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Clinical Trial Results:
A Sequential Phase I study of MEK1/2 inhibitors PD-0325901 or Binimetinib combined with cMET inhibitor Crizotinib in RAS Mutant and RAS Wild Type(with aberrant c-MET) Colorectal Cancer

Summary
EudraCT number	2014-000463-40
Trial protocol	GB IE
Global end of trial date	03 Dec 2018

Results information
Results version number	v1(current)
This version publication date	05 Jan 2020
First version publication date	05 Jan 2020
Other versions

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

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Trial information

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Sponsor protocol code

OCTO_049

ISRCTN number

ISRCTN18043777

US NCT number

NCT02510001

WHO universal trial number (UTN)

Sponsor organisation name

University of Oxford

Sponsor organisation address

Joint Research Office, 1st Floor, Boundary Brook House, Churchill Drive, Headington,n, Oxford, United Kingdom, OX3 7GB

Public contact

Mrs Jennifer Houlden, Oncology Clinical Trials Office, 44 01865227194, octo-mercuric@oncology.ox.ac.uk

Scientific contact

Mrs Jennifer Houlden, Oncology Clinical Trials Office, 44 01865227194, octo-mercuric@oncology.ox.ac.uk

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

18 Jul 2019

Is this the analysis of the primary completion data?

Yes

Primary completion date

03 Dec 2018

Global end of trial reached?

Yes

Global end of trial date

03 Dec 2018

Was the trial ended prematurely?

Main objective of the trial

In the dose escalation part of the trial the main objective is to find the best doses for the combination of MEK inhibitors PD-0325901 or Binimetinib with cMET inhibitor Crizotinib. In the second (expansion) part of the trial we want to see how well this combination works in three particular sub-types of bowel cancer. We want to do this by looking at tumour shrinkage, and at the molecular level through a variety of tests on tumour and bloods samples.

Protection of trial subjects

The Sponsor and Investigators ensured that this protocol was conducted in compliance with the European Clinical Trials Regulations, the Principles of Good Clinical Practice (GCP)3 and the applicable policies of the sponsoring organisation. Together, these implement the ethical principles of the Declaration of Helsinki (1996) and the regulatory requirements for clinical trials of an investigational medicinal product under the European Union Clinical Trials Directive. Following the end of study visit, patients will receive subsequent standard active, clinical trial, supportive and palliative care as appropriate.

Background therapy

Evidence for comparator

Actual start date of recruitment

01 Aug 2014

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Spain: 12

Country: Number of subjects enrolled

United Kingdom: 39

Country: Number of subjects enrolled

Belgium: 15

Country: Number of subjects enrolled

France: 12

Country: Number of subjects enrolled

Ireland: 4

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

Initial escalation phase start Dec2014 over 4 sites, Oxford, Belfast, Belgium and Spain to Nov2015 . Further escalation phase start Aug2016 over same sites plus Cardiff (activated Mar2017) to Jun2017. Expansion phase start Oct2017 over same sites plus 2 sites in Paris, France and 1 site Dublin, Ireland. Study recruitment end Oct2018.

Screening details

Escalation phases 45/71 screened patients recruited. Expansion phase 36/57 screened patients recruited to RAS MT CRC cohort; 1/4 patients RAS WT CRC. Some patients declined due to 2 required tumour biopsies; RAS WT CRC cohort for eligibility biopsy availability. Both phases most exclusions due to raised liver function, CK and albumin results.

Period 1 title

Baseline (overall) (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Dose escalation phase cohort 1 dose level 1

Arm description

Arm type

Experimental

Investigational medicinal product name

PD-0325901

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

2mg BD Day 1-21 every 28 day cycle

Investigational medicinal product name

PF-02341066

Investigational medicinal product code

Other name

Crizotinib

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

250mg OD Days 1-28 continuously

Dose escalation phase cohort 2 dose level 2

Arm description

Arm type

Experimental

Investigational medicinal product name

PD-0325901

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

2mg BD Day 1-21 every 28 day cycle

Investigational medicinal product name

PF-02341066

Investigational medicinal product code

Other name

Crizotinib

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

250mg BD Days 1-28 continuously

Dose escalation phase cohort 3 dose level 3

Arm description

Arm type

Experimental

Investigational medicinal product name

PD-0325901

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

4mg BD Day 1-21 every 28 day cycle

Investigational medicinal product name

PF-02341066

Investigational medicinal product code

Other name

Crizotinib

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

200mg BD Days 1-28 continuously

Dose escalation phase cohort 4 dose level 4

Arm description

Arm type

Experimental

Investigational medicinal product name

PD-0325901

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

8mg BD Day 1-21 every 28 day cycle

Investigational medicinal product name

PF-02341066

Investigational medicinal product code

Other name

Crizotinib

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

200mg BD Days 1-28 continuously

Dose escalation phase cohort 7 dose level 5

Arm description

Arm type

Experimental

Investigational medicinal product name

PF-02341066

Investigational medicinal product code

Other name

Crizotinib

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

200mg BD Days 1-28 continuously

Investigational medicinal product name

Binimetinib

Investigational medicinal product code

Other name

MEK162

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

30mg BD continuously

Dose escalation phase cohort 12 dose level 5a

Arm description

Arm type

Experimental

Investigational medicinal product name

PF-02341066

Investigational medicinal product code

Other name

Crizotinib

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

250mg OD Days 1-28 continuously

Investigational medicinal product name

Binimetinib

Investigational medicinal product code

Other name

MEK162

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

30mg BD days 1-21 every 28 days

Dose escalation phase cohort 13 dose level 5 (interval dosing)

Arm description

Arm type

Experimental

Investigational medicinal product name

PF-02341066

Investigational medicinal product code

Other name

Crizotinib

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

200mg BD Days 1-28 continuously

Investigational medicinal product name

Binimetinib

Investigational medicinal product code

Other name

MEK162

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

30mg BD continuously

Dose expansion phase

Arm description

Dosage determined following the recommended phase II dose identification in the dose escalation phase.

Arm type

Experimental

Investigational medicinal product name

PF-02341066

Investigational medicinal product code

Other name

Crizotinib

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

250mg OD Days 1-28 continuously

Investigational medicinal product name

Binimetinib

Investigational medicinal product code

Other name

MEK162

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

30mg BD days 1-21 every 28 day cycle

Number of subjects in period 1	Dose escalation phase cohort 1 dose level 1	Dose escalation phase cohort 2 dose level 2	Dose escalation phase cohort 3 dose level 3	Dose escalation phase cohort 4 dose level 4	Dose escalation phase cohort 7 dose level 5	Dose escalation phase cohort 12 dose level 5a	Dose escalation phase cohort 13 dose level 5 (interval dosing)	Dose expansion phase
Started	6	5	6	8	8	7	5	37
Completed	6	5	6	6	4	5	3	30
Not completed	0	0	0	2	4	2	2	7
Physician decision	-	-	-	-	1	-	-	-
Consent withdrawn by subject	-	-	-	-	-	-	-	2
Adverse event, non-fatal	-	-	-	1	2	1	2	5
Early disease progression	-	-	-	1	1	1	-	-

Baseline characteristics

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Reporting group title

Dose escalation phase cohort 1 dose level 1

Reporting group description

Reporting group title

Dose escalation phase cohort 2 dose level 2

Reporting group description

Reporting group title

Dose escalation phase cohort 3 dose level 3

Reporting group description

Reporting group title

Dose escalation phase cohort 4 dose level 4

Reporting group description

Reporting group title

Dose escalation phase cohort 7 dose level 5

Reporting group description

Reporting group title

Dose escalation phase cohort 12 dose level 5a

Reporting group description

Reporting group title

Dose escalation phase cohort 13 dose level 5 (interval dosing)

Reporting group description

Reporting group title

Dose expansion phase

Reporting group description

Dosage determined following the recommended phase II dose identification in the dose escalation phase.

Reporting group values	Dose escalation phase cohort 1 dose level 1	Dose escalation phase cohort 2 dose level 2	Dose escalation phase cohort 3 dose level 3	Dose escalation phase cohort 4 dose level 4	Dose escalation phase cohort 7 dose level 5	Dose escalation phase cohort 12 dose level 5a	Dose escalation phase cohort 13 dose level 5 (interval dosing)	Dose expansion phase	Total
Number of subjects	6	5	6	8	8	7	5	37	82
Age categorical
Units: Subjects
Adults (18-64 years)	4	3	5	5	6	5	4	24	56
From 65-84 years	2	2	1	3	2	2	1	13	26
Age continuous
Units: years
median (full range (min-max))	65.8 (36 to 78)	64.8 (48 to 69)	58.4 (52 to 71)	61.2 (36 to 73)	51 (33 to 72)	60 (46 to 70)	55 (40 to 65)	62 (32 to 78)	-
Gender categorical
Units: Subjects
Female	4	3	5	5	6	5	4	24	56
Male	2	2	1	3	2	2	1	13	26

End points

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Reporting group title

Dose escalation phase cohort 1 dose level 1

Reporting group description

Reporting group title

Dose escalation phase cohort 2 dose level 2

Reporting group description

Reporting group title

Dose escalation phase cohort 3 dose level 3

Reporting group description

Reporting group title

Dose escalation phase cohort 4 dose level 4

Reporting group description

Reporting group title

Dose escalation phase cohort 7 dose level 5

Reporting group description

Reporting group title

Dose escalation phase cohort 12 dose level 5a

Reporting group description

Reporting group title

Dose escalation phase cohort 13 dose level 5 (interval dosing)

Reporting group description

Reporting group title

Dose expansion phase

Reporting group description

Dosage determined following the recommended phase II dose identification in the dose escalation phase.

Subject analysis set title

Dose Escalation Phase Binimetinib/PF-02341066

Subject analysis set type

Intention-to-treat

Subject analysis set description

Second dose escalation phase - cohorts 7, 12 and 13

Subject analysis set title

Dose expansion phase

Subject analysis set type

Intention-to-treat

Subject analysis set description

Dose expansion phase all patients

Primary: Maximal Tolerated Dose (MTD) of PD-0325901 and PF-02341066

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End point title

Maximal Tolerated Dose (MTD) of PD-0325901 and PF-02341066 ^[1] ^[2]

End point description

Determine maximum tolerated dose (MTD) of PD-0325901 with Crizotinib (PF-02341066) according to toxicities graded by NCI CTCAE v4.03, in patients with advanced solid tumours. MTD for the PDB 0325901/ PF-02341066 combination was 8mg BD(days1-21) and 200mg BD continuously in a 28 day cycle.

End point type

Primary

End point timeframe

Dose Escalation Phase: treatment Cycle 1 28 days (plus 7 day run-in for PD0325901/PF-02341066 combination)

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: The outcome is just number of DLTs occurring, there is no statistical analysis necessary.
[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: There are three different phases in the trial (two dose escalation phases, with different drugs, and one dose expansion phase), and each phase has a different primary outcome.

End point values	Dose escalation phase cohort 1 dose level 1	Dose escalation phase cohort 2 dose level 2	Dose escalation phase cohort 3 dose level 3	Dose escalation phase cohort 4 dose level 4
Number of subjects analysed	6	5	4	6
Units: Dose Limiting Toxicities (DLTs)	0	0	0	1

No statistical analyses for this end point

Primary: Maximal Tolerated Dose (MTD) of PD-Binimetinib and PF-02341066

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End point title

Maximal Tolerated Dose (MTD) of PD-Binimetinib and PF-02341066 ^[3] ^[4]

End point description

To determine the maximal tolerated dose (MTD) of Binimetinib with PF-02341066 according to toxicities graded by NCI CTCAE V4.03 in cycle 1 of treatment. Binimetinib 30mg BD on days 1 - 21 every 28 days with Crizotinib 250 mg OD continuously is the recommended dose and schedule for further evaluation in our and other trials.

End point type

Primary

End point timeframe

Dose Escalation Phase: treatment Cycle 1 - 28 days

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The outcome is just number of DLTs occurring, there is no statistical analysis necessary.
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: There are three different phases in the trial (two dose escalation phases, with different drugs, and one dose expansion phase), and each phase has a different primary outcome.

End point values	Dose escalation phase cohort 7 dose level 5	Dose escalation phase cohort 12 dose level 5a	Dose escalation phase cohort 13 dose level 5 (interval dosing)
Number of subjects analysed	6	5	5
Units: Dose Limiting Toxicities (DLTs)	2	2	1

No statistical analyses for this end point

Primary: Clinical Response to Binimetinib Combined With PF-02341066

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End point title

Clinical Response to Binimetinib Combined With PF-02341066 ^[5] ^[6]

End point description

To investigate best response to treatment with RPII dose of Binimetinib with Crizotinib (PF-02341066), in patients with a) RASMT CRC or b) RASWT/cMET mut amplified CRC or c) RASWT/c-MET over-expressed CRC, as defined by stable, partially or completely responding disease using RECIST version 1.1.

End point type

Primary

End point timeframe

Dose Expansion phase: change from baseline and up to 12 months.

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: The outcome is just the number of patients experiencing each response category, there is no statistical analysis necessary.
[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: There are three different phases in the trial (two dose escalation phases, with different drugs, and one dose expansion phase), and each phase has different outcomes.

End point values	Dose expansion phase
Number of subjects analysed	30
Units: Participants
Stable Disease	7
Progressive Disease	22
Early death from malignant disease	1

No statistical analyses for this end point

Secondary: Progression free survival

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End point title

Progression free survival ^[7]

End point description

End point type

Secondary

End point timeframe

Length of study

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: There are three different phases in the trial (two dose escalation phases, with different drugs, and one dose expansion phase), and each phase has different outcomes.

End point values	Dose expansion phase	Dose Escalation Phase Binimetinib/PF-02341066
Number of subjects analysed	36	20
Units: Months
median (confidence interval 95%)	1.81 (1.51 to 2.04)	2.66 (1.81 to 5.79)

No statistical analyses for this end point

Secondary: Overall survival

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End point title

Overall survival ^[8]

End point description

End point type

Secondary

End point timeframe

Length of study

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: There are three different phases in the trial (two dose escalation phases, with different drugs, and one dose expansion phase), and each phase has different outcomes.

End point values	Dose expansion phase	Dose Escalation Phase Binimetinib/PF-02341066
Number of subjects analysed	36	20
Units: months
median (confidence interval 95%)	5.62 (2.79 to 7.40)	8.22 (3.95 to 100000)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Adverse event monitoring starts from the time the patient consents to the study until they complete the trial

Assessment type

Systematic

Dictionary name

NCI CTCAE

Dictionary version

4.03

Reporting group title

Dose escalation phase 1 - PF-02341066 and PD-0325901

Reporting group description

Cohorts 1, 2, 3, 4

Reporting group title

Dose escalation phase 2 - PF-02341066 and Binimetinib

Reporting group description

Cohorts 7, 12, 13

Reporting group title

Dose expansion phase - PF-02341066 and Binimetinib

Reporting group description

Serious adverse events	Dose escalation phase 1 - PF-02341066 and PD-0325901	Dose escalation phase 2 - PF-02341066 and Binimetinib	Dose expansion phase - PF-02341066 and Binimetinib
Total subjects affected by serious adverse events
subjects affected / exposed	9 / 25 (36.00%)	12 / 20 (60.00%)	18 / 37 (48.65%)
number of deaths (all causes)	18	15	27
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Brain metastases
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Vascular disorders
Postural hypotension
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	0 / 37 (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
Pulmonary embolism
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	2 / 37 (5.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Thromboembolic event
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	0 / 37 (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
General disorders and administration site conditions
Edema face
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fever
subjects affected / exposed	2 / 25 (8.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Muscositis
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Dyspnea
subjects affected / exposed	1 / 25 (4.00%)	1 / 20 (5.00%)	2 / 37 (5.41%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lower respiratory infection
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	0 / 37 (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
Investigations
Ejection fraction decreased
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	0 / 37 (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
Postoperative haemorrhage
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Cardiac failure
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Pericarditis
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Tingling in lower limbs
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vertigo
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Eye disorders
Central serous retinopathy (Bilateral)
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ascites
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	0 / 37 (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
Bowel obstruction
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	0 / 37 (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
Colonic obstruction
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	0 / 37 (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
Constipation
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	2 / 37 (5.41%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	0 / 37 (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
Lower gastrointestinal haemorrhage
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Hypertransaminasaemia
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Osteonecrosis of jaw
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	0 / 37 (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
Worsening back pain
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
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
Abdominal infection
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	0 / 37 (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
Lung infection
subjects affected / exposed	0 / 25 (0.00%)	3 / 20 (15.00%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 0	1 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin infection
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	0 / 37 (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
Wound infection
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	0 / 37 (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
Metabolism and nutrition disorders
Cytolysis
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dehydration
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypoalbuminaemia
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Dose escalation phase 1 - PF-02341066 and PD-0325901	Dose escalation phase 2 - PF-02341066 and Binimetinib	Dose expansion phase - PF-02341066 and Binimetinib
Total subjects affected by non serious adverse events
subjects affected / exposed	25 / 25 (100.00%)	20 / 20 (100.00%)	37 / 37 (100.00%)
Vascular disorders
Haematoma
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Hot flush
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	1
Hypertension
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	2 / 37 (5.41%)
occurrences all number	0	0	2
Hypotension
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	2 / 37 (5.41%)
occurrences all number	0	0	2
Lymphoedema
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	0 / 37 (0.00%)
occurrences all number	5	0	0
Postural hypotension
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	2
Thrombosis
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Surgical and medical procedures
Cataract operation
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	1
General disorders and administration site conditions
Asthenia
subjects affected / exposed	2 / 25 (8.00%)	6 / 20 (30.00%)	9 / 37 (24.32%)
occurrences all number	2	10	12
Chest pain
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	0 / 37 (0.00%)
occurrences all number	0	2	0
Chills
subjects affected / exposed	2 / 25 (8.00%)	1 / 20 (5.00%)	0 / 37 (0.00%)
occurrences all number	2	1	0
Edema
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	1	0	1
Edema face
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	1
Edema limbs
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	1
Edema lower limb
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	1
Edema extremities
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	1
Edema of legs
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	1
Fatigue
subjects affected / exposed	10 / 25 (40.00%)	10 / 20 (50.00%)	14 / 37 (37.84%)
occurrences all number	18	16	30
Fever
subjects affected / exposed	2 / 25 (8.00%)	1 / 20 (5.00%)	4 / 37 (10.81%)
occurrences all number	2	1	5
Flu like symptoms
subjects affected / exposed	1 / 25 (4.00%)	1 / 20 (5.00%)	0 / 37 (0.00%)
occurrences all number	1	1	0
Foot oedema
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Generalised oedema
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	0 / 37 (0.00%)
occurrences all number	1	0	0
Hand swelling
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Headache
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	1
Leg oedema
subjects affected / exposed	2 / 25 (8.00%)	2 / 20 (10.00%)	0 / 37 (0.00%)
occurrences all number	2	3	0
Malaise
subjects affected / exposed	1 / 25 (4.00%)	1 / 20 (5.00%)	0 / 37 (0.00%)
occurrences all number	1	1	0
Mucositis
subjects affected / exposed	2 / 25 (8.00%)	1 / 20 (5.00%)	1 / 37 (2.70%)
occurrences all number	2	1	2
Oedema
subjects affected / exposed	1 / 25 (4.00%)	2 / 20 (10.00%)	1 / 37 (2.70%)
occurrences all number	4	4	1
Oedema abdomen
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	0 / 37 (0.00%)
occurrences all number	1	0	0
Oedema arms
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	0 / 37 (0.00%)
occurrences all number	2	0	0
Oedema extremities
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Oedema of lower extremities
subjects affected / exposed	1 / 25 (4.00%)	1 / 20 (5.00%)	1 / 37 (2.70%)
occurrences all number	1	1	1
Orafacial oedema
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	1	0	1
Pain
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Peripheral oedema
subjects affected / exposed	0 / 25 (0.00%)	2 / 20 (10.00%)	0 / 37 (0.00%)
occurrences all number	0	4	0
Retrosternal chest pain
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Rigors
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Serous discharge
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	0 / 37 (0.00%)
occurrences all number	1	0	0
Swelling of legs
subjects affected / exposed	1 / 25 (4.00%)	1 / 20 (5.00%)	0 / 37 (0.00%)
occurrences all number	1	1	0
Teeth chattering
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	0 / 37 (0.00%)
occurrences all number	1	0	0
Immune system disorders
Hypersensitivity
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	3 / 25 (12.00%)	6 / 20 (30.00%)	5 / 37 (13.51%)
occurrences all number	4	9	8
Dysphonia
subjects affected / exposed	1 / 25 (4.00%)	1 / 20 (5.00%)	5 / 37 (13.51%)
occurrences all number	2	1	8
Epistaxis
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	0 / 37 (0.00%)
occurrences all number	1	0	0
Exertional dyspnoea
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	2 / 37 (5.41%)
occurrences all number	0	0	2
Hoarseness
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	0 / 37 (0.00%)
occurrences all number	0	2	0
Pleural effusion
subjects affected / exposed	0 / 25 (0.00%)	2 / 20 (10.00%)	0 / 37 (0.00%)
occurrences all number	0	3	0
Pleurisy
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	1
Pneumothorax
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	1
Productive cough
subjects affected / exposed	0 / 25 (0.00%)	2 / 20 (10.00%)	0 / 37 (0.00%)
occurrences all number	0	2	0
Pulmonary embolism
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Respiratory distress
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	1
Rib pain
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	2	0	1
Shortness of breath
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	2 / 37 (5.41%)
occurrences all number	1	0	2
Sore throat
subjects affected / exposed	2 / 25 (8.00%)	2 / 20 (10.00%)	0 / 37 (0.00%)
occurrences all number	2	2	0
Wheezing
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	1 / 37 (2.70%)
occurrences all number	0	1	1
Psychiatric disorders
Anxiety
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	2 / 37 (5.41%)
occurrences all number	0	0	2
Cognitive disorder
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	1
Confusional state
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	1
Depressed mood
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	1
Insomnia
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	2	0	1
Libido decreased
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	1
Low mood
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	1
Investigations
Alanine aminotransferase increased
subjects affected / exposed	3 / 25 (12.00%)	3 / 20 (15.00%)	8 / 37 (21.62%)
occurrences all number	5	4	17
Aspartate aminotransferase increased
subjects affected / exposed	3 / 25 (12.00%)	3 / 20 (15.00%)	9 / 37 (24.32%)
occurrences all number	4	5	13
Blood albumin decreased
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	2
Blood alkaline phosphatase increased
subjects affected / exposed	5 / 25 (20.00%)	0 / 20 (0.00%)	6 / 37 (16.22%)
occurrences all number	7	0	9
Blood creatine phosphokinase increased
subjects affected / exposed	0 / 25 (0.00%)	7 / 20 (35.00%)	11 / 37 (29.73%)
occurrences all number	0	19	25
Blood creatine increased
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	1	0	1
Blood glucose increased
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	1
Blood lactate dehydrogenase increased
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	1	0	1
Blood potassium decreased
subjects affected / exposed	0 / 25 (0.00%)	2 / 20 (10.00%)	0 / 37 (0.00%)
occurrences all number	0	2	0
Blood pressure increased
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Blood sodium decreased
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Body temperature increased
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	1
C-reactive protein increased
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Ejection fraction decreased
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	2 / 37 (5.41%)
occurrences all number	0	1	2
Electrocardiogram Qtc Interval Prolonged
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	0 / 37 (0.00%)
occurrences all number	2	0	0
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	2
Ggt increased
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	2 / 37 (5.41%)
occurrences all number	1	0	2
Glucose increased
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	1
Ldh increased
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	1	0	1
Left ventricular ejection fraction decreased
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	1 / 37 (2.70%)
occurrences all number	0	1	1
Platelet count decreased
subjects affected / exposed	1 / 25 (4.00%)	1 / 20 (5.00%)	2 / 37 (5.41%)
occurrences all number	1	1	2
Protein total decreased
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	0 / 37 (0.00%)
occurrences all number	1	0	0
Qt prolonged
subjects affected / exposed	4 / 25 (16.00%)	0 / 20 (0.00%)	0 / 37 (0.00%)
occurrences all number	4	0	0
Sodium decreased
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Transaminases increased
subjects affected / exposed	1 / 25 (4.00%)	1 / 20 (5.00%)	0 / 37 (0.00%)
occurrences all number	1	4	0
Transaminitis
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	1
Troponin increased
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	2
Weight gain
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	0 / 37 (0.00%)
occurrences all number	0	2	0
Weight loss
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	1
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	2 / 25 (8.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	2	0	1
Intestinal stoma Complication
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	1
Prolapse of intestinal stoma
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	1
Scar
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	1
Stoma site bleeding
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	1
Vascular access complication
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	0 / 37 (0.00%)
occurrences all number	1	0	0
Wound pain
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	1
K+ decreased
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	0 / 37 (0.00%)
occurrences all number	0	2	0
Cardiac disorders
Bradycardia
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Extrasystoles
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Pericardial effusion
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Sinus bradycardia
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	1
Nervous system disorders
Amnesia
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Aphasia
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	0 / 37 (0.00%)
occurrences all number	1	0	0
Dizziness
subjects affected / exposed	1 / 25 (4.00%)	4 / 20 (20.00%)	2 / 37 (5.41%)
occurrences all number	1	5	3
Dizziness postural
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Dysgeusia
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	2 / 37 (5.41%)
occurrences all number	1	0	2
Expressive dysphasia
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	0 / 37 (0.00%)
occurrences all number	1	0	0
Localised numbness
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	0 / 37 (0.00%)
occurrences all number	1	0	0
Neuropathic pain
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Neuropathy
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	2 / 37 (5.41%)
occurrences all number	0	0	2
Neuropathy peripheral
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Neurotoxicity
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	2
Paraesthesia
subjects affected / exposed	2 / 25 (8.00%)	1 / 20 (5.00%)	0 / 37 (0.00%)
occurrences all number	3	1	0
Paraesthesia Lower limb
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	0 / 37 (0.00%)
occurrences all number	1	0	0
Peripheral sensory neuropathy
subjects affected / exposed	0 / 25 (0.00%)	3 / 20 (15.00%)	0 / 37 (0.00%)
occurrences all number	0	3	0
Presyncope
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	2 / 37 (5.41%)
occurrences all number	0	1	4
Tremor
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Vasovagal attack
subjects affected / exposed	2 / 25 (8.00%)	0 / 20 (0.00%)	0 / 37 (0.00%)
occurrences all number	2	0	0
Visual field defect
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	0 / 37 (0.00%)
occurrences all number	1	0	0
Weakness left or right side
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	0 / 37 (0.00%)
occurrences all number	2	0	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	7 / 25 (28.00%)	1 / 20 (5.00%)	9 / 37 (24.32%)
occurrences all number	9	1	16
Neutropenia
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Thrombocytopenia
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	1
Ear and labyrinth disorders
Ear disorder
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Vertigo
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	1
Eye disorders
Blepharitis
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Chorioretinopathy
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	2 / 37 (5.41%)
occurrences all number	0	0	2
Conjunctival haemorrhage
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	2 / 37 (5.41%)
occurrences all number	0	0	2
Corneal opacity
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	0 / 37 (0.00%)
occurrences all number	1	0	0
Dry eye
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Eye disorder
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Eyelid function disorder
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	0 / 37 (0.00%)
occurrences all number	1	0	0
Periorbital oedema
subjects affected / exposed	0 / 25 (0.00%)	3 / 20 (15.00%)	1 / 37 (2.70%)
occurrences all number	0	3	1
Photophobia
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	2
Retinal detachment
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	2 / 37 (5.41%)
occurrences all number	0	0	2
Retinal haemorrhage
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	1
Subconjunctival haemorrhage
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	0 / 37 (0.00%)
occurrences all number	2	0	0
Vision abnormal
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	0 / 37 (0.00%)
occurrences all number	0	2	0
Visual disturbance
subjects affected / exposed	3 / 25 (12.00%)	0 / 20 (0.00%)	0 / 37 (0.00%)
occurrences all number	3	0	0
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	1
Abdominal pain
subjects affected / exposed	3 / 25 (12.00%)	1 / 20 (5.00%)	5 / 37 (13.51%)
occurrences all number	3	3	7
Abdominal pain lower
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	1
Ascites
subjects affected / exposed	1 / 25 (4.00%)	1 / 20 (5.00%)	0 / 37 (0.00%)
occurrences all number	1	6	0
Constipation
subjects affected / exposed	12 / 25 (48.00%)	4 / 20 (20.00%)	9 / 37 (24.32%)
occurrences all number	20	5	12
Diarrhoea
subjects affected / exposed	10 / 25 (40.00%)	14 / 20 (70.00%)	18 / 37 (48.65%)
occurrences all number	15	28	29
Dyspepsia
subjects affected / exposed	2 / 25 (8.00%)	1 / 20 (5.00%)	1 / 37 (2.70%)
occurrences all number	2	1	1
Dry mouth
subjects affected / exposed	2 / 25 (8.00%)	1 / 20 (5.00%)	1 / 37 (2.70%)
occurrences all number	2	1	1
Epigastric pain
subjects affected / exposed	1 / 25 (4.00%)	1 / 20 (5.00%)	0 / 37 (0.00%)
occurrences all number	1	1	0
Frequent bowel movements
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	1
Gastritis
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	0 / 37 (0.00%)
occurrences all number	1	0	0
Gastrooesophageal reflux disease
subjects affected / exposed	2 / 25 (8.00%)	1 / 20 (5.00%)	0 / 37 (0.00%)
occurrences all number	2	1	0
Haemorrhoids
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	0 / 37 (0.00%)
occurrences all number	1	0	0
Heartburn
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Intestinal obstruction
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	1
Loose stools
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	0 / 37 (0.00%)
occurrences all number	3	0	0
Nausea
subjects affected / exposed	11 / 25 (44.00%)	11 / 20 (55.00%)	20 / 37 (54.05%)
occurrences all number	20	16	29
Nausea and vomiting
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	0 / 37 (0.00%)
occurrences all number	1	0	0
Oesophagitis
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	0 / 37 (0.00%)
occurrences all number	1	0	0
Postprandial Emesis
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	1
Rectal pain
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	1
Right upper quadrant pain
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	1
Sore gums
subjects affected / exposed	2 / 25 (8.00%)	0 / 20 (0.00%)	0 / 37 (0.00%)
occurrences all number	2	0	0
Stomach cramps
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	1
Stomach pain
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	0 / 37 (0.00%)
occurrences all number	2	0	0
Stomatitis
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	0 / 37 (0.00%)
occurrences all number	1	0	0
Vomiting
subjects affected / exposed	10 / 25 (40.00%)	6 / 20 (30.00%)	19 / 37 (51.35%)
occurrences all number	20	9	37
Swelling of hands
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Hepatobiliary disorders
Hepatic haemorrhage
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	1
Hyperbilirubinaemia
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	1
Hypertransaminasaemia
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	2
Liver pain
subjects affected / exposed	0 / 25 (0.00%)	2 / 20 (10.00%)	1 / 37 (2.70%)
occurrences all number	0	2	1
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	1 / 25 (4.00%)	2 / 20 (10.00%)	0 / 37 (0.00%)
occurrences all number	1	2	0
Dermatitis acneiform
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	1
Dry skin
subjects affected / exposed	2 / 25 (8.00%)	1 / 20 (5.00%)	3 / 37 (8.11%)
occurrences all number	2	1	3
Facial rash
subjects affected / exposed	3 / 25 (12.00%)	0 / 20 (0.00%)	0 / 37 (0.00%)
occurrences all number	3	0	0
Genital itching
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Itchy scalp
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	0 / 37 (0.00%)
occurrences all number	1	0	0
Macular rash
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	1
Maculopapular rash
subjects affected / exposed	2 / 25 (8.00%)	1 / 20 (5.00%)	0 / 37 (0.00%)
occurrences all number	2	1	0
Neck rash
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	1
Night sweats
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	3 / 37 (8.11%)
occurrences all number	1	0	3
Papular rash
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	1
Pruritus
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	5 / 37 (13.51%)
occurrences all number	0	0	6
Rash
subjects affected / exposed	7 / 25 (28.00%)	7 / 20 (35.00%)	11 / 37 (29.73%)
occurrences all number	8	12	21
Rash acneiform
subjects affected / exposed	9 / 25 (36.00%)	8 / 20 (40.00%)	13 / 37 (35.14%)
occurrences all number	12	12	19
Rash face
subjects affected / exposed	2 / 25 (8.00%)	2 / 20 (10.00%)	1 / 37 (2.70%)
occurrences all number	2	2	1
Rosacea
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Seborrhoeic dermatitis
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Skin lesion
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	0 / 37 (0.00%)
occurrences all number	1	0	0
Skin oedema
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Skin peeling
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	1
Skin rash
subjects affected / exposed	0 / 25 (0.00%)	3 / 20 (15.00%)	0 / 37 (0.00%)
occurrences all number	0	5	0
Skin toxicity
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	2 / 37 (5.41%)
occurrences all number	0	0	4
Rash on Legs and Arms
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	1
Renal and urinary disorders
Haematuria
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	0 / 37 (0.00%)
occurrences all number	1	0	0
Renal impairment
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	0 / 37 (0.00%)
occurrences all number	1	0	0
Urinary frequency
subjects affected / exposed	12 / 25 (48.00%)	0 / 20 (0.00%)	0 / 37 (0.00%)
occurrences all number	2	0	0
Urine incontinence
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	0 / 37 (0.00%)
occurrences all number	1	0	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	3 / 37 (8.11%)
occurrences all number	0	5	4
Back pain
subjects affected / exposed	2 / 25 (8.00%)	0 / 20 (0.00%)	2 / 37 (5.41%)
occurrences all number	2	0	4
Finger cramps
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	0 / 37 (0.00%)
occurrences all number	1	0	0
Flank pain
subjects affected / exposed	1 / 25 (4.00%)	1 / 20 (5.00%)	0 / 37 (0.00%)
occurrences all number	2	1	0
Hypokalaemia
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	0 / 37 (0.00%)
occurrences all number	1	0	0
Intercostal pain
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	1
Joint instability
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	0 / 37 (0.00%)
occurrences all number	1	0	0
Muscle ache
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	1	0	1
Myalgia
subjects affected / exposed	0 / 25 (0.00%)	3 / 20 (15.00%)	1 / 37 (2.70%)
occurrences all number	0	3	1
Myalgia of lower extremities
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	1
Neck pain
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	1
Osteoarticular pain
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Osteonecrosis of jaw
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	0 / 37 (0.00%)
occurrences all number	1	0	0
Pain in hip
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	0 / 37 (0.00%)
occurrences all number	0	3	0
Pain in jaw
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	0 / 37 (0.00%)
occurrences all number	3	0	0
Painful hips
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	1
Shoulder pain
subjects affected / exposed	2 / 25 (8.00%)	0 / 20 (0.00%)	0 / 37 (0.00%)
occurrences all number	2	0	0
Infections and infestations
Abdominal abscess
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	0 / 37 (0.00%)
occurrences all number	1	0	0
Candida infection
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	1
Device related infection
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Ear infection
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Folliculitis
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	1
Furunculosis
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	1
Herpes lesion Intra-Oral
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	1
Intra-abdominal abscess
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	0 / 37 (0.00%)
occurrences all number	1	0	0
Lower respiratory tract infection
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	2 / 37 (5.41%)
occurrences all number	0	0	3
Oral candida
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	1
Paronychia
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	0 / 37 (0.00%)
occurrences all number	1	0	0
Parotiditis
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	0 / 37 (0.00%)
occurrences all number	1	0	0
Periorbital infection
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	0 / 37 (0.00%)
occurrences all number	0	2	0
Pneumonia
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	0 / 37 (0.00%)
occurrences all number	0	2	0
Pustular rash
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Upper respiratory tract infection
subjects affected / exposed	2 / 25 (8.00%)	1 / 20 (5.00%)	1 / 37 (2.70%)
occurrences all number	2	1	1
Urinary tract infection
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	2 / 37 (5.41%)
occurrences all number	1	0	3
Wound infection
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	0 / 37 (0.00%)
occurrences all number	1	0	0
Metabolism and nutrition disorders
Anorexia
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	1
Decreased appetite
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	1
Dehydration
subjects affected / exposed	0 / 25 (0.00%)	0 / 20 (0.00%)	1 / 37 (2.70%)
occurrences all number	0	0	1
Gout
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	1 / 37 (2.70%)
occurrences all number	0	1	1
Hyperglycaemia
subjects affected / exposed	0 / 25 (0.00%)	1 / 20 (5.00%)	1 / 37 (2.70%)
occurrences all number	0	1	1
Hypoalbuminaemia
subjects affected / exposed	7 / 25 (28.00%)	3 / 20 (15.00%)	3 / 37 (8.11%)
occurrences all number	10	4	5
Hypoglycaemia
subjects affected / exposed	1 / 25 (4.00%)	0 / 20 (0.00%)	0 / 37 (0.00%)
occurrences all number	2	0	0

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Were there any global substantial amendments to the protocol? Yes

05 Aug 2014

In response to MHRA Notice For Grounds for Non Acceptance: clarification re maximum tolerated dose (MTD) and dose modification; Protocol and Patient Information Sheet (PIS) inclusion of MHRA contraception guidelines; IMP information correction to Clinical Trial Application (CTA).

04 Feb 2015

Amend IRAS Dataset updated with changes and changes to trial documents: Protocol; Dose Escalation and Dose Expansion PIS and Consent forms (CFs); Patient Diary Card; Patient Study Card Belfast site Principal Investigator (PI) - notice of change of status. Patient types changes from KRASMT AND KRASWT to RASMT AND RASWT - biomarker studies shown NRASMT colorectal cancer (CRC) behaves in similar way to KRASMT CRC so RAS categorisation prevents exclusion of eligible patients. Patient number clarification as 12 per cohort. Change to laboratory information for sample transfer and corrections to sample collection timepoints. Additional information for PIS on potential side effects as PPI request. Study schedule changes for feasibility purposes. Management of dosing change from drugs being taken separately to same time for patient tolerability and ease as according to pharmacological company guidance. Dose modification clarifications and amendment of contraception section according to MHRA update guidelines. IRAS dataset changes for additional information on collaborating laboratories, radiation information and optional CT guided biopsy clarifications in line with radiation risk assessment, participating site information corrected as one site previously not included plus other minor administrative changes.

21 Jul 2015

Protocol amendment for Inclusion of interim dose level schedule as considered likely that highest dose level would not be tolerated and sound scientific rationale that PD-0325901 treatment would be tolerated at a higher than 4mg dose but less that the higher 8mg dose currently scheduled according to emergent clinical data and dose limiting toxicities. Additional exclusion criteria further to clinical decision to avoid recruiting patients who had pre-study hypoalbuminaemia or had required multiple ascites or pleural taps as the first 3 recruited trial patients experienced hypoalbuminaemia at Grade 1 and 2. Removal of Ondansetron from Protocol as recommended treatment for nausea and vomiting as the drug has confirmed risk of QT prolongation which is a trial exclusion criteria. Correction to omission in IRAS dataset, Protocol schedule of events table, Dose Escalation and Dose Expansion phase PIS for ECG event Cycle 1 Day 15 in line with schedule of assessments text. Protocol footnotes for dose escalation and expansion phases schedule of events tables changes to remove time window for PBMC samples as inappropriate to the requirement of the protocol sample collection times.

06 May 2016

Replacement of study drug MEK inhibitor Pfizer's PD-0325901 for Array Biopharma's Binimetinib to be combined with the same Pfizer MET inhibitor PF-02341066 (Crizotinib) which also included change to study title on all study documentation to reflect the inclusion of two different MEK inhibitors used in the trial. This change was due to Pfizer's internal decision to discontinue PD-0325901 development therefore creating an issue of drug security for the remainder of this trial and Binimetinib was chosen due to availability of sound data on the drug and its considered suitability as a combination therapy with Pfizer's PF-02341066. A further short 3 dose escalation phase was therefore required to assess safety and tolerability and to determine the recommended dose for the dose expansion phase of the trial. Change to protocol and patient documents for the study design of the dose expansion phase to incorporate specific cohorts of RAS wild type colorectal patients and the greater patient recruitment target to include specific RAS Wild type c_MET high, super and amplified colorectal cancer patient groups. This change was made from experience gained on relegant Phase III studies which led the consortium members to consider that it is beneficial to study the effect of the combined treatment on these patients due to their dependency on c_MET, and who are therefore most likely to benefit from such treatment. It was also to provide a clear positive signal for the next protocol phase and so provide credence to the rationale for Protocol 2. this also led to changes to the sample collection timepoints and study schedule in line with the changed drug dosing regimen. Binimetinib Investigator Brochure, and protocol and patient documents included Array dose modification and safety information. Notification of change of investigator at an existing site: formerly Prof Pierre Laurent-Puig at the European St Georges Pompidou Hospital, Paris, to Dr Geraldine Perkins.

28 Mar 2017

Protocol change to dose limiting (DLT) criteria and change to IMP dose modifications classified as grade 3 and 4 specifically for creatinine kinase (CK) elevation following information provided by Array Biopharma (provider of Binimetinib IMP) which has been reviewed and approved by the FDA.

20 Jun 2017

Amendment to protocol and patient documentation for the change to study design of the dose expansion phase to incorporate a two-staged review design using a greater number of patients for each of the three specific cohorts of RAS mutant and RAS wild type c-MET aberrant colorectal cancer patients. Further information from relevant phase III studies led to the MErCuRIC consortium's decision to expand the RASWT/cMET group so the effect of the combined treatment could be evaluated in c-MET high expressors as well as c-MET superexpressor groups and potentially a c-MET amplified cohort. The c-MET high expressor and amplified patient groups are the most likely patients with dependency on c-MET who would benefit from treatment and be more likely to provide a clear positive signal and information for patient selection in the phase II trial. Update to eligibility criteria to include prior treatment with an EGFR target monoclonal antibody and contraception guidelines Update to the dose modification guidelines for current information for pneumonitis and left ventricular systolic dysfunctions. Update to number of participating sites (4 to 5) in the dose escalation phase to aid recruitment as well as to the potential number (8 to 10) for the dose expansion phase supporting recruitment to the rarer groups of colorectal cancer patients. Patient numbers amended for escalation phase from 24 to 25 reflecting the numbers actually required for exploring tolerability of the IMP combination at intermediate dose levels previously not anticipated. Change to the dose expansion phase sample collection profile for pharmacodynamics samples, removing the pERK analysis of PBMC samples in blood. Skin biopsies are also reduced to be only performed on the first 10 patients enrolled to the dose expansion phase. Update/clarification of Dose Expansion Schedule changes for clarification of post end of treatment and follow up.

04 Oct 2018

Update to Protocol and CTA to include new laboratory details for processing of screening tumour samples for evaluation of RAS Wild Type CRC c-MET expression and amplification. the assay required for completion of evaluation processes as needed for the genotyping for the protocol was no longer available at the designated QUB molecular pathology laboratory in Belfast. The new central laboratory facility has been included to perform these required procedures under the directorship of the Paris Descartes University molecular laboratory (PDUM). A new material transfer agreement was also completed for transfer of the extracted DNA samples to this laboratory. Update to Screening Patient Information Sheet for tumour test reporting clarification as the transfer to the new laboratory facility required a potentially longer reporting time from within 7-14 days to being available from 7-14 days. This amendment did not halt the progress of trial as sites were able to continue to recruit patients to the RAS Mutant CRC cohort, however it did cause delays to the recruitment for the RAS Wild Type CRC cohorts.

26 Nov 2018

Change to protocol synopsis for information on early closure of recruitment to the trial as closed 23Oct2018 with 82 patients recruited. This was following significant difficulties encountered in recruiting to the dose expansion phase RAS WT CRC patient cohorts within the constraints of the EU grant supporting the trial. The decision was made by the Trial Management Group with the support of the FP7 consortium members and trial sponsor. Clarifications were also made to the binimetinib dose modification for creatinine kinase in line with Array biopharma FDA approved guidelines as inconsistencies were noted between 2 sections of the protocol.

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.

Following regulatory approval for recruitment to the RAS Wild Type CRC patient cohorts there was evidential lack of feasibility for recruiting to the rarer RAS wild type CRC cohorts within the remaining funding period.

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Clinical Trial Results:
A Sequential Phase I study of MEK1/2 inhibitors PD-0325901 or Binimetinib combined with cMET inhibitor Crizotinib in RAS Mutant and RAS Wild Type(with aberrant c-MET) Colorectal Cancer

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Primary: Maximal Tolerated Dose (MTD) of PD-0325901 and PF-02341066

Primary: Maximal Tolerated Dose (MTD) of PD-0325901 and PF-02341066

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Clinical Trial Results: A Sequential Phase I study of MEK1/2 inhibitors PD-0325901 or Binimetinib combined with cMET inhibitor Crizotinib in RAS Mutant and RAS Wild Type(with aberrant c-MET) Colorectal Cancer

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Subject disposition

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Baseline characteristics

Baseline characteristics

End points

End points

Primary: Maximal Tolerated Dose (MTD) of PD-0325901 and PF-02341066

Primary: Maximal Tolerated Dose (MTD) of PD-0325901 and PF-02341066

Primary: Maximal Tolerated Dose (MTD) of PD-Binimetinib and PF-02341066

Primary: Maximal Tolerated Dose (MTD) of PD-Binimetinib and PF-02341066

Primary: Clinical Response to Binimetinib Combined With PF-02341066

Primary: Clinical Response to Binimetinib Combined With PF-02341066

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Substantial protocol amendments (globally)

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Clinical Trial Results:
A Sequential Phase I study of MEK1/2 inhibitors PD-0325901 or Binimetinib combined with cMET inhibitor Crizotinib in RAS Mutant and RAS Wild Type(with aberrant c-MET) Colorectal Cancer