, 1)	2	1
C5D1: Deteriorated (N=4, 1)	0	0
C6D1: Improved (N=3, 1)	2	0
C6D1: Stable (N=3, 1)	0	1
C6D1: Deteriorated (N=3, 1)	1	0
C7D1: Improved (N=4, 1)	2	0
C7D1: Stable (N=4, 1)	2	0
C7D1: Deteriorated (N=4, 1)	0	1
C8D1: Improved (N=4, 0)	2	0
C8D1: Stable (N=4, 0)	2	0
C8D1: Deteriorated (N=4, 0)	0	0
C9D1: Improved (N=4, 0)	1	0
C9D1: Stable (N=4, 0)	2	0
C9D1: Deteriorated (N=4, 0)	1	0
C10D1: Improved (N=2, 0)	0	0
C10D1: Stable (N=2, 0)	2	0
C10D1: Deteriorated (N=2, 0)	0	0
C11D1: Improved (N=2, 0)	0	0
C11D1: Stable (N=2, 0)	2	0
C11D1: Deteriorated (N=2, 0)	0	0
C12D1: Improved (N=1, 0)	0	0
C12D1: Stable (N= 1, 0)	1	0
C12D1: Deteriorated (N=1, 0)	0	0
C13D1: Improved (N=1, 0)	0	0
C13D1: Stable (N=1, 0)	1	0
C13D1: Deteriorated (N=1, 0)	0	0
End of treatment visit: Improved (N=7, 7)	2	3
End of treatment visit: Stable (N=7, 7)	5	4
End of treatment visit: Deteriorated (N=7, 7)	0	0

Notes
[68] - SAF included all subjects with at least one drug dose.
[69] - SAF included all subjects with at least one drug dose.

No statistical analyses for this end point

Other pre-specified: Number of Subjects With Improvement or Deterioration in Worst Pain: Phase II

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End point title

Number of Subjects With Improvement or Deterioration in Worst Pain: Phase II ^[70]

End point description

A MID for the ‘worst’ pain item of BPI-SF scale (11 point scale; range 0 [no pain] to 10 [worst pain]), had been estimated as a 2-point change. The proportions of subjects who have improved [a decrease of >= 2-points from baseline], remained stable (not reached a MID), deteriorated (an increase of >=2-points from baseline) scored by the ‘worst’ pain item were summarized at each time point.

End point type

Other pre-specified

End point timeframe

C2D1, C4D1, C6D1, C8D1, C10D1, C12D1, End of treatment visit

Notes
[70] - 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: This endpoint was related to Phase II arms only, hence not reporting statistics for all the arms in the baseline period.

End point values	Refametinib (BAY86-9766), 50 mg twice daily, Phase II
Number of subjects analysed	60 ^[71]
Units: subjects
C2D1: Improved (N=34)	16
C2D1: Stable (N=34)	12
C2D1: Deteriorated (N=34)	6
C4D1: Improved (N=23)	8
C4D1: Stable (N=23)	13
C4D1: Deteriorated (N=23)	2
C6D1: Improved (N=14)	4
C6D1: Stable (N=14)	8
C6D1: Deteriorated (N=14)	2
C8D1: Improved (N=9)	2
C8D1: Stable (N=9)	7
C8D1: Deteriorated (N=9)	0
C10D1: Improved (N=4)	1
C10D1: Stable (N=4)	3
C10D1: Deteriorated (N=4)	0
C12D1: Improved (N=2)	1
C12D1: Stable (N=2)	1
C12D1: Deteriorated (N=2)	0
End of treatment visit: Improved (N=34)	14
End of treatment visit: Stable (N=34)	15
End of treatment visit: Deteriorated (N=34)	5

Notes
[71] - PAS included the first 60 PPS subjects.

No statistical analyses for this end point

Other pre-specified: Number of Subjects With Pain Response: Phase I

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End point title

Number of Subjects With Pain Response: Phase I ^[72]

End point description

Number of subjects with pain response were classified as yes, no or unknown. Pain response yes indicates decrease of at least 2 points from baseline in worst pain, an item of BPI-SF scale (11 point scale; range 0 [no pain] to 10 [worst pain]), and no increase in pain medication score; no indicates decrease less than 2 points from baseline in worst pain, or increase in pain medication score; and unknown indicates 1. decrease at least 2 points from baseline in worst pain, but the change in pain medication score is unknown and 2. no increase in pain medication score, but decrease from baseline in worst pain is unknown.

End point type

Other pre-specified

End point timeframe

C1D29, C2D1, C3D1, C4D1, C5D1, C6D1, C7D1, C8D1, C9D1, C10D1, C11D1, C12D1, C13D1, End of treatment visit

Notes
[72] - 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: This endpoint was related to Phase I arms only, hence not reporting statistics for all the arms in the baseline period.

End point values	Refametinib (BAY86-9766), 30 mg twice daily, Phase I	Refametinib (BAY86-9766), 50 mg twice daily, Phase I
Number of subjects analysed	10 ^[73]	10 ^[74]
Units: subjects
C1D29: No (N=9, 6)	3	3
C1D29: Yes (N=9, 6)	4	1
C1D29: Unknown (N=9, 6)	2	2
C2D1: No (N=9, 6)	6	3
C2D1: Yes (N=9, 6)	2	2
C2D1: Unknown (N=9, 6)	1	1
C3D1: No (N=5, 5)	3	2
C3D1: Yes (N=5, 5)	1	2
C3D1: Unknown (N=5, 5)	1	1
C4D1: No (N=4, 3)	2	2
C4D1: Yes (N=4, 3)	2	0
C4D1: Unknown (N=4, 3)	0	1
C5D1: No (N=4, 1)	2	1
C5D1: Yes (N=4, 1)	2	0
C5D1: Unknown (N=4, 1)	0	0
C6D1: No (N=4, 1)	1	1
C6D1: Yes (N=4, 1)	2	0
C6D1: Unknown (N=4, 1)	1	0
C7D1: No (N=4, 1)	2	1
C7D1: Yes (N=4, 1)	2	0
C7D1: Unknown (N=4, 1)	0	0
C8D1: No (N=4, 0)	2	0
C8D1: Yes (N=4, 0)	1	0
C8D1: Unknown (N=4, 0)	1	0
C9D1: No (N=4, 0)	3	0
C9D1: Yes (N=4, 0)	1	0
C9D1: Unknown (N=4, 0)	0	0
C10D1: No (N=2, 0)	2	0
C10D1: Yes (N=2, 0)	0	0
C10D1: Unknown (N=2, 0)	0	0
C11D1: No (N=2, 0)	2	0
C11D1: Yes (N=2, 0)	0	0
C11D1: Unknown (N=2, 0)	0	0
C12D1: No (N=1, 0)	1	0
C12D1: Yes (N=1, 0)	0	0
C12D1: Unknown (N=1, 0)	0	0
C13D1: No (N=1, 0)	1	0
C13D1: Yes (N=1, 0)	0	0
C13D1: Unknown (N=1, 0)	0	0
End of treatment visit: No (N=7, 8)	6	4
End of treatment visit: Yes (N=7, 8)	1	2
End of treatment visit: Unknown (N=7, 8)	0	2

Notes
[73] - SAF included all subjects with at least one drug dose.
[74] - SAF included all subjects with at least one drug dose.

No statistical analyses for this end point

Other pre-specified: Number of Subjects With Pain Response: Phase II

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End point title

Number of Subjects With Pain Response: Phase II ^[75]

End point description

End point type

Other pre-specified

End point timeframe

C2D1, C4D1, C6D1, C8D1, C10D1, C12D1, End of treatment visit

Notes
[75] - 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: This endpoint was related to Phase II arms only, hence not reporting statistics for all the arms in the baseline period.

End point values	Refametinib (BAY86-9766), 50 mg twice daily, Phase II
Number of subjects analysed	60 ^[76]
Units: subjects
C2D1: No (N=34)	18
C2D1: Yes (N=34)	10
C2D1: Unknown (N=34)	8
C4D1: No (N=25)	16
C4D1: Yes (N=25)	4
C4D1: Unknown (N=25)	5
C6D1: No (N=15)	10
C6D1: Yes (N=15)	2
C6D1: Unknown (N=15)	3
C8D1: No (N=10)	7
C8D1: Yes (N=10)	2
C8D1: Unknown (N=10)	1
C10D1: No (N=5)	3
C10D1: Yes (N=5)	1
C10D1: Unknown (N=5)	1
C12D1: No (N=3)	1
C12D1: Yes (N=3)	1
C12D1: Unknown (N=3)	1
End of treatment visit: No (N=37)	20
End of treatment visit: Yes (N=37)	8
End of treatment visit: Unknown (N=37)	9

Notes
[76] - PAS included the first 60 PPS subjects.

No statistical analyses for this end point

Other pre-specified: Brief Pain Inventory – Short Form (BPI-SF) score: Phase I

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End point title

Brief Pain Inventory – Short Form (BPI-SF) score: Phase I ^[77]

End point description

Patient Reported Outcomes (PROs) data, as measured by the BPI-SF and the pain medication diary. BPI-SF was a 15-item, self administered, clinically valid, reliable and responsive measure developed to assess pain related to cancer. The instrument was available in validated multilingual versions; on average, it requires less than 10 minutes to complete the questionnaire. BPI-SF is typically scored by averaging the pain severity score and overall pain interference score. Scores range from 0-10 and a higher score indicates a higher level of pain/interference. Data presented for BPI-SF as total score, pain severity score, pain interference score (PIS) and for the average of general activity, walking, and work [activity-related dimension], and of relations, mood, and enjoyment [mood-related dimension] at each assessment time point. '99999' in the reported data indicates that there were no subjects evaluated at the specified time point.

End point type

Other pre-specified

End point timeframe

Baseline, C1D29, C2D1, C3D1, C4D1, C5D1, C6D1, C7D1, C8D1, C9D1, C10D1, C11D1, C12D1, C13D1, End of treatment (EOT) visit

Notes
[77] - 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: This endpoint was related to Phase I arms only, hence not reporting statistics for all the arms in the baseline period.

End point values	Refametinib (BAY86-9766), 30 mg twice daily, Phase I	Refametinib (BAY86-9766), 50 mg twice daily, Phase I
Number of subjects analysed	10 ^[78]	10 ^[79]
Units: units on a scale
arithmetic mean (standard deviation)
Baseline: Pain severity score (N=10, 9)	2.95 ± 2.54	2 ± 2.05
C1D29: Pain severity score (N=7, 6)	0.79 ± 0.81	0.42 ± 0.68
C2D1: Pain severity score (N=9, 6)	1.31 ± 2.2	1.04 ± 1.37
C3D1: Pain severity score (N=5, 5)	0.25 ± 0.43	1.25 ± 1.21
C4D1: Pain severity score (N=4, 3)	0.25 ± 0.5	0.33 ± 0.58
C5D1: Pain severity score (N=4, 1)	0.5 ± 1	0 ± 99999
C6D1: Pain severity score (N=3, 1)	1 ± 1.73	0 ± 99999
C7D1: Pain severity score (N=4, 1)	0.5 ± 1	4.5 ± 99999
C8D1: Pain severity score (N=4, 0)	0.56 ± 1.13	99999 ± 99999
C9D1: Pain severity score (N=4, 0)	1.13 ± 1.79	99999 ± 99999
C10D1: Pain severity score (N=2, 0)	1 ± 1.41	99999 ± 99999
C11D1: Pain severity score (N=2, 0)	0.75 ± 1.06	99999 ± 99999
C12D1: Pain severity score (N=1, 0)	0 ± 99999	99999 ± 99999
C13D1: Pain severity score (N=1, 0)	0 ± 99999	99999 ± 99999
End of treatment: Pain severity score (N=7, 8)	0.93 ± 0.85	1.16 ± 1.28
Baseline: PIS (N=10, 9)	2.7 ± 2.59	1.98 ± 2.54
C1D29: PIS (N=7, 6)	1.41 ± 2.18	0.48 ± 0.79
C2D1: PIS (N=9, 6)	1.41 ± 2.47	1.52 ± 1.8
C3D1: PIS (N=5, 5)	0.4 ± 0.82	1.91 ± 2.22
C4D1: PIS (N=4, 3)	0.64 ± 1.29	2.05 ± 3.55
C5D1: PIS (N=4, 1)	0.57 ± 1.14	0 ± 99999
C6D1: PIS (N=3, 1)	0.95 ± 1.65	0 ± 99999
C7D1: PIS (N=4, 1)	0.57 ± 1.14	5.57 ± 99999
C8D1: PIS (N=4, 0)	0.57 ± 1.14	99999 ± 99999
C9D1: PIS (N=4, 0)	1.11 ± 1.69	99999 ± 99999
C10D1: PIS (N=2, 0)	0.5 ± 0.71	99999 ± 99999
C11D1: PIS (N=2, 0)	0.64 ± 0.91	99999 ± 99999
C12D1: PIS (N=1, 0)	0 ± 99999	99999 ± 99999
C13D1: PIS (N=1, 0)	0 ± 99999	99999 ± 99999
End of treatment visit: PIS (N=7, 8)	1.53 ± 2.37	1.86 ± 2.19
Baseline: PIS-activity-related dimension (N=10, 9)	2.73 ± 2.96	1.96 ± 2.66
C1D29: PIS-activity-related dimension (N=7, 6)	1.67 ± 2.86	0.33 ± 0.52
C2D1: PIS-activity-related dimension (N=9, 6)	1.37 ± 2.37	1.44 ± 1.71
C3D1: PIS-activity-related dimension (N=5, 5)	0.47 ± 0.87	1.93 ± 2.28
C4D1: PIS-activity-related dimension (N=4, 3)	0.5 ± 1	1.33 ± 2.31
C5D1: PIS-activity-related dimension (N=4, 1)	0.58 ± 1.17	0 ± 99999
C6D1: PIS-activity-related dimension (N=3, 1)	1 ± 1.73	0 ± 99999
C7D1: PIS-activity-related dimension (N=4, 1)	0.58 ± 1.17	7 ± 99999
C8D1: PIS-activity-related dimension (N=4, 0)	0.5 ± 1	99999 ± 99999
C9D1: PIS-activity-related dimension (N=4, 0)	1.08 ± 1.57	99999 ± 99999
C10D1: PIS-activity-related dimension (N=2, 0)	0.67 ± 0.94	99999 ± 99999
C11D1: PIS-activity-related dimension (N=2, 0)	0.83 ± 1.18	99999 ± 99999
C12D1: PIS-activity-related dimension (N=1, 0)	0 ± 99999	99999 ± 99999
C13D1: PIS-activity-related dimension (N=1, 0)	0 ± 99999	99999 ± 99999
EOT: PIS-activity-related dimension (N=7, 8)	1.67 ± 2.51	1.58 ± 1.68
Baseline: PIS-mood-related dimension (N=10, 9)	2.33 ± 2.87	1.93 ± 2.42
C1D29: PIS-mood-related dimension (N=7, 6)	1.38 ± 2.14	0.61 ± 1.2
C2D1: PIS-mood-related dimension (9, 6)	1.56 ± 2.82	1.89 ± 2.25
C3D1: PIS-mood-related dimension (N=5, 5)	0.33 ± 0.75	1.87 ± 2.22
C4D1: PIS-mood-related dimension (N=4, 3)	0.67 ± 1.33	2.67 ± 4.62
C5D1: PIS-mood-related dimension (N=4, 1)	0.5 ± 1	0 ± 99999
C6D1: PIS-mood-related dimension (N=3, 1)	0.89 ± 1.54	0 ± 99999
C7D1: PIS-mood-related dimension (N=4, 1)	0.5 ± 1	5.67 ± 99999
C8D1: PIS-mood-related dimension (N=4, 0)	0.5 ± 1	99999 ± 99999
C9D1: PIS-mood-related dimension (N=4, 0)	1.17 ± 1.91	99999 ± 99999
C10D1: PIS-mood-related dimension (N=2, 0)	0.33 ± 0.47	99999 ± 99999
C11D1: PIS-mood-related dimension (N=2, 0)	0.67 ± 0.94	99999 ± 99999
C12D1: PIS-mood-related dimension (N=1, 0)	0 ± 99999	99999 ± 99999
C13D1: PIS-mood-related dimension (N=1, 0)	0 ± 99999	99999 ± 99999
EOT: PIS-mood-related dimension (N=7, 8)	1.67 ± 2.87	2.04 ± 2.69

Notes
[78] - SAF included all subjects with at least one drug dose.
[79] - SAF included all subjects with at least one drug dose.

No statistical analyses for this end point

Other pre-specified: Brief Pain Inventory – Short Form (BPI-SF) score: Phase II

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End point title

Brief Pain Inventory – Short Form (BPI-SF) score: Phase II ^[80]

End point description

PROs data, as measured by the BPI-SF and the pain medication diary. BPI-SF was a 15-item, self administered, clinically valid, reliable and responsive measure developed to assess pain related to cancer. The instrument was available in validated multilingual versions; on average, it requires less than 10 minutes to complete the questionnaire. BPI-SF is typically scored by averaging the pain severity score and overall pain interference score. Scores range from 0-10 and a higher score indicates a higher level of pain/interference. Data presented for BPI-SF as total score, pain severity score, PIS and for the average of general activity, walking, and work [activity-related dimension], and of relations, mood, and enjoyment [mood-related dimension] at each assessment time point.

End point type

Other pre-specified

End point timeframe

Baseline,C1D1, C1D29, C2D1, C3D1, C4D1, C5D1, C6D1, C7D1, C8D1, C9D9, C10D1, C11D1, C12D1, C13D1, End of treatment visit

Notes
[80] - 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: This endpoint was related to Phase II arms only, hence not reporting statistics for all the arms in the baseline period.

End point values	Refametinib (BAY86-9766), 50 mg twice daily, Phase II
Number of subjects analysed	60 ^[81]
Units: units on a scale
arithmetic mean (standard deviation)
Baseline: Pain severity score (N=54)	1.64 ± 1.67
C1D1: Pain severity score (N=1)	3.5 ± 99999
C1D29: Pain severity score (N=39)	1.28 ± 1.66
C2D1: Pain severity score (N=36)	0.97 ± 1.63
C3D1: Pain severity score (N=30)	0.94 ± 1.51
C4D1: Pain severity score (N=23)	0.73 ± 1.39
C5D1: Pain severity score (N=23)	0.86 ± 1.78
C6D1: Pain severity score (N=15)	1.02 ± 2.52
C7D1: Pain severity score (N=12)	0.58 ± 1.32
C8D1: Pain severity score (N=10)	0.1 ± 0.32
C9D1: Pain severity score (N=9)	0.42 ± 0.64
C10D1: Pain severity score (N=5)	0.05 ± 0.11
C11D1: Pain severity score (N=3)	0 ± 0
C12D1: Pain severity score (N=3)	0.17 ± 0.29
C13D1: Pain severity score (N=1)	0 ± 99999
End of treatment: Pain severity score (N=37)	1.36 ± 2
Baseline: PIS (N=53)	1.62 ± 2.1
C1D1: PIS (N=1)	4.86 ± 99999
C1D29: PIS (N=39)	1.27 ± 2.17
C2D1: PIS (N=36)	1.22 ± 2.05
C3D1: PIS (N=29)	1.4 ± 1.91
C4D1: PIS (N=24)	1.08 ± 1.99
C5D1: PIS (N=23)	0.84 ± 1.96
C6D1: PIS (N=15)	0.93 ± 2.32
C7D1: PIS (N=12)	0.71 ± 1.62
C8D1: PIS (N=10)	0.34 ± 0.56
C9D1: PIS (N=9)	0.33 ± 0.6
C10D1: PIS (N=5)	0.06 ± 0.13
C11D1: PIS (N=3)	0 ± 0
C12D1: PIS (N=3)	0.1 ± 0.16
C13D1: PIS (N=1)	0 ± 99999
End of treatment visit: PIS (N=37)	2.01 ± 2.76
Baseline: PIS-activity-related dimension (N=52)	1.49 ± 2.32
C1D1: PIS-activity-related dimension (N=1)	5 ± 99999
C1D29: PIS-activity-related dimension (N=39)	1.22 ± 2.19
C2D1: PIS-activity-related dimension (N=36)	1.2 ± 2.03
C3D1: PIS-activity-related dimension (N=29)	1.41 ± 2.09
C4D1: PIS-activity-related dimension (N=24)	1.07 ± 2.07
C5D1: PIS-activity-related dimension (N=23)	0.8 ± 2.01
C6D1: PIS-activity-related dimension (N=15)	0.96 ± 2.52
C7D1: PIS-activity-related dimension (N=12)	1.08 ± 2.21
C8D1: PIS-activity-related dimension (N=10)	0.47 ± 0.79
C9D1: PIS-activity-related dimension (N=8)	0.33 ± 0.71
C10D1: PIS-activity-related dimension (N=5)	0 ± 0
C11D1: PIS-activity-related dimension (N=3)	0 ± 0
C12D1: PIS-activity-related dimension (N=3)	0.22 ± 0.38
C13D1: PIS-activity-related dimension (N=1)	0 ± 99999
EOT: PIS-activity-related dimension (N=37)	2.09 ± 2.86
Baseline: PIS-mood-related dimension (N=51)	1.5 ± 2.01
C1D1: PIS-mood-related dimension (N=1)	5.67 ± 99999
C1D29: PIS-mood-related dimension (N=39)	1.23 ± 2.26
C2D1: PIS-mood-related dimension (N=35)	1.19 ± 2.01
C3D1: PIS-mood-related dimension (N=29)	1.46 ± 1.95
C4D1: PIS-mood-related dimension (N=24)	1.17 ± 2.33
C5D1: PIS-mood-related dimension (N=23)	0.91 ± 2.08
C6D1: PIS-mood-related dimension (N=15)	0.87 ± 2.03
C7D1: PIS-mood-related dimension (N=12)	0.53 ± 1.63
C8D1: PIS-mood-related dimension (N=10)	0.3 ± 0.51
C9D1: PIS-mood-related dimension (N=9)	0.3 ± 0.51
C10D1: PIS-mood-related dimension (N=5)	0.07 ± 0.15
C11D1: PIS-mood-related dimension (N=3)	0 ± 0
C12D1: PIS-mood-related dimension (N=3)	0 ± 0
C13D1: PIS-mood-related dimension (N=1)	0 ± 99999
EOT: PIS-mood-related dimension (N=37)	1.92 ± 2.72

Notes
[81] - PAS included the first 60 PPS subjects.

No statistical analyses for this end point

Other pre-specified: Number of Subjects Recorded Pain Medication in Diary: Phase I

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End point title

Number of Subjects Recorded Pain Medication in Diary: Phase I ^[82]

End point description

Pain is directly associated with the use of analgesics. Therefore, a diary was also completed by the subjects to ensure all key information (that is, type of pain medication, dosage and frequency) related to the use of analgesics commonly used to control pain in pancreatic cancer was fully captured. Subjects were to record all pain medications taken during the last 48 hours, only, prior to their scheduled visit at the study site.

End point type

Other pre-specified

End point timeframe

Baseline, C1D29, C2D1, C3D1, C4D1, C5D1, C6D1, C7D1, C8D1, C9D1, C10D1, C11D1, C12D1, C13D1, End of treatment visit

Notes
[82] - 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: This endpoint was related to Phase I arms only, hence not reporting statistics for all the arms in the baseline period.

End point values	Refametinib (BAY86-9766), 30 mg twice daily, Phase I	Refametinib (BAY86-9766), 50 mg twice daily, Phase I
Number of subjects analysed	10 ^[83]	10 ^[84]
Units: subjects
Baseline: No (N=10, 9)	0	0
Baseline: Yes (N=10, 9)	10	9
C1D29: No (N=9, 5)	3	0
C1D29: Yes (N=9, 5)	6	5
C2D1: No (N=9, 6)	1	0
C2D1: Yes (N=9, 6)	8	6
C3D1: No (N=5, 5)	0	1
C3D1: Yes (N=5, 5)	5	4
C4D1: No (N =4, 3)	0	0
C4D1: Yes (N=4, 3)	4	3
C5D1: No (N=4, 1)	0	0
C5D1: Yes (N=4, 1)	4	1
C6D1: No (N=4, 0)	0	0
C6D1: Yes (N=4, 0)	4	0
C7D1: No (N=4, 1)	0	0
C7D1: Yes (N=4, 1)	4	1
C8D1: No (N=4, 0)	0	0
C8D1: Yes (N=4, 0)	4	0
C9D1: No (N=4, 0)	0	0
C9D1: Yes (N=4, 0)	4	0
C10D1: No (N=2, 0)	0	0
C10D1: Yes (N=2, 0)	2	0
C11D1: No (N=2, 0)	0	0
C11D1: Yes (N=2, 0)	2	0
C12D1: No (N=1, 0)	0	0
C12D1: Yes (N=1, 0)	1	0
C13D1: No (N=1, 0)	0	0
C13D1: Yes (N=1, 0)	1	0
End of treatment visit: No (N=7, 8)	2	0
End of treatment visit: Yes (N=7, 8)	5	8

Notes
[83] - SAF included all subjects with at least one drug dose.
[84] - SAF included all subjects with at least one drug dose.

No statistical analyses for this end point

Other pre-specified: Number of Subjects Recorded Pain Medication in Diary: Phase II

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End point title

Number of Subjects Recorded Pain Medication in Diary: Phase II ^[85]

End point description

End point type

Other pre-specified

End point timeframe

Baseline, C1D29, C2D1, C3D1, C4D1, C5D1, C6D1, C7D1, C8D1, C9D1, C10D1, C11D1, C12D1, C13D1, End of treatment visit

Notes
[85] - 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: This endpoint was related to Phase II arms only, hence not reporting statistics for all the arms in the baseline period.

End point values	Refametinib (BAY86-9766), 50 mg twice daily, Phase II
Number of subjects analysed	60 ^[86]
Units: subjects
Baseline: No (N=57)	8
Baseline: Yes (N=57)	49
C1D29: No (N=43)	10
C1D29: Yes (N=43)	33
C2D1: No (N=35)	5
C2D1: Yes (N=35)	30
C3D1: No (N=29)	5
C3D1: Yes (N=29)	24
C4D1: No (N=24)	3
C4D1: Yes (N=24)	21
C5D1: No (N=23)	2
C5D1: Yes (N=23)	21
C6D1: No (N=14)	2
C6D1: Yes (N=14)	12
C7D1: No (N=14)	2
C7D1: Yes (N=14)	12
C8D1: No (N=11)	2
C8D1: Yes (N=11)	9
C9D1: No (N=9)	2
C9D1: Yes (N=9)	7
C10D1: No (N=4)	0
C10D1: Yes (N=4)	4
C11D1: No (N=3)	0
C11D1: Yes (N=3)	3
C12D1: No (N=3)	0
C12D1: Yes (N=3)	3
C13D1: No (N=1)	0
C13D1: Yes (N=1)	1
End of treatment visit: No (N=35)	6
End of treatment visit: Yes (N=35)	29

Notes
[86] - PAS included the first 60 PPS subjects.

No statistical analyses for this end point

Other pre-specified: Number of subjects with KRAS Mutational Status

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End point title

Number of subjects with KRAS Mutational Status

End point description

End point type

Other pre-specified

End point timeframe

From start of treatment until 134 weeks assessed every 8 weeks

End point values	Refametinib (BAY86-9766), 30 mg twice daily, Phase I	Refametinib (BAY86-9766), 50 mg twice daily, Phase I	Refametinib (BAY86-9766), 50 mg twice daily, Phase II
Number of subjects analysed	0 ^[87]	0 ^[88]	0 ^[89]
Units: subjects

Notes
[87] - Finalized data is not available to report, and would be updated once report is finalized.
[88] - Finalized data is not available to report, and would be updated once report is finalized.
[89] - Finalized data is not available to report, and would be updated once report is finalized.

No statistical analyses for this end point

Other pre-specified: Number of subjects with the BRAF loci Mutational Status

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End point title

Number of subjects with the BRAF loci Mutational Status

End point description

End point type

Other pre-specified

End point timeframe

From start of treatment until 134 weeks assessed every 8 weeks

End point values	Refametinib (BAY86-9766), 30 mg twice daily, Phase I	Refametinib (BAY86-9766), 50 mg twice daily, Phase I	Refametinib (BAY86-9766), 50 mg twice daily, Phase II
Number of subjects analysed	0 ^[90]	0 ^[91]	0 ^[92]
Units: subjects

Notes
[90] - Finalized data is not available to report, and would be updated once report is finalized.
[91] - Finalized data is not available to report, and would be updated once report is finalized.
[92] - Finalized data is not available to report, and would be updated once report is finalized.

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Baseline up to 30 days after last dose

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

15.0

Reporting group title

Refametinib (BAY86-9766), 50 mg twice daily, Phase I

Reporting group description

Refametinib was administered orally on Day 2 at a dose of 50 mg twice daily during the treatment cycle. Gemcitabine was administered on Day 1 at a dose of 1000 mg/m^2 IV infusion over 30 minutes weekly for 7 out of 8 weeks (cycle 1), thereafter, 3 out of 4 weeks (cycle 2 and subsequent). The treatment was continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met.

Reporting group title

Refametinib (BAY86-9766), 50 mg twice daily, Phase II

Reporting group description

Refametinib was administered orally on Day 1 at a dose of 50 mg twice daily during the treatment cycle. Gemcitabine was administered on Day 1 at a dose of 1000 mg/m^2 IV infusion dose over 30 minutes weekly for 7 out of 8 weeks (cycle 1), thereafter, 3 out of 4 weeks (cycle 2 and subsequent). The treatment was continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met.

Reporting group title

Refametinib (BAY86-9766), 30 mg twice daily, Phase I

Reporting group description

Refametinib was administered orally on Day 2 at a dose of 30 mg twice daily during the treatment cycle. Gemcitabine was administered on Day 1 at a dose of 1000 mg/m^2 IV infusion over 30 minutes weekly for 7 out of 8 weeks (cycle 1), thereafter, 3 out of 4 weeks (cycle 2 and subsequent). The treatment was continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met.

Serious adverse events	Refametinib (BAY86-9766), 50 mg twice daily, Phase I	Refametinib (BAY86-9766), 50 mg twice daily, Phase II	Refametinib (BAY86-9766), 30 mg twice daily, Phase I
Total subjects affected by serious adverse events
subjects affected / exposed	5 / 10 (50.00%)	48 / 70 (68.57%)	7 / 10 (70.00%)
number of deaths (all causes)	7	40	10
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Pancreatic carcinoma
subjects affected / exposed	0 / 10 (0.00%)	1 / 70 (1.43%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Vascular disorders
Circulatory collapse
subjects affected / exposed	0 / 10 (0.00%)	1 / 70 (1.43%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypotension
subjects affected / exposed	0 / 10 (0.00%)	2 / 70 (2.86%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Death
subjects affected / exposed	0 / 10 (0.00%)	4 / 70 (5.71%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 4	0 / 0
Multi-organ failure
subjects affected / exposed	0 / 10 (0.00%)	1 / 70 (1.43%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
General physical health deterioration
subjects affected / exposed	0 / 10 (0.00%)	4 / 70 (5.71%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 5	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 4	0 / 0
Pyrexia
subjects affected / exposed	1 / 10 (10.00%)	4 / 70 (5.71%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 1	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	1 / 10 (10.00%)	1 / 70 (1.43%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Interstitial lung disease
subjects affected / exposed	1 / 10 (10.00%)	1 / 70 (1.43%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Laryngeal haemorrhage
subjects affected / exposed	0 / 10 (0.00%)	1 / 70 (1.43%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lung disorder
subjects affected / exposed	0 / 10 (0.00%)	1 / 70 (1.43%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	1 / 10 (10.00%)	1 / 70 (1.43%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	2 / 2	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lung infiltration
subjects affected / exposed	0 / 10 (0.00%)	1 / 70 (1.43%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	1 / 10 (10.00%)	2 / 70 (2.86%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	3 / 3	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	0 / 10 (0.00%)	6 / 70 (8.57%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	5 / 7	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Confusional state
subjects affected / exposed	0 / 10 (0.00%)	1 / 70 (1.43%)	2 / 10 (20.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Investigations
Aspartate aminotransferase increased
subjects affected / exposed	0 / 10 (0.00%)	1 / 70 (1.43%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood creatine phosphokinase increased
subjects affected / exposed	0 / 10 (0.00%)	3 / 70 (4.29%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	8 / 9	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood bilirubin increased
subjects affected / exposed	0 / 10 (0.00%)	1 / 70 (1.43%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Electrocardiogram T wave abnormal
subjects affected / exposed	0 / 10 (0.00%)	1 / 70 (1.43%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood phosphorus decreased
subjects affected / exposed	0 / 10 (0.00%)	0 / 70 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Platelet count decreased
subjects affected / exposed	0 / 10 (0.00%)	1 / 70 (1.43%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	3 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
White blood cell count decreased
subjects affected / exposed	0 / 10 (0.00%)	1 / 70 (1.43%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Femoral neck fracture
subjects affected / exposed	0 / 10 (0.00%)	1 / 70 (1.43%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Clavicle fracture
subjects affected / exposed	0 / 10 (0.00%)	1 / 70 (1.43%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	0 / 10 (0.00%)	1 / 70 (1.43%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	0 / 10 (0.00%)	1 / 70 (1.43%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Cardiac failure
subjects affected / exposed	0 / 10 (0.00%)	1 / 70 (1.43%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Atrioventricular block
subjects affected / exposed	0 / 10 (0.00%)	1 / 70 (1.43%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Left ventricular failure
subjects affected / exposed	0 / 10 (0.00%)	1 / 70 (1.43%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	0 / 10 (0.00%)	1 / 70 (1.43%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Presyncope
subjects affected / exposed	0 / 10 (0.00%)	1 / 70 (1.43%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Somnolence
subjects affected / exposed	0 / 10 (0.00%)	0 / 70 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Status epilepticus
subjects affected / exposed	0 / 10 (0.00%)	0 / 70 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 10 (0.00%)	1 / 70 (1.43%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 10 (0.00%)	4 / 70 (5.71%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	3 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Eye disorders
Retinal haemorrhage
subjects affected / exposed	0 / 10 (0.00%)	1 / 70 (1.43%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 10 (0.00%)	2 / 70 (2.86%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	0 / 10 (0.00%)	1 / 70 (1.43%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ascites
subjects affected / exposed	0 / 10 (0.00%)	1 / 70 (1.43%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	0 / 10 (0.00%)	1 / 70 (1.43%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 10 (0.00%)	1 / 70 (1.43%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ileus
subjects affected / exposed	0 / 10 (0.00%)	1 / 70 (1.43%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 10 (0.00%)	1 / 70 (1.43%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
subjects affected / exposed	0 / 10 (0.00%)	1 / 70 (1.43%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 10 (0.00%)	2 / 70 (2.86%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Stomatitis
subjects affected / exposed	0 / 10 (0.00%)	1 / 70 (1.43%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Hepatic failure
subjects affected / exposed	0 / 10 (0.00%)	1 / 70 (1.43%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Cholestasis
subjects affected / exposed	0 / 10 (0.00%)	1 / 70 (1.43%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bile duct obstruction
subjects affected / exposed	0 / 10 (0.00%)	1 / 70 (1.43%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatic function abnormal
subjects affected / exposed	0 / 10 (0.00%)	0 / 70 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatotoxicity
subjects affected / exposed	0 / 10 (0.00%)	1 / 70 (1.43%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	3 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatic steatosis
subjects affected / exposed	0 / 10 (0.00%)	0 / 70 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1
Renal and urinary disorders
Renal failure acute
subjects affected / exposed	0 / 10 (0.00%)	0 / 70 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Diverticulitis
subjects affected / exposed	1 / 10 (10.00%)	0 / 70 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Erysipelas
subjects affected / exposed	0 / 10 (0.00%)	1 / 70 (1.43%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dermatitis infected
subjects affected / exposed	0 / 10 (0.00%)	0 / 70 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infected dermal cyst
subjects affected / exposed	0 / 10 (0.00%)	0 / 70 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infection
subjects affected / exposed	0 / 10 (0.00%)	1 / 70 (1.43%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Klebsiella sepsis
subjects affected / exposed	0 / 10 (0.00%)	1 / 70 (1.43%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lung abscess
subjects affected / exposed	0 / 10 (0.00%)	1 / 70 (1.43%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peritonitis
subjects affected / exposed	0 / 10 (0.00%)	1 / 70 (1.43%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lung infection
subjects affected / exposed	0 / 10 (0.00%)	1 / 70 (1.43%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 10 (10.00%)	4 / 70 (5.71%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Sepsis
subjects affected / exposed	0 / 10 (0.00%)	1 / 70 (1.43%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peritonitis bacterial
subjects affected / exposed	0 / 10 (0.00%)	0 / 70 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 10 (0.00%)	1 / 70 (1.43%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	1 / 10 (10.00%)	0 / 70 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 10 (0.00%)	1 / 70 (1.43%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Decreased appetite
subjects affected / exposed	0 / 10 (0.00%)	1 / 70 (1.43%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	0 / 10 (0.00%)	1 / 70 (1.43%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Refametinib (BAY86-9766), 50 mg twice daily, Phase I	Refametinib (BAY86-9766), 50 mg twice daily, Phase II	Refametinib (BAY86-9766), 30 mg twice daily, Phase I
Total subjects affected by non serious adverse events
subjects affected / exposed	10 / 10 (100.00%)	69 / 70 (98.57%)	10 / 10 (100.00%)
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	1 / 10 (10.00%)	8 / 70 (11.43%)	1 / 10 (10.00%)
occurrences all number	1	9	1
Axillary vein thrombosis
subjects affected / exposed	1 / 10 (10.00%)	0 / 70 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Embolism
subjects affected / exposed	1 / 10 (10.00%)	2 / 70 (2.86%)	0 / 10 (0.00%)
occurrences all number	1	2	0
Subclavian vein thrombosis
subjects affected / exposed	0 / 10 (0.00%)	0 / 70 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Jugular vein thrombosis
subjects affected / exposed	1 / 10 (10.00%)	0 / 70 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Hypotension
subjects affected / exposed	1 / 10 (10.00%)	2 / 70 (2.86%)	0 / 10 (0.00%)
occurrences all number	2	3	0
Hypertension
subjects affected / exposed	3 / 10 (30.00%)	7 / 70 (10.00%)	2 / 10 (20.00%)
occurrences all number	12	36	2
General disorders and administration site conditions
Chills
subjects affected / exposed	1 / 10 (10.00%)	3 / 70 (4.29%)	0 / 10 (0.00%)
occurrences all number	1	3	0
Fatigue
subjects affected / exposed	3 / 10 (30.00%)	33 / 70 (47.14%)	8 / 10 (80.00%)
occurrences all number	5	82	20
Asthenia
subjects affected / exposed	0 / 10 (0.00%)	9 / 70 (12.86%)	0 / 10 (0.00%)
occurrences all number	0	20	0
Oedema
subjects affected / exposed	1 / 10 (10.00%)	7 / 70 (10.00%)	1 / 10 (10.00%)
occurrences all number	1	7	1
Influenza like illness
subjects affected / exposed	1 / 10 (10.00%)	2 / 70 (2.86%)	1 / 10 (10.00%)
occurrences all number	1	2	1
Malaise
subjects affected / exposed	1 / 10 (10.00%)	0 / 70 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Mucosal inflammation
subjects affected / exposed	0 / 10 (0.00%)	15 / 70 (21.43%)	0 / 10 (0.00%)
occurrences all number	0	42	0
Pain
subjects affected / exposed	0 / 10 (0.00%)	2 / 70 (2.86%)	1 / 10 (10.00%)
occurrences all number	0	2	2
Pyrexia
subjects affected / exposed	6 / 10 (60.00%)	26 / 70 (37.14%)	4 / 10 (40.00%)
occurrences all number	10	46	8
Oedema peripheral
subjects affected / exposed	2 / 10 (20.00%)	39 / 70 (55.71%)	7 / 10 (70.00%)
occurrences all number	2	84	17
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	2 / 10 (20.00%)	11 / 70 (15.71%)	1 / 10 (10.00%)
occurrences all number	2	14	1
Alveolitis
subjects affected / exposed	0 / 10 (0.00%)	0 / 70 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Oropharyngeal pain
subjects affected / exposed	0 / 10 (0.00%)	4 / 70 (5.71%)	0 / 10 (0.00%)
occurrences all number	0	4	0
Epistaxis
subjects affected / exposed	0 / 10 (0.00%)	5 / 70 (7.14%)	0 / 10 (0.00%)
occurrences all number	0	5	0
Dyspnoea
subjects affected / exposed	2 / 10 (20.00%)	19 / 70 (27.14%)	0 / 10 (0.00%)
occurrences all number	2	32	0
Pulmonary embolism
subjects affected / exposed	1 / 10 (10.00%)	5 / 70 (7.14%)	0 / 10 (0.00%)
occurrences all number	1	6	0
Pleural effusion
subjects affected / exposed	1 / 10 (10.00%)	8 / 70 (11.43%)	0 / 10 (0.00%)
occurrences all number	1	8	0
Psychiatric disorders
Agitation
subjects affected / exposed	1 / 10 (10.00%)	1 / 70 (1.43%)	0 / 10 (0.00%)
occurrences all number	1	1	0
Anxiety
subjects affected / exposed	1 / 10 (10.00%)	3 / 70 (4.29%)	0 / 10 (0.00%)
occurrences all number	1	3	0
Hallucination
subjects affected / exposed	0 / 10 (0.00%)	2 / 70 (2.86%)	1 / 10 (10.00%)
occurrences all number	0	2	1
Insomnia
subjects affected / exposed	1 / 10 (10.00%)	8 / 70 (11.43%)	0 / 10 (0.00%)
occurrences all number	1	9	0
Confusional state
subjects affected / exposed	0 / 10 (0.00%)	4 / 70 (5.71%)	1 / 10 (10.00%)
occurrences all number	0	6	1
Sleep disorder
subjects affected / exposed	1 / 10 (10.00%)	0 / 70 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Investigations
Blood albumin decreased
subjects affected / exposed	0 / 10 (0.00%)	1 / 70 (1.43%)	1 / 10 (10.00%)
occurrences all number	0	2	7
Aspartate aminotransferase increased
subjects affected / exposed	2 / 10 (20.00%)	21 / 70 (30.00%)	3 / 10 (30.00%)
occurrences all number	6	73	12
Alanine aminotransferase increased
subjects affected / exposed	2 / 10 (20.00%)	25 / 70 (35.71%)	4 / 10 (40.00%)
occurrences all number	5	74	18
Blood creatine phosphokinase increased
subjects affected / exposed	1 / 10 (10.00%)	14 / 70 (20.00%)	0 / 10 (0.00%)
occurrences all number	6	40	0
Blood calcium decreased
subjects affected / exposed	0 / 10 (0.00%)	0 / 70 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	2
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 10 (0.00%)	6 / 70 (8.57%)	1 / 10 (10.00%)
occurrences all number	0	8	1
Blood lactate dehydrogenase increased
subjects affected / exposed	0 / 10 (0.00%)	6 / 70 (8.57%)	1 / 10 (10.00%)
occurrences all number	0	6	1
Blood phosphorus decreased
subjects affected / exposed	0 / 10 (0.00%)	0 / 70 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	2
Haemoglobin decreased
subjects affected / exposed	0 / 10 (0.00%)	0 / 70 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	3
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 10 (0.00%)	1 / 70 (1.43%)	1 / 10 (10.00%)
occurrences all number	0	1	3
Neutrophil count decreased
subjects affected / exposed	3 / 10 (30.00%)	10 / 70 (14.29%)	3 / 10 (30.00%)
occurrences all number	6	38	10
Lipase increased
subjects affected / exposed	0 / 10 (0.00%)	5 / 70 (7.14%)	0 / 10 (0.00%)
occurrences all number	0	10	0
Protein total decreased
subjects affected / exposed	0 / 10 (0.00%)	0 / 70 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Prothrombin time shortened
subjects affected / exposed	0 / 10 (0.00%)	0 / 70 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Platelet count decreased
subjects affected / exposed	2 / 10 (20.00%)	22 / 70 (31.43%)	4 / 10 (40.00%)
occurrences all number	4	62	22
White blood cell count decreased
subjects affected / exposed	0 / 10 (0.00%)	3 / 70 (4.29%)	1 / 10 (10.00%)
occurrences all number	0	22	16
Weight increased
subjects affected / exposed	0 / 10 (0.00%)	1 / 70 (1.43%)	2 / 10 (20.00%)
occurrences all number	0	1	2
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	0 / 10 (0.00%)	3 / 70 (4.29%)	1 / 10 (10.00%)
occurrences all number	0	3	1
Head injury
subjects affected / exposed	0 / 10 (0.00%)	1 / 70 (1.43%)	1 / 10 (10.00%)
occurrences all number	0	1	1
Cardiac disorders
Atrioventricular block
subjects affected / exposed	1 / 10 (10.00%)	1 / 70 (1.43%)	0 / 10 (0.00%)
occurrences all number	1	1	0
Tachycardia
subjects affected / exposed	0 / 10 (0.00%)	1 / 70 (1.43%)	1 / 10 (10.00%)
occurrences all number	0	3	1
Nervous system disorders
Dysgeusia
subjects affected / exposed	0 / 10 (0.00%)	10 / 70 (14.29%)	0 / 10 (0.00%)
occurrences all number	0	10	0
Burning sensation mucosal
subjects affected / exposed	1 / 10 (10.00%)	0 / 70 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Dizziness
subjects affected / exposed	2 / 10 (20.00%)	6 / 70 (8.57%)	1 / 10 (10.00%)
occurrences all number	2	7	1
Headache
subjects affected / exposed	1 / 10 (10.00%)	3 / 70 (4.29%)	0 / 10 (0.00%)
occurrences all number	1	3	0
Epilepsy
subjects affected / exposed	0 / 10 (0.00%)	0 / 70 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Encephalopathy
subjects affected / exposed	0 / 10 (0.00%)	0 / 70 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Metabolic encephalopathy
subjects affected / exposed	0 / 10 (0.00%)	0 / 70 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Peripheral sensory neuropathy
subjects affected / exposed	0 / 10 (0.00%)	1 / 70 (1.43%)	1 / 10 (10.00%)
occurrences all number	0	1	1
Presyncope
subjects affected / exposed	1 / 10 (10.00%)	3 / 70 (4.29%)	0 / 10 (0.00%)
occurrences all number	1	4	0
Somnolence
subjects affected / exposed	0 / 10 (0.00%)	3 / 70 (4.29%)	1 / 10 (10.00%)
occurrences all number	0	6	1
Syncope
subjects affected / exposed	2 / 10 (20.00%)	4 / 70 (5.71%)	0 / 10 (0.00%)
occurrences all number	2	4	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	2 / 10 (20.00%)	40 / 70 (57.14%)	4 / 10 (40.00%)
occurrences all number	2	178	29
Leukopenia
subjects affected / exposed	0 / 10 (0.00%)	9 / 70 (12.86%)	0 / 10 (0.00%)
occurrences all number	0	47	0
Neutropenia
subjects affected / exposed	1 / 10 (10.00%)	26 / 70 (37.14%)	4 / 10 (40.00%)
occurrences all number	1	121	27
Thrombocytopenia
subjects affected / exposed	2 / 10 (20.00%)	30 / 70 (42.86%)	2 / 10 (20.00%)
occurrences all number	3	118	6
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	0 / 10 (0.00%)	6 / 70 (8.57%)	1 / 10 (10.00%)
occurrences all number	0	17	3
Eye disorders
Conjunctivitis
subjects affected / exposed	1 / 10 (10.00%)	0 / 70 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Retinopathy hypertensive
subjects affected / exposed	1 / 10 (10.00%)	0 / 70 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	3 / 10 (30.00%)	19 / 70 (27.14%)	1 / 10 (10.00%)
occurrences all number	4	26	5
Abdominal pain upper
subjects affected / exposed	0 / 10 (0.00%)	9 / 70 (12.86%)	1 / 10 (10.00%)
occurrences all number	0	16	1
Aphthous stomatitis
subjects affected / exposed	1 / 10 (10.00%)	1 / 70 (1.43%)	0 / 10 (0.00%)
occurrences all number	1	1	0
Constipation
subjects affected / exposed	3 / 10 (30.00%)	15 / 70 (21.43%)	2 / 10 (20.00%)
occurrences all number	3	18	3
Ascites
subjects affected / exposed	0 / 10 (0.00%)	6 / 70 (8.57%)	1 / 10 (10.00%)
occurrences all number	0	11	1
Dry mouth
subjects affected / exposed	2 / 10 (20.00%)	9 / 70 (12.86%)	0 / 10 (0.00%)
occurrences all number	3	13	0
Dyspepsia
subjects affected / exposed	0 / 10 (0.00%)	7 / 70 (10.00%)	2 / 10 (20.00%)
occurrences all number	0	9	2
Faecal incontinence
subjects affected / exposed	0 / 10 (0.00%)	0 / 70 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Diarrhoea
subjects affected / exposed	3 / 10 (30.00%)	34 / 70 (48.57%)	4 / 10 (40.00%)
occurrences all number	5	59	9
Flatulence
subjects affected / exposed	0 / 10 (0.00%)	2 / 70 (2.86%)	1 / 10 (10.00%)
occurrences all number	0	2	1
Gastrooesophageal reflux disease
subjects affected / exposed	1 / 10 (10.00%)	2 / 70 (2.86%)	0 / 10 (0.00%)
occurrences all number	1	2	0
Haemorrhoids
subjects affected / exposed	0 / 10 (0.00%)	3 / 70 (4.29%)	3 / 10 (30.00%)
occurrences all number	0	3	3
Nausea
subjects affected / exposed	6 / 10 (60.00%)	33 / 70 (47.14%)	6 / 10 (60.00%)
occurrences all number	10	66	9
Vomiting
subjects affected / exposed	4 / 10 (40.00%)	31 / 70 (44.29%)	2 / 10 (20.00%)
occurrences all number	9	61	3
Stomatitis
subjects affected / exposed	1 / 10 (10.00%)	11 / 70 (15.71%)	0 / 10 (0.00%)
occurrences all number	1	20	0
Regurgitation
subjects affected / exposed	0 / 10 (0.00%)	0 / 70 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Hepatobiliary disorders
Jaundice
subjects affected / exposed	0 / 10 (0.00%)	1 / 70 (1.43%)	1 / 10 (10.00%)
occurrences all number	0	1	1
Liver injury
subjects affected / exposed	0 / 10 (0.00%)	0 / 70 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Portal vein thrombosis
subjects affected / exposed	1 / 10 (10.00%)	1 / 70 (1.43%)	0 / 10 (0.00%)
occurrences all number	1	1	0
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	0 / 10 (0.00%)	8 / 70 (11.43%)	0 / 10 (0.00%)
occurrences all number	0	8	0
Acne
subjects affected / exposed	0 / 10 (0.00%)	0 / 70 (0.00%)	2 / 10 (20.00%)
occurrences all number	0	0	2
Dry skin
subjects affected / exposed	2 / 10 (20.00%)	7 / 70 (10.00%)	1 / 10 (10.00%)
occurrences all number	2	13	1
Dermatitis acneiform
subjects affected / exposed	3 / 10 (30.00%)	9 / 70 (12.86%)	1 / 10 (10.00%)
occurrences all number	5	19	2
Nail bed inflammation
subjects affected / exposed	1 / 10 (10.00%)	0 / 70 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Night sweats
subjects affected / exposed	1 / 10 (10.00%)	0 / 70 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Pruritus
subjects affected / exposed	0 / 10 (0.00%)	6 / 70 (8.57%)	2 / 10 (20.00%)
occurrences all number	0	10	2
Onychoclasis
subjects affected / exposed	0 / 10 (0.00%)	0 / 70 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Skin fissures
subjects affected / exposed	2 / 10 (20.00%)	6 / 70 (8.57%)	0 / 10 (0.00%)
occurrences all number	2	11	0
Rash
subjects affected / exposed	6 / 10 (60.00%)	44 / 70 (62.86%)	4 / 10 (40.00%)
occurrences all number	14	135	16
Renal and urinary disorders
Urinary incontinence
subjects affected / exposed	0 / 10 (0.00%)	0 / 70 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Musculoskeletal and connective tissue disorders
Pain in extremity
subjects affected / exposed	1 / 10 (10.00%)	6 / 70 (8.57%)	2 / 10 (20.00%)
occurrences all number	1	7	2
Muscular weakness
subjects affected / exposed	0 / 10 (0.00%)	4 / 70 (5.71%)	0 / 10 (0.00%)
occurrences all number	0	5	0
Back pain
subjects affected / exposed	0 / 10 (0.00%)	9 / 70 (12.86%)	1 / 10 (10.00%)
occurrences all number	0	12	1
Infections and infestations
Atypical pneumonia
subjects affected / exposed	1 / 10 (10.00%)	0 / 70 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Folliculitis
subjects affected / exposed	1 / 10 (10.00%)	0 / 70 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Genital candidiasis
subjects affected / exposed	1 / 10 (10.00%)	0 / 70 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Cystitis
subjects affected / exposed	1 / 10 (10.00%)	1 / 70 (1.43%)	0 / 10 (0.00%)
occurrences all number	1	1	0
Rhinitis
subjects affected / exposed	1 / 10 (10.00%)	0 / 70 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Pneumonia
subjects affected / exposed	1 / 10 (10.00%)	1 / 70 (1.43%)	0 / 10 (0.00%)
occurrences all number	1	1	0
Infection
subjects affected / exposed	0 / 10 (0.00%)	6 / 70 (8.57%)	1 / 10 (10.00%)
occurrences all number	0	8	1
Nasopharyngitis
subjects affected / exposed	2 / 10 (20.00%)	2 / 70 (2.86%)	0 / 10 (0.00%)
occurrences all number	2	2	0
Upper respiratory tract infection
subjects affected / exposed	1 / 10 (10.00%)	1 / 70 (1.43%)	0 / 10 (0.00%)
occurrences all number	1	1	0
Urinary tract infection
subjects affected / exposed	1 / 10 (10.00%)	8 / 70 (11.43%)	1 / 10 (10.00%)
occurrences all number	1	9	1
Tracheitis
subjects affected / exposed	1 / 10 (10.00%)	0 / 70 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	2 / 10 (20.00%)	22 / 70 (31.43%)	3 / 10 (30.00%)
occurrences all number	2	35	3
Hyperkalaemia
subjects affected / exposed	1 / 10 (10.00%)	0 / 70 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0
Hypoalbuminaemia
subjects affected / exposed	0 / 10 (0.00%)	3 / 70 (4.29%)	1 / 10 (10.00%)
occurrences all number	0	4	8
Hypoglycaemia
subjects affected / exposed	1 / 10 (10.00%)	1 / 70 (1.43%)	0 / 10 (0.00%)
occurrences all number	2	1	0
Hyperglycaemia
subjects affected / exposed	0 / 10 (0.00%)	5 / 70 (7.14%)	1 / 10 (10.00%)
occurrences all number	0	8	1
Hypokalaemia
subjects affected / exposed	1 / 10 (10.00%)	15 / 70 (21.43%)	4 / 10 (40.00%)
occurrences all number	1	23	13
Hypomagnesaemia
subjects affected / exposed	0 / 10 (0.00%)	4 / 70 (5.71%)	2 / 10 (20.00%)
occurrences all number	0	9	5
Hypophosphataemia
subjects affected / exposed	0 / 10 (0.00%)	0 / 70 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	2
Vitamin D deficiency
subjects affected / exposed	0 / 10 (0.00%)	0 / 70 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1
Vitamin K deficiency
subjects affected / exposed	0 / 10 (0.00%)	0 / 70 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

08 Jun 2011

Amendment 1 included new data from preclinical and clinical trials and revised the informed consent form for genetic testing due to regulatory requirements / requests. In addition, inconsistencies and errors were corrected, and clarifications to the original protocol were made. In Amendment 1, the protocol was: 1. Revised to indicate that drug-drug interactions with substrates of CYP2C8 cannot be ruled out. Caution was recommended when considering or administering medications that are metabolized by cytochrome enzyme CYP2C8 (eg, repaglinide and torsemide). Such concomitant medications were to be avoided, if possible. 2. Revised to include additions of two new exclusion criteria: to exclude patients with history or current retinal vein occlusion or retinopathy; or retinal pathology considered a risk factor for these conditions. This change was made to be consistent with exclusion criteria in other MEK-inhibitor studies. 3. Revised to indicate that both gemcitabine and refametinib seem to have a largely non-overlapping adverse event (AE) profile. An additional recommendation was given regarding the necessity for careful observation of the intensity and frequency of AEs (side effects) as well as the occurrence of new and unexpected AEs for the combination of the drugs administered to the patients. 4. Revised to add a separate genetic informed consent. Also, a baseline blood plasma sample for mutational analysis is not to be collected from patients who reside in countries that require a separate genetic consent form, and fail to provide genetic consent. 5. Revised to add a new table regarding dose adjustments and treatment interruptions triggered by transaminase elevations.

26 Apr 2012

Amendment 2 introduced a more intensive treatment for skin toxicity, added Creatine phosphokinase (CPK) examinations to the chemistry panel, removed Cycle 1 Day 50 and Cycle 2 Day 22 from the schedule of examinations and clarified ophthalmologic examinations, exclusion criteria and echocardiography assessments. In addition, inconsistencies and errors were corrected and clarifications were made. In Amendment 2, the protocol was: 1. Revised to include the application of systemic antibiotics for skin toxicity CTCAE Grade 1. 2. Revised to add CPK examination to the chemistry panel, scheduled to be performed at screening, weekly within the first 4 weeks, afterwards every 2 weeks. Closer evaluations in case of CTCAE Grade 3 elevations were required. Dose modifications were required in case of CPK increase greater than or equal to (>=) CTCAE Grade 3 for refametinib. 3. Revised to include CPK increase > CTCAE Grade 3 as adverse event of special interest. 4. Revised to reduce the number of visits on days patients do not require a full in-hospital visit (Cycle 1 Day 50 and Cycle 2 Day 22). 5. Revised to change the day of ophthalmologic examination to within 8 days (+/-) from Cycle 1 Day 43. 6. Revised to extend the time required for adequate contraception from 3 months to 6 months after last study treatment. 7. Revised to specify that echocardiography assessments should be performed by an experienced qualified technician or cardiologist and should be evaluated by an experienced cardiologist. The expression experienced “investigator” is not correct.

13 May 2013

Amendment 3 reduced the number of efficacy and safety measurements performed after the primary completion date. 1. Reduced the frequency of tumor assessments from every 8 weeks to every 12 weeks. 2. Specified that beyond the cut-off date for the final analysis, safety data (AEs of CTCAE Grades 3 and 4 and Serious AEs) for each patient continuing on study drug would be captured until 30 days after the individual patient had stopped study treatment. 3. Eliminated the need to (1) collect diary and records of pain medication taken before patient’s visit to study site, and (2) collect blood plasma samples for end of treatment analysis for determination of the apoptosis marker cleaved cytokeratin 18 (CK18) "M30" and possibly other biomarkers of tumor response, after Amendment 3 became effective.

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.

'99999' in the posting indicates that data were not calculated. Decimal places were automatically truncated if last decimal equals zero.

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Clinical trials

Clinical Trial Results: A multi-center, phase I/II study of BAY86-9766 in combination with gemcitabine in patients with locally advanced inoperable or metastatic pancreatic cancer

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of Subjects With Dose Limiting Toxicities (DLT): Phase I

Primary: Number of Subjects With Dose Limiting Toxicities (DLT): Phase I

Primary: Tumor Response (Adjudicated Blinded Read Assessment): Phase II

Primary: Tumor Response (Adjudicated Blinded Read Assessment): Phase II

Secondary: Tumor Response: Investigator Assessment: Phase I

Secondary: Tumor Response: Investigator Assessment: Phase I

Secondary: Disease Control (DC): Phase I

Secondary: Disease Control (DC): Phase I

Secondary: Disease Control (DC): Phase II

Secondary: Disease Control (DC): Phase II

Secondary: Duration of Response (DOR): Phase I

Secondary: Duration of Response (DOR): Phase I

Secondary: Duration of Response: Phase II

Secondary: Duration of Response: Phase II

Secondary: Time to Progression (TTP): Phase I

Secondary: Time to Progression (TTP): Phase I

Secondary: Progression-Free Survival (PFS): Phase I

Secondary: Progression-Free Survival (PFS): Phase I

Secondary: Time to Progression (TTP): Phase II

Secondary: Time to Progression (TTP): Phase II

Secondary: Progression-Free Survival (PFS): Phase II

Secondary: Progression-Free Survival (PFS): Phase II

Secondary: Overall Survival (OS): Phase I

Secondary: Overall Survival (OS): Phase I

Secondary: Overall Survival (OS): Phase II

Secondary: Overall Survival (OS): Phase II

Other pre-specified: Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose: Phase I

Other pre-specified: Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose: Phase I

Other pre-specified: Maximum Observed Drug Concentration in Plasma (Cmax) of Refametinib and Metabolite

Other pre-specified: Maximum Observed Drug Concentration in Plasma (Cmax) of Refametinib and Metabolite

Other pre-specified: Maximum Observed Drug Concentration in Plasma (Cmax) of Gemcitabine and its Metabolite

Other pre-specified: Maximum Observed Drug Concentration in Plasma (Cmax) of Gemcitabine and its Metabolite

Other pre-specified: Time to Reach Maximum Drug Concentration in Plasma (Tmax) of Refametinib and Metabolite

Other pre-specified: Time to Reach Maximum Drug Concentration in Plasma (Tmax) of Refametinib and Metabolite

Other pre-specified: Time to Reach Maximum Drug Concentration in Plasma (Tmax) of Gemcitabine and its Metabolite

Other pre-specified: Time to Reach Maximum Drug Concentration in Plasma (Tmax) of Gemcitabine and its Metabolite

Other pre-specified: Area Under the Curve From Time Zero to Last Quantifiable Concentration AUC (0-tlast) of Refametinib and Metabolite

Other pre-specified: Area Under the Curve From Time Zero to Last Quantifiable Concentration AUC (0-tlast) of Refametinib and Metabolite

Other pre-specified: Area Under the Curve From Time Zero to Last Quantifiable Concentration AUC (0-tlast) of Gemcitabine and its Metabolite

Other pre-specified: Area Under the Curve From Time Zero to Last Quantifiable Concentration AUC (0-tlast) of Gemcitabine and its Metabolite

Other pre-specified: Area Under the Curve From Time Zero to 8 hours [AUC (0 -8)] of Refametinib and Metabolite

Other pre-specified: Area Under the Curve From Time Zero to 8 hours [AUC (0 -8)] of Refametinib and Metabolite

Other pre-specified: Area under the Concentration-Time Curve (AUC) of Gemcitabine and its Metabolite

Other pre-specified: Area under the Concentration-Time Curve (AUC) of Gemcitabine and its Metabolite

Other pre-specified: Half Life Associated With Terminal Slope (t1/2) of Refametinib and Metabolite

Other pre-specified: Half Life Associated With Terminal Slope (t1/2) of Refametinib and Metabolite

Other pre-specified: Half Life Associated With Terminal Slope (t1/2) of Gemcitabine and its Metabolite

Other pre-specified: Half Life Associated With Terminal Slope (t1/2) of Gemcitabine and its Metabolite

Other pre-specified: Number of Subjects With Improvement or Deterioration in Worst Pain: Phase I

Other pre-specified: Number of Subjects With Improvement or Deterioration in Worst Pain: Phase I

Other pre-specified: Number of Subjects With Improvement or Deterioration in Worst Pain: Phase II

Other pre-specified: Number of Subjects With Improvement or Deterioration in Worst Pain: Phase II

Other pre-specified: Number of Subjects With Pain Response: Phase I

Other pre-specified: Number of Subjects With Pain Response: Phase I

Other pre-specified: Number of Subjects With Pain Response: Phase II

Other pre-specified: Number of Subjects With Pain Response: Phase II

Other pre-specified: Brief Pain Inventory – Short Form (BPI-SF) score: Phase I

Other pre-specified: Brief Pain Inventory – Short Form (BPI-SF) score: Phase I

Other pre-specified: Brief Pain Inventory – Short Form (BPI-SF) score: Phase II

Other pre-specified: Brief Pain Inventory – Short Form (BPI-SF) score: Phase II

Other pre-specified: Number of Subjects Recorded Pain Medication in Diary: Phase I

Other pre-specified: Number of Subjects Recorded Pain Medication in Diary: Phase I

Other pre-specified: Number of Subjects Recorded Pain Medication in Diary: Phase II

Other pre-specified: Number of Subjects Recorded Pain Medication in Diary: Phase II

Other pre-specified: Number of subjects with KRAS Mutational Status

Other pre-specified: Number of subjects with KRAS Mutational Status

Other pre-specified: Number of subjects with the BRAF loci Mutational Status

Other pre-specified: Number of subjects with the BRAF loci Mutational Status

Adverse events

Adverse events

Clinical Trial Results:
A multi-center, phase I/II study of BAY86-9766 in combination with gemcitabine in patients with locally advanced inoperable or metastatic pancreatic cancer