A Sequential Phase I Study of MEK1/2 Inhibitors PD-0325901 or Binimetinib Combined With cMET Inhibitor PF-02341066 in Patients With RAS Mutant and RAS Wild Type (With Aberrant c-MET) Colorectal Cancer
Phase: PHASE1
Conditions: Solid Tumor, Colorectal Cancer
Sponsor: University of Oxford

 
 
 
Full title: A Sequential Phase I study of MEK1/2 inhibitors PD-0325901 or 
Binimetinib combined with cMET inhibitor PF-02341066 in Patients with 
RAS Mutant and RAS Wild Type (with aberrant c-MET) Colorectal Cancer  
Short title: MErCuRIC1: MEK and MET Inhibition in Colorectal Cancer 
 
Protocol Version & date: 
Version 9.0; 29Oct2018 
Sponsor Protocol Number: 
OCTO_049 
Ethics Number: 
14/SC/1010 
EudraCT Number: 
2014-000463-40  
Funding Reference Number  
602901-2 
 
Sponsored by the University of Oxford 
 
 
Funder: European Commission’s Seventh Framework Program (FP7) 
 
 
 
 
 
 
 
 
 
 
 
Confidentiality Statement 
This document contains confidential information that must not be disclosed to anyone other than the 
Sponsor, the Trials Office, the Investigator Team, host NHS Trust(s), regulatory authorities, and members of 
the Research Ethics Committee.   
 
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GENERAL CONTACT INFORMATION 
Trial Office (OCTO) 
MErCuRIC Trial Office 
 
Oncology Clinical Trials Office (OCTO) 
 
Department of Oncology, The University of Oxford 
Oxford Cancer and Haematology Centre 
 
Churchill Hospital 
 
Oxford 
 
Tel: +44 (0)1865 227194 
 
Email: octo-MErCuRIC@oncology.ox.ac.uk 
 
Website: http://www.oncology.ox.ac.uk/research/oncology-
clinical-trials-office-octo 
 
 
Chief Investigator 
Professor Mark Middleton 
 
Department of Oncology, University of Oxford 
 
Oxford Cancer and Haematology Centre 
 
Churchill Hospital 
Oxford 
OX3 7LE 
Tel: +44 (0)1865 235 315 
Email : mark.middleton@oncology.ox.ac.uk 
 
 
Investigator  
and Scientific Project Lead 
Professor Richard Wilson 
 
 
Consultant and Professor in Cancer Medicine 
Centre for Cancer Research and Cell Biology 
Queen’s University Belfast, 97 Lisburn Road 
Belfast BT9 7BL 
Northern Ireland, UK 
 
Tel.: +44 (0) 28 95048492 
Email: r.wilson@qub.ac.uk 
 
 
FP7 Co-ordinator 
Dr Sandra Van Schaeybroeck 
Senior Lecturer and Honorary Consultant in Medical 
Oncology 
 
Centre for Cancer Research and Cell Biology 
 
Lisburn Road 97 
Belfast BT9 7BL 
Northern Ireland 
 
Tel: +44 (0) 28 9097 2954 
Email: s.vanschaeybroeck@qub.ac.uk 
 
 
Pathology Lead 
Professor Manuel Salto-Tellez 
Chair in Molecular Pathology 
 
Centre for Cancer Research and Cell Biology 
 
Lisburn Road 97 
Belfast BT9 7BL 
Northern Ireland 
Tel: +44 (0)28 9097 2178 
Email: m.salto-tellez@qub.ac.uk 
 
 
Lead NHS Trust 
Ms Heather House 
 
 
R&D Department, Oxford University Hospitals NHS 
Foundation Trust 
 
Joint Research Department, Block 60, Churchill Hospital 
 
Oxford OX3 7LE 
 
Fax +44 (0) 1865 572242 
 
E-mail: ouhtma@nhs.net 
 
 
Trial Statisticians 
 
 
 
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Ms Jane Holmes 
Senior Trial Statistician 
Oxford Clinical Trials Research Unit (OCTRU) 
Centre for Statistics in Medicine, The University of 
Oxford 
Botnar Research Centre 
Windmill Road 
Oxford OX3 7LD 
Tel: +44 (0) 1865 223452 
Email:  jane.holmes@csm.ox.ac.uk 
 
 
 
Mr William Sones 
Statistician 
Oxford Clinical Trials Research Unit (OCTRU) 
Centre for Statistics in Medicine, The University of 
Oxford 
Botnar Research Centre 
Windmill Road 
Oxford OX3 7LD 
Tel: +44 (0) 1865 227887 
Email: william.sones@ndorms.ox.ac.uk 
 
 
 
 
 
 
Patient Representative 
Mrs Margaret Grayson 
N. Ireland Cancer Trials Network, 
Belfast City Hospital, 
Lisburn Road 
Belfast BT9 7AB 
Northern Ireland, UK 
 
Tel.: +44 (0) 28 90638468 
Email: maggieg50@aol.com 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical queries and emergency contact details  
 
During office hours: Clinical Queries should be directed to the MErCuRIC Trial Office and contact the 
Clinical Trial Coordinator.  The call will be passed on to the Chief Investigator or to the Clinical Coordinator 
(medically qualified) or an appropriate member of the Trial Management Group. 
 
Out of office hours: call the Churchill Hospital switchboard on Tel: +44 (0) 1865 741 841 and ask to call the 
MErCuRIC Clinical Coordinator. 
 
 
Patient Registration: See section 4.5 
 
 
 
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TABLE OF CONTENTS 
GENERAL CONTACT INFORMATION ............................................................................................................ 2 
TABLE OF CONTENTS .................................................................................................................................... 4 
PROTOCOL SYNOPSIS ................................................................................................................................... 7 
SUMMARY SCHEDULE OF EVENTS ............................................................................................................ 18 
DOSE ESCALATION PHASE- SCHEDULE OF EVENTS FOR PF-02341066 WITH BINIMETINIB ............................... 17 
DOSE EXPANSION PHASE - SCHEDULE OF EVENTS FOR PF-02341066 WITH BINIMETINIB .............................. 189 
ABBREVIATIONS ........................................................................................................................................... 22 
1 
INTRODUCTION ........................................................................................................................... 24 
1.1 
BACKGROUND .................................................................................................................................. 24 
1.2 
INVESTIGATIONAL MEDICINAL PRODUCTS USED IN THE STUDY ............................................................. 25 
1.3 
OTHER RESEARCH INTERVENTIONS .................................................................................................... 30 
1.4 
RATIONALE FOR THE STUDY .............................................................................................................. 30 
1.5 
PRIMARY HYPOTHESIS OF THE TRIAL .................................................................................................. 33 
2 
TRIAL DESIGN ............................................................................................................................. 34 
2.1 
OUTLINE .......................................................................................................................................... 34 
2.2 
TREATMENT SCHEDULE AND DURATION.............................................................................................. 34 
2.3 
PROJECTED NUMBER OF SUBJECTS .................................................................................................. 36 
2.4 
REPLACEMENT OF SUBJECTS ............................................................................................................ 36 
2.5 
POST-TRIAL CARE AND FOLLOW-UP .................................................................................................... 36 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................. 40 
4 
PATIENT SELECTION .................................................................................................................. 38 
4.1 
INCLUSION CRITERIA ......................................................................................................................... 38 
4.2 
EXCLUSION CRITERIA ........................................................................................................................ 39 
4.3 
PROTOCOL DEVIATIONS AND WAIVERS TO ENTRY CRITERIA .................................................................. 40 
4.4 
RE-SCREENING IF PATIENT DOES NOT MEET INCLUSION/EXCLUSION CRITERIA FIRST TIME ROUND .......... 40 
4.5 
PATIENT REGISTRATION PROCEDURE ................................................................................................. 40 
5 
TRIAL ASSESSMENTS AND PROCEDURES ............................................................................ 41 
5.1 
PRE-TRIAL SCREENING CONSENT AND PROCEDURE (DOSE-EXPANSION PHASE ONLY) ............................ 41 
5.2 
INFORMED CONSENT FOR MAIN STUDY ............................................................................................... 41 
5.3 
INFORMED CONSENT FOR TRANSLATIONAL SUB-STUDIES ..................................................................... 42 
5.4 
MAIN SCREENING: PRE-DOSING EVALUATIONS .................................................................................... 42 
5.5 
EVALUATIONS DURING DOSING .......................................................................................................... 43 
5.6 
END OF TREATMENT EVALUATIONS ..................................................................................................... 46 
5.7 
POST TREATMENT FOLLOW-UP - EVALUATIONS ................................................................................... 46 
5.8 
EVALUATIONS ON EARLY WITHDRAWAL ............................................................................................... 46 
6. 
EARLY PATIENT WITHDRAWAL ................................................................................................ 47 
6.1 
TREATMENT WITHDRAWAL ................................................................................................................ 47 
6.2 
WITHDRAWAL OF CONSENT ............................................................................................................... 47 
6.3 
PATIENT EVALUABILITY AND REPLACEMENT ........................................................................................ 47 
7. 
SAMPLES FOR LABORATORY ANALYSIS ............................................................................... 47 
7.1 
SAMPLES TO BE ANALYSED IN LOCAL LABORATORIES .......................................................................... 48 
7.2 
SAMPLES TO BE SENT TO AND ANALYSED IN A CENTRAL LABORATORY ................................................. 48 
7.3 
PHARMACOKINETIC ASSAYS............................................................................................................... 48 
7.4 
PHARMACODYNAMIC ASSAYS ............................................................................................................. 49 
7.5 
SAMPLES FOR MOLECULAR ANALYSIS AND PATIENT DERIVED XENOGRAFTS .......................................... 49 
7.6 
SUMMARY OF SAMPLES/ASSAYS TO BE TAKEN DURING THE STUDY ....................................................... 49 
7.7 
SAMPLES FOR BIOBANKING ............................................................................................................... 49 
7.8 
LABELLING AND CONFIDENTIALITY OF SAMPLES SENT .......................................................................... 49 
7.9 
CLINICAL REPORTING OF EXPLORATORY RESEARCH ASSAY RESULTS ................................................... 54 
7.10 
TRIAL SAMPLE RETENTION AT END OF STUDY ...................................................................................... 54 
7.11 
WITHDRAWAL OF CONSENT FOR SAMPLE COLLECTION AND/OR RETENTION ........................................... 50 
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8. 
INVESTIGATIONAL MEDICINAL PRODUCTS (IMPS) ............................................................... 50 
8.1 
NAME OF IMPS ................................................................................................................................. 50 
8.2 
TREATMENT DOSE ............................................................................................................................ 50 
8.3 
DURATION OF TREATMENT ................................................................................................................. 50 
8.4 
MANAGEMENT OF DRUG ADMINISTRATION .......................................................................................... 51 
8.5 
DOSE MODIFICATION ......................................................................................................................... 52 
8.6 
COMPLIANCE .................................................................................................................................... 62 
8.7 
MANAGEMENT OF OVERDOSE ............................................................................................................ 62 
9. 
OTHER TREATMENTS (NON-IMPS) ........................................................................................... 62 
9.1 
SUPPORTIVE MEDICATION ................................................................................................................. 62 
9.2 
CONCOMITANT MEDICATION AND NON-DRUG THERAPIES ..................................................................... 62 
9.3 
PROHIBITED THERAPIES .................................................................................................................... 62 
9.4 
(POTENTIAL) DRUG INTERACTIONS .................................................................................................... 62 
10 
DRUG MANAGEMENT ................................................................................................................. 63 
10.1 
DRUG SUPPLIES ................................................................................................................................ 63 
10.2 
DRUG ORDERING .............................................................................................................................. 63 
10.3 
IMP RECEIPT ................................................................................................................................... 64 
10.4 
HANDLING AND STORAGE .................................................................................................................. 64 
10.5 
LABELLING ....................................................................................................................................... 64 
10.6 
DOSING DISPENSING ......................................................................................................................... 64 
10.7 
DRUG ACCOUNTABILITY ..................................................................................................................... 64 
10.8 
DRUG RETURNS FROM PATIENTS ....................................................................................................... 64 
10.9 
DRUG DESTRUCTION ......................................................................................................................... 65 
10.10 
OCCUPATIONAL SAFETY .................................................................................................................... 65 
11 
EVALUATION OF RESPONSE .................................................................................................... 65 
11.1 
MEASUREMENT OF DISEASE FOR SOLID TUMOUR ................................................................................ 65 
11.2 
TUMOUR ASSESSMENT ...................................................................................................................... 65 
11.3 
TUMOUR RESPONSE.......................................................................................................................... 66 
11.4 
OTHER DEFINITIONS OF OUTCOME: .................................................................................................... 66 
12 
ASSESSMENT OF SAFETY ......................................................................................................... 66 
12.1 
ADVERSE EVENT DEFINITIONS ........................................................................................................... 66 
12.2 
CLINICAL LABORATORY ABNORMALITIES AND OTHER ABNORMAL ASSESSMENTS AS AES AND SAES ...... 68 
12.3 
DETERMINING ADVERSE EVENT CAUSALITY ......................................................................................... 68 
12.4 
EXPECTED ADVERSE EVENTS ............................................................................................................ 68 
12.5 
SUSPECTED UNEXPECTED SERIOUS ADVERSE DRUG REACTIONS (SUSARS) ..................................... 69 
12.6 
EXPEDITED REPORTING OF SAES ...................................................................................................... 69 
12.7 
FOLLOW-UP OF SERIOUS ADVERSE EVENTS ...................................................................................... 69 
12.8 
REPORTING ADVERSE EVENTS ON THE CRF ...................................................................................... 70 
12.9 
EVENTS EXEMPT FROM BEING REPORTED AS AE/ SAES ..................................................................... 71 
12.10 
DEVELOPMENT SAFETY UPDATE REPORTS ........................................................................................ 71 
12.11 
INFORMING INVESTIGATORS OF NEW SAFETY INFORMATION ................................................................. 71 
13 
PREGNANCY AND BREAST FEEDING ...................................................................................... 71 
14 
DEFINING THE END OF TRIAL ................................................................................................... 71 
15 
STATISTICAL CONSIDERATIONS .............................................................................................. 72 
15.1 
SAMPLE SIZE .................................................................................................................................... 72 
15.2 
STATISTICAL ANALYSIS PLAN ............................................................................................................. 72 
16 
TRIAL COMMITTEES ................................................................................................................... 73 
16.1 
TRIAL MANAGEMENT GROUP (TMG) ................................................................................................. 73 
16.2 
DATA AND SAFETY MONITORING ........................................................................................................ 73 
16.3 
TRIAL STEERING COMMITTEE ............................................................................................................ 73 
 
 
 
 
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17 
DATA MANAGEMENT .................................................................................................................. 73 
17.1 
DATABASE CONSIDERATIONS ............................................................................................................. 73 
17.2 
CASE REPORT FORMS (CRFS) .......................................................................................................... 73 
17.3 
ACCOUNTING FOR MISSING, UNUSED, OR SPURIOUS DATA. .................................................................. 74 
18 
CLINICAL STUDY REPORT ......................................................................................................... 74 
19 
STUDY SITE MANAGEMENT ...................................................................................................... 74 
19.1 
STUDY SITE RESPONSIBILITIES ........................................................................................................... 74 
19.2 
STUDY SITE SET UP AND ACTIVATION .................................................................................................. 75 
19.3 
ARRANGEMENTS FOR SITES OUTSIDE THE UK .................................................................................... 75 
19.4 
STUDY DOCUMENTATION ................................................................................................................... 75 
20 
REGULATORY AND ETHICAL CONSIDERATIONS .................................................................. 75 
20.1 
ETHICAL CONDUCT OF THE TRIAL AND ETHICS APPROVAL .................................................................... 75 
20.2 
REGULATORY AUTHORITY APPROVAL ................................................................................................. 75 
20.3 
LOCAL APPROVALS ........................................................................................................................... 75 
20.4 
PROTOCOL AMENDMENTS ................................................................................................................. 75 
20.5 
URGENT SAFETY MEASURES .............................................................................................................. 75 
20.6 
TEMPORARY HALT ............................................................................................................................. 76 
20.7 
SERIOUS BREACHES ......................................................................................................................... 76 
20.8 
REPORTS: PROGRESS, SAFETY AND END OF STUDY REPORTS ........................................................... 76 
21 
EXPENSES AND BENEFITS ........................................................................................................ 76 
22 
QUALITY ASSURANCE ............................................................................................................... 76 
22.1 
RISK ASSESSMENT AND MONITORING ................................................................................................. 77 
22.2 
AUDIT AND REGULATORY INSPECTION ............................................................................................... 77 
23 
RECORDS RETENTION & ARCHIVING ...................................................................................... 77 
24 
PATIENT CONFIDENTIALITY ...................................................................................................... 77 
25 
STUDY FUNDING ......................................................................................................................... 77 
26 
SPONSORSHIP AND INDEMNITY ............................................................................................... 78 
26.1 
SPONSORSHIP .................................................................................................................................. 78 
26.2 
INSURANCE ...................................................................................................................................... 78 
26.3 
CONTRACTS/AGREEMENTS ............................................................................................................... 78 
27 
PUBLICATION POLICY ................................................................................................................ 78 
28 
REFERENCES .............................................................................................................................. 79 
APPENDIX 1: ECOG PERFORMANCE SCALE .............................................................................................................. 82 
APPENDIX 2: COCKCROFT AND GAULT FORMULATION ESTIMATE GFR ............................................................... 83 
APPENDIX 3: NCI-CTCAE V4.0 CRITERIA NEUROLOGIC DISORDERS ..................................................................... 84 
APPENDIX 4: MEASUREMENT OF DISEASE - RECIST 1.1 CRITERIA ........................................................................ 85 
APPENDIX 5: MEDICATIONS TO BE AVOIDED OR USED WITH CAUTION WITH PF-02341066 ............................... 86 
APPENDIX 6: RECOMMENDED DOSE MODIFICATIONS FOR BINIMETINIB (MEK162)………………………………...88 
APPENDIX 6A: RECOMMENDED DOSE MODIFICATIONS FOR BINIMETINIB (MEK162)…UPDATED 
 
APPENDIX 7: INCLUSION AND EXCLUSION CRITERIA FOR DOSE ESCALATION PHASE USING PF-02341066 
WITH PD0325901…………………………………………………………………………………………………………………….96 
 
APPENDIX 8: STUDY EVALUATIONS FOR DOSE ESCALATION PHASE USING PF-02341066 WITH PD-
0325901……………………………………………………………………………………………………………………………….98 
 
APPENDIX 9: SCHEDULE OF EVENTS FOR DOSE ESCALATION PHASE USING PF-02341066 WITH PD-
0325901……………………………………………………………………………………………………………………………...102 
 
APPENDIX 10: AMENDMENT HISTORY……………………………………………………………………………………….104 
 
 
 
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PROTOCOL SYNOPSIS 
Full Title of study: 
MErCuRIC1: A Sequential Phase I study of MEK1/2 inhibitors PD-0325901 or 
Binimetinib combined with cMET inhibitor PF-02341066 in Patients with RAS 
Mutant and RAS Wild Type (with aberrant c-MET) Colorectal Cancer  
Short Title: 
MErCuRIC1: MEK and MET Inhibition in Colorectal Cancer 
Trial Acronym: 
MErCuRIC1 
Objectives: 
 
1a.  Perform a dose escalation phase with combination PD-0325901 and 
PF-02341066: 
 
PRIMARY OBJECTIVES: 
• 
To assess the safety and toxicity profile of PD-0325901/PF-02341066 
combination in patients with advanced solid tumours using the NCI 
CTCAE V4.03, and determine the maximum tolerated dose (MTD). 
 
SECONDARY OBJECTIVES: 
• 
To define the recommended phase II (RPII) dose and schedule of  
PD-0325901 in combination with PF-02341066.  
• 
To investigate the pharmacokinetics (PK) of PD-0325901 with PF-
02341066 when administrated in combination. 
• 
To investigate pharmacodynamic (PD) biomarkers of PD-0325901 and 
PF-02341066 in paired skin biopsies, tumour biopsies (where possible), 
in serum and PBMCs. 
• 
To preliminarily assess the efficacy of RPII dose of PF-02341066 in 
combination with PD-0325901. 
 
1b.  Perform a further dose escalation phase with combination 
Binimetinib and PF-02341066:  
  
PRIMARY OBJECTIVES: 
• 
To assess the safety and toxicity profile of Binimetinib/PF-02341066 
combination in patients with advanced solid tumours using the NCI 
CTCAE V4.03, and determine the maximum tolerated dose (MTD). 
 
SECONDARY OBJECTIVES: 
• 
To define the recommended phase II (RPII) dose and schedule of  
Binimetinib in combination with PF-02341066.  
• 
To investigate the pharmacokinetics (PK) of Binimetinib with PF-
02341066 when administrated in combination. 
• 
To investigate pharmacodynamic (PD) biomarkers of Binimetinib and PF-
02341066 in paired skin biopsies, tumour biopsies (where possible), in 
serum and PBMCs. 
• 
To preliminarily assess the efficacy of RPII dose of PF-02341066 in 
combination with Binimetinib. 
 
2.  Perform a dose expansion cohort phase: 
 
PRIMARY OBJECTIVES: 
• 
To investigate the response to treatment with RPII dose of PF-02341066 
in combination with Binimetinib in patients with a) RAS mutant (MT) and 
b) RAS wild type (WT) c-METmut/amplified CRC and c) RAS wild type 
(WT) c-MET overexpressed CRC. 
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SECONDARY OBJECTIVES:  
• 
To assess the efficacy of RPII dose of PF-02341066 in combination with 
Binimetinib in patients with a) RASMT and b) RASWT/c-MET 
mut/amplified CRC and c) RASWT/c-MET over-expressed CRC. 
• 
To further investigate the safety and toxicity profile/tolerability of 
Binimetinib and PF-02341066 combination. 
• 
To investigate pharmacokinetic (PK) biomarkers of PF-02341066 and 
Binimetinib in blood. 
• 
To measure pharmacodynamic (PD) effect of PF-02341066 in 
combination with Binimetinib in paired skin biopsies, tumour biopsies, 
plasma and PBMCs. 
TERTIARY AND EXPLORATORY OBJECTIVES:  
• 
To identify molecular signatures of response and resistance to combined 
PF-02341066 and PD-0325901 treatment.  
• 
To identify molecular signatures of response and resistance to combined 
PF-02341066 and Binimetinib treatment. 
• 
Develop a liquid biopsy platform for routine assessment of therapeutic 
efficacy 
Scientific rationale: 
To identify novel targets/pathways critical for the survival of RASMT tumours, 
both basally and following MEK inhibitor (i) treatment, we have employed a 
systems biology approach, comprising gene expression profiling, metacore 
pathway analysis and siRNA screening. We found that JAK1/2-STAT3 and the 
upstream receptor tyrosine kinase c-MET are important pro-survival signals in 
RASMT CRC (Van Schaeybroeck et al, Cancer Cell, in revision). Further studies 
indicated that c-MET is acutely activated following MEK1/2 inhibition in RASMT 
CRC cells. c-MET silencing (using different siRNA sequences and/or the small 
molecule inhibitor crizotinib (PF-02341066) strongly decreased basal and 
MEK1/2-induced c-MET and JAK/STAT3 activity and resulted in potent increase 
in cell death when combined with the MEK1/2 inhibitor AZD6244 in RASMT CRC 
cells. Importantly, combining PF-02341066 with the MEKi AZD6244 resulted 
in synergistic reduction in tumour growth in RASMT xenograft models. These in 
vitro and in vivo data support the further clinical evaluation of combined 
MEKi/METi treatment to combat metastases in RASMT CRC patients. 
Clinical rationale: 
Standard of care for treatment of mCRC in first and second line involves the use 
of 5-FU-containing regimens in combination with either Irinotecan (FOLFIRI) or 
Oxaliplatin (FOLFOX) (De Gramont, 2000; Douillard, 2000). However, 
development of resistance occurs in the vast majority of patients. There are 
activating mutations in exon 2, 3 or 4 of KRAS or NRAS in approximately 55-60% 
of CRC patients (RASMT), while 40-45% exhibit a wild type genotype (RASWT). 
Employing RAS mutational status as a selection tool for EGFR monoclonal 
antibody (MoAb) therapies has led to significant improvement in both PFS and 
OS in patients with RASWT tumours, but has shown no benefit in those patients 
harbouring RASMT metastases (Lievre, 2006). In addition, only 40-50% of wild-
type RAS patients respond to anti-EGFR MoAbs (De Roock, 2011). Thus, 
clinicians now have an urgent need to better understand the biologies of both 
RASMT and RASWT disease, in order to devise effective therapies in these 
defined genetic settings. Thus, a significant requirement exists to identify new 
modalities of tumour biology targeted therapy, both for 50% of mCRC patients 
with RASWT tumours and 100% of patients with RASMT metastases. 
Primary Endpoint: 
Dose escalation  phase using PD-0325901 in combination with PF-
02341066: 
• 
Maximal tolerated dose (MTD) of PD-0325901 with PF-02341066 
according to toxicities graded by NCI CTCAE v4.03 in cycle 1 of 
treatment. 
Dose escalation  phase using Binimetinib in combination with PF-
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02341066: 
• 
Maximal tolerated dose (MTD) of Binimetinib with PF-02341066 
according to toxicities graded by NCI CTCAE v4.03 in cycle 1 of 
treatment. 
Dose expansion phase: 
• 
Clinical and radiological response to Binimetinib with PF-02341066 as 
defined by stable, partially or completely responding disease using 
RECIST version 1.1. 
Secondary 
Endpoints: 
Dose escalation phase using PD-0325901 in combination with PF-02341066: 
• 
To define the recommended phase II dose and schedule (RPII) of the 
combination, guided by safety, PK and PD data.  
• 
To investigate pharmacokinetics (PK) of the drug combination by 
determining plasma Cmax, Cmin, AUC, oral clearance and t1/2 etc. for PF-
02341066 and PD‐0325901 and its metabolite. 
• 
To measure pharmacodynamic (PD) biomarkers of the drug combination 
using 
ELISA 
for 
soluble 
c-MET 
and 
HGF 
in 
plasma; 
ERK 
phosphorylation (pERK) in PBMC; Immunohistochemistry (IHC) for 
pERK1/2, and c-METY1234/1235 in (mandatory) skin and (optional) tumour 
biopsies. 
• 
To preliminarily assess the efficacy of RPII dose of the drug combination, 
using objective response from CT scan and modified RECIST version 
1.1, and progression free and overall survival. 
Dose escalation  phase using Binimetinib in combination with PF-
02341066: 
• 
To define the recommended phase II dose and schedule (RPII) of the 
combination, guided by safety, PK and PD data.  
• 
To investigate pharmacokinetics (PK) of the drug combination by 
determining plasma Cmax, Cmin, AUC, oral clearance and t1/2 etc. for PF-
02341066 and Binimetinib. 
• 
To measure pharmacodynamic (PD) biomarkers of the drug combination 
using 
ELISA 
for 
soluble 
c-MET 
and 
HGF 
in 
plasma; 
ERK 
phosphorylation (pERK) in PBMC; Immunohistochemistry (IHC) for 
pERK1/2, and c-METY1234/1235 in (mandatory) skin and (optional) tumour 
biopsies. 
• 
To preliminarily assess the efficacy of RPII dose of the drug combination, 
using objective response from CT scan and modified RECIST version 
1.1, and progression free and overall survival. 
 
Dose expansion phase:  
• 
To assess the efficacy of RPII dose of the combination of Binimetinib and 
PF-02341066 in patients with RASMT and RASWT/c-MET+ CRC for 
progression free and overall survival. 
• 
To further investigate the safety and toxicity profile/tolerability of the drug 
combination using adverse events according to NCI CTCAE V4.03 
across all treatment cycles. 
• 
To investigate pharmacokinetic (PK) biomarkers of the drugs in blood by 
determining plasma Cmax, Cmin, AUC, oral clearance and t1/2 etc. for 
PF-02341066 and Binimetinib. 
• 
To measure pharmacodynamic (PD) effect of PF-02341066 in 
combination with Binimetinib using ELISA for soluble c-MET and HGF in 
plasma; ERK phosphorylation in skin (Western blotting) , and c-
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METY1234/1235 in skin and tumour biopsies.  
Exploratory and 
Tertiary Endpoints: 
• 
Whole exome sequencing and miRNA profiling on tumour biopsies taken 
prior to treatment and upon resistance to PF-02341066 and PD-0325901 
treatment. 
• 
Whole exome sequencing and miRNA profiling on tumour biopsies taken 
prior to treatment and upon resistance to PF-02341066 and Binimetinib 
treatment. 
• 
Gene sequencing outputs from ctDNA in serially collected plasma 
samples from mCRC patients in the dose expansion phase. 
Study Design: 
This will be a multicentre, open label, single arm phase I combination study of a 
MET inhibitor (PF-02341066) and a MEK inhibitor (PD-0325901 or Binimetinib). 
There was an initial dose escalation phase using patients with advanced solid 
tumours receiving the combined study treatment of PF-02341066 with PD-
0325901. A second escalation phase using patients with advanced solid tumours 
will involve patients receiving the combined study treatment of PF-02341066 with 
Binimetinib.  
Once the RPII dose has been identified this will be followed by a dose expansion 
phase recruiting patients with a) RASMT metastatic CRC or b) RASWT/c-
METmut/amplified metastatic CRC or c) RASWT/c-MET over-expressed 
metastatic CRC who will receive the combined study treatment of PF-02341066 
with Binimetinib.  
All patients in the RASWT group will receive full c-MET testing prior to 
recruitment to detect: (a) overexpression at protein level (IHC), (b) 
overexpression at mRNA level (RNAscope), (c) MET amplification, and (d) MET 
mutation. This would allow us to assess the potential correlation between MET 
amplification or mutation and MET protein/mRNA overexpression, and, 
importantly, to assess initial benefit from this treatment in each of two different 
molecular groups independently: cohorts  (b) RASWT CRC with amplification or 
mutation  c-MET gene or c) RASWT CRC with over-expression of c-MET on 
protein or mRNA) 
1a. Dose escalation phase of the study using the combination of PF-
02341066 with PD-0325901  
For this dose escalation phase a rolling six design has been chosen. Dose level 
assignment will be based on the number of patients currently enrolled in the 
cohort, the number of dose limiting toxicities (DLTs) observed, and the number of 
patients at risk for developing a DLT. Once the MTD has been exceeded the 
cohort at the next lowest dose level will be expanded to six patients. If the MTD is 
not defined at the highest dose level to be explored (Dose Level 4, Figure 3), 
then this dose level will be defined as the RPII dose.  
1b. Dose escalation phase of the study using the combination of PF-
02341066 with Binimetinib,  
A similar design to 1a.(combination of PF-02341066 with PD-0325901), will be 
used to determine the dose level to be defined as the RPII dose. There will be 
flexibility to explore alternate dosing schedules of Binimetinib, as the dosing 
schedule will be started as continuous dosing but reduced to dosing with a 7 day 
off treatment period every 28 days with a dosing schedule on days 1-21 every 28 
days if continuous dosing is not well tolerated. 
The definition of MTD is clearly outlined in the protocol and will be discussed and 
agreed at regular teleconferences throughout the dose escalation phase of the 
study. Once the MTD has been defined, dosing at a higher dose must not occur. 
It is now anticipated that up to 25 patients will be required for the dose escalation 
phase of the study. Successful first phase of dose escalation triggers preparation 
of participating centres for the dose expansion phase of the study. 
 
2. Dose expansion phase of study 
Once the RPII dose and schedule have been identified, up to 40 patients (22 
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patients only for stage 1) with RASMT CRC, up to 29 patients with RASWT/c-
METmut/amplified CRC (10 patients only for stage 1) and up to 29 with 
RASWT/c-MET over-expressed CRC (10 patients only for stage 1) will be 
enrolled in the RPII dose expansion phase to study the safety, PK, PD and 
treatment response. This phase of the study is organised over 2 phases where 
patients will only be recruited to Stage 2 for each cohort where evidence of 
responsiveness is shown at Stage 1. In the dose expansion phase, patients will 
undergo an image-guided biopsy of representative metastases for c-MET testing 
and further mutational analysis and pharmacodynamic (PD) endpoints including 
pMETY1234/1235) before and after combination treatment. Other PD endpoints 
include sMET, sHGF in plasma and IHC for pERK1/2 in skin biopsies (for first 10 
patients) before and after combination treatment. CT imaging to assess disease 
status will be performed every 8 weeks (2 cycles) during the study until subjects 
withdraw, cannot tolerate therapy or have progression of disease. At this time, 
patients who have given consent will undergo an optional USS or CT-guided 
metastasis biopsy for further mutational analysis. Blood samples for detection of 
ctDNA will be obtained every 4 weeks together with safety bloods until 
progression of disease. 
Patient Numbers: 
25 evaluable patients with solid tumours were recruited in order to reach the 
MTD for the initial dose escalation phase of the study using PF-02341066 with 
PD-0325901. It is anticipated that up to 25 patients will be required for the further 
dose escalation phase of the study using the combination of PF-02341066 with 
Binimetinib. The dose expansion phase will include 3 cohorts where up to 22-40 
patients will be required for the RASMT cohort and 10-29 each for the RASWT/c-
METmut/amplified CRC and RASWT/c-MET over-expressed CRC cohorts. The 
total patient number for the study will be between 92 - 148. 
Target Population: 
Dose escalation phase 
Adult patients with pathologically proven, advanced and incurable solid tumours 
for whom use of the combination of a MEK and c-MET inhibitor are considered to 
be a reasonable option according to clinical opinion. 
 
Dose Expansion phase 
Adult patients with a) RASMT CRC or b) RASWT/c-METmut/amplified CRC or c) 
RASWT/c-MET over-expressed CRC. In view of the mandatory tumour biopsies, 
all patients must have accessible metastatic sites suitable for biopsy and must 
consent to repeated biopsies.  
Inclusion and 
exclusion criteria 
INCLUSION CRITERIA 
(Inclusion criteria for the completed initial dose escalation phase using PF-
02341066/PD-0325901 are listed in Appendix 7.) 
All patients 
− 
Age ≥ 16 years 
− 
ECOG performance status 0-1 (Appendix 1) 
− 
Adequate respiratory function on clinical assessment 
− 
Left ventricular ejection fraction (LVEF) ≥ 50% as determined by a 
multigated acquisition (MUGA) scan or echocardiogram┼ 
− 
Able to give informed consent prior to any screening procedures being 
performed and be capable of complying with the protocol and its 
requirements  
− 
Haematological and biochemical indices within the ranges shown below: 
− 
Haemoglobin (Hb) ≥ 9g/dl (transfusion to achieve this allowed ),  
− 
Neutrophils ≥ 1,500/µl,  
− 
Platelet count ≥ 100,000/µl,  
− 
AST or ALT ≤ 2.5 x ULN,  patient with liver metastases ≤ 5 × ULN, 
− 
Alkaline phosphatase ≤ 5 x ULN, 
− 
Serum Bilirubin ≤ 1.5 x ULN,  
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− 
Creatinine Clearance ≥ 50ml/min (Calculated by Cockcroft Gault 
equation, or by EDTA) (Appendix 2) 
− 
Able to swallow oral medication 
− 
Life expectancy of at least 3 months. 
Dose escalation phase:  
− 
Patients with any advanced solid tumours  
− 
Patients for whom the combination of PF-02341066 with Binimetinib is a 
reasonable option.  
Dose expansion phase: 
Patients will be eligible for pre-screening for this phase provided that: 
− 
They have given informed consent to screening. 
− 
They are willing to undergo a biopsy for assessment of tumour RAS 
mutation status and c-MET assessment. 
− 
The Investigator anticipates that they are likely to satisfy the eligibility 
criteria for the trial. Formal screening should not be performed until the 
tumour pre-screening result is known.  
Eligibility for the trial, in patients passing pre-screening, requires: 
− 
Histologically confirmed colorectal adenocarcinoma that is either a) 
RASMT (KRAS codon 12, 13, 61, 117, 146; NRAS codon 12, 13, 61, 
117, 146) mutations) or b) RASWT/c-MET mutated or amplified CRC or 
c) RASWT/c-MET over-expressed with progressive disease on or within 
6 months of completion of adjuvant therapy or after chemotherapy and/or 
targeted therapies for metastatic disease.  
− 
Prior treatment with an EGFR targeted monoclonal antibody for patients 
with RASWT/c-MET mutated or amplified CRC or RASWT/c-MET over-
expressed. 
− 
No evidence for a mutation in BRAF at codon600 
− 
Metastases accessible for biopsy on 2-3 occasions 
− 
At least one other measurable lesion (according to RECIST v1.1). 
− 
Unsuitable for potential curative resection.  
 
┼For non-UK territories: if echocardiogram (ECHO) cannot be performed, a MUGA 
scan may be performed in compliance with local policy, applicable national 
legislation and relevant approvals. Cardiac ejection fraction must be determined as 
measured by ECHO in the UK. 
 
EXCLUSION CRITERIA 
(Exclusion criteria for the completed initial dose escalation phase using PF-
02341066/PD-0325901 are listed in Appendix 7.) 
All patients 
− 
Unstable 
ischaemic 
heart 
disease, 
cardiac 
dysrhythmias, 
coronary/peripheral artery bypass graft or cerebrovascular accident 
within 6 months prior to starting treatment.  
− 
Uncontrolled arterial hypertension despite medical treatment. 
− 
Ongoing congestive heart failure or cardiac dysrhythmias of NCI CTCAE 
Grade ≥2 or uncontrolled atrial fibrillation.  
− 
History of extensive disseminated/bilateral or known presence of Grade 
3 or 4 interstitial fibrosis or interstitial lung disease, including a history of 
pneumonitis, 
hypersensitivity 
pneumonitis, 
interstitial 
pneumonia, 
interstitial lung disease (ILD), obliterative bronchiolitis, and pulmonary 
fibrosis. A history of prior radiation pneumonitis is allowed.  
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− 
Any active central nervous system (CNS) lesion (i.e., those with 
radiographically unstable, symptomatic lesions) and/or leptomeningeal 
metastases. However, patients treated with stereotactic radiotherapy or 
surgery are eligible if the patient remained without evidence of CNS 
disease progression ≥ 3 months. Patients must be off corticosteroid 
therapy for ≥ 3 weeks. 
− 
Patients who have neuromuscular disorders that are associated with 
elevated CK (e.g., inflammatory myopathies, muscular dystrophy, 
amyotrophic lateral sclerosis, spinal muscular atrophy); 
− 
Patients who are planning on embarking on a new strenuous exercise 
regimen after first dose of study treatment. NB: Muscular activities, such 
as strenuous exercise, that can result in significant increases in plasma 
CK levels should be avoided while on Binimetinib treatment 
− 
Spinal cord compression unless treated with the patient attaining good 
pain control and stable or recovered neurologic function.  
− 
Carcinomatous meningitis or leptomeningeal disease.  
− 
History of hypoalbuminaemia, or patients with peritoneal disease or 
pleural disease, where there is a requirement for ascitic or pleural taps. 
− 
History of retinal vein occlusion, intraocular pressure > 21 mmHg or 
patient considered at risk of retinal vein thrombosis (e.g. history of 
hyperviscosity or hypercoagulability syndromes). 
− 
History of retinal degenerative disease. 
− 
History of Gilbert’s syndrome. 
− 
Active infections (including chronic hepatitis type B or C and HIV 
infection if status known), severe immunologic defect, compromised 
bone marrow function. 
− 
Other severe acute or chronic medical (including severe gastro-intestinal 
disorders 
e.g. 
partial 
bowel 
obstruction, 
malabsorption, 
active 
inflammatory bowel disease) or psychiatric conditions or laboratory 
abnormalities that the investigator considers would make the patient a 
poor trial candidate, would impart excess risk associated with study 
participation or drug administration or could interfere with protocol 
compliance or the interpretation of trial results. 
− 
Patients who have undergone major surgery ≤ 3 weeks prior to starting 
study drug or who have not recovered from side effects of such 
procedure. 
− 
Use of drugs or foods that are known potent CYP3A4 inhibitors or 
inhibitors or are CYP3A4 substrates with narrow therapeutic indices (see 
Appendix 5).  
− 
Radiotherapy (except for palliative reasons), endocrine therapy, 
immunotherapy or chemotherapy during the previous four weeks (six 
weeks for nitrosoureas, Mitomycin-C) and four weeks for investigational 
medicinal products before treatment. Patients with prostate cancer may 
continue to receive endocrine therapy to maintain castrate levels of 
androgens. 
− 
Resting ECG with QTc > 480msec at 2 or more time points within a 24h 
period (using Fredericia correction). 
− 
Requirement for medication known to prolong QT interval (Appendix 5). 
− 
History of other malignancy less than 3 years before the diagnosis of 
current cancer, EXCLUDING the following: Non-melanoma skin cancer, 
in situ carcinoma of the cervix treated surgically with curative intent, other 
malignant tumours that have been treated curatively and patient is 
deemed disease-free  
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− 
Women with the ability to become pregnant (or already pregnant or 
lactating).  However, those female patients who have a negative serum  
pregnancy test before enrolment and agree to use one highly effective 
form of contraception (oral, injected or implanted hormonal contraception 
or intra-uterine device) in addition to condom plus spermicide, for four 
weeks before entering the trial, during the trial and for six months 
afterwards are considered eligible.  
− 
Male patients with partners of child-bearing potential (unless they agree 
to take measures not to father children by using one form of highly 
effective contraception including oral, injected or implanted hormonal 
contraception or intra-uterine device) in addition to condom plus 
spermicide during the trial and for six months afterwards).  Men with 
pregnant or lactating partners should be advised to use barrier method 
contraception (condom plus spermicidal gel) to prevent exposure to the 
foetus or neonate. 
− 
Prior exposure to any of a HGF, cMET or a MEK inhibitor. 
Trial dose and 
administration: 
Dose escalation phase: PF-02341066 in combination with PD-0325901 
In this non-randomised study, patients with advanced solid tumours will be 
recruited where no potentially curative surgery is planned. Patients who 
successfully complete the screening will receive PD-0325901 orally continuously 
as monotherapy for one week (day minus 7 to day minus 1). Thereafter 
combination dosing of both agents will begin. The dose levels are defined in 
Figure 3. 
Oral PD-0325901 will be administered on days 1 - 21 of each 28 day cycle (after 
the one week run-in of monotherapy). The dose of PD-0325901 will not be 
escalated beyond 8mg BD. PF‐02341066 capsules will be taken orally, once or 
twice daily on a continuous schedule. 
 
Dose escalation phase:  PF-02341066 in combination with Binimetinib 
In this non-randomised study, patients with advanced solid tumours, where no 
potentially curative surgery is planned, will be recruited. Patients who 
successfully complete the screening will receive the oral combined therapy of 
PF-02341066 and Binimetinib.  Binimetinib tablets will be administered twice 
daily from Day 1 continuously throughout the study treatment period or on days 1 
– 21 of each 28 day cycle if continuous dosing is not well tolerated.  PF-
02341066 capsules will be administered either once or twice daily on a 
continuous schedule.  The dose of Binimetinib will not be escalated beyond 
45mg BD. 
Dose expansion phase 
In the dose expansion cohort, patients with advanced RASMT, RASWT/c-MET 
mut/amplified CRC or RASWT/c-MET over-expressed CRC tumours will be 
recruited. The RPII dose and schedule of PF‐02341066 in combination with 
Binimetinib will be used in this part of the study. No randomisation or dose 
escalation will be carried out, but dose reduction or delay for toxicities will be 
allowed.  
In the dose expansion phase, patients will undergo a biopsy of a representative 
metastasis for c‐MET testing, mutational analysis and pharmacodynamic studies. 
RAS mutational status will be determined on archival tumour tissue or a fresh 
biopsy if archival material is not available. 
CT imaging to assess disease status will be performed every 8 weeks (2 x 28 
day cycles) during the study until subjects withdraw, cannot tolerate therapy or 
have progression of disease, as defined by RECIST v1.1 or clinically. At this 
time, patients who have given their consent will undergo a biopsy of a tumour 
metastasis for further mutational analysis. Blood samples for detection of ctDNA 
will be obtained every 4 weeks. 
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Duration on study: 
Patients will continue on study (with appropriate dose delay and/or modification if 
necessary) until disease progression, intolerable side effects or they choose to 
withdraw. We estimate that the median time to progression in the expansion 
cohort will be 6 months. 
Study Procedures 
and frequency: 
Dose escalation phase using PD-0325901 in combination with PF-02341066 
Detailed adverse event monitoring will be conducted according to CTCAE v4.03 
(or version 5.0 if this becomes available before the trial starts).  The dose limiting 
toxicity (DLT) is defined as any adverse event or laboratory abnormality 
considered to be related to PF‐02341066 or PD‐0325901 that begins in the first 
treatment cycle. In the dose escalation stage patients will undergo 
pharmacokinetic blood testing as per the timelines outlines in section 7.3. 
Patients will be reviewed on day 1 of every cycle with ECG and safety bloods. An 
echocardiogram will be performed at screening and repeated as clinically 
indicated. Serum CEA and cross-sectional imaging will be performed every 2 
cycles. Ophthalmologic testing will be performed at screening, in cycle 1 and 
repeated as clinically indicated. PBMC/plasma samples for PD assessment will 
be obtained on days 1, 2, 15 and 16. Fresh skin (mandatory) and tumour 
(optional) biopsies for PD assessment will be performed at screening. A second 
mandatory skin biopsy will be performed during cycle 1 on day 15. Upon disease 
progression, patients will undergo an optional, second biopsy of a tumour 
metastasis for further mutational analysis. Patients will be followed up until 
progression or death or study closure depending on which happens first. 
 
Dose escalation phase using Binimetinib in combination with PF-02341066 
Detailed adverse event monitoring will be conducted according to CTCAE v4.03 
(or version 5.0 if this becomes available before the trial starts).  The dose limiting 
toxicity (DLT) is defined as any adverse event or laboratory abnormality 
considered to be related to PF‐02341066 or Binimetinib that begins in the first 
treatment cycle. In the dose escalation stage patients will undergo 
pharmacokinetic blood testing as per the timelines outlines in section 7.3. 
Patients will be reviewed on day 1 of every cycle with ECG and safety bloods. An 
echocardiogram or MUGA will be performed at screening, at 3 weeks, and then 
every 8 weeks until cycle 5, after which they will be performed every 12 weeks. 
At any time necessary, an echocardiogram or MUGA will be repeated as 
clinically indicated. Serum tumour marker sampling and cross-sectional imaging 
will be performed every 2 cycles. Ophthalmologic testing will be performed at 
screening, and then every 8 weeks until cycle 6, after which they will be 
performed every 12 weeks. At any time necessary, ophthalmic testing will be 
repeated as clinically indicated. PBMC/plasma samples for PD assessment will 
be obtained on days 1, 2, 15 and 16. Fresh skin (mandatory) and tumour 
(optional) biopsies for PD assessment will be performed at screening. A second 
mandatory skin biopsy will be performed during cycle 1 on day 15. Upon disease 
progression, patients will undergo an optional, second biopsy of a tumour 
metastasis for further mutational analysis. Patients will be followed up until 
progression or death or study closure depending on which happens first. 
 
Dose expansion phase 
All patients will undergo safety assessments as outlined for the PF-02341066 
and Binimetinib dose escalation group. Pharmacokinetic sampling, serum tumour 
marker sampling and CT scans will be carried out as outlined for the dose 
escalation phase. Patients will undergo a biopsy of representative metastases for 
c‐MET testing, mutational analysis and PD analysis at screening. Mandatory 
fresh skin biopsies for an initial cohort of 10 patients and PD assessment for all 
patients will be obtained at screening and on day 15 of cycle 1. For those 
patients who have consented, upon disease progression patients will undergo a 
biopsy of a metastasis for further mutational analysis. Blood samples for 
detection of ctDNA will be obtained every 4 weeks. 
Patient care post-
trial: 
Patients may receive further standard treatment, treatment within another clinical 
trial or palliative and supportive care as appropriate and all will have long-term 
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follow-up for further disease progression and overall survival. 
Criteria for 
evaluation: 
 
Efficacy: 
Disease status will be monitored according to RECIST version 1.1. 
Safety: 
Safety and toxicity will be reported using NCI CTCAE (currently version 4.03).  
Pharmacokinetic 
assays: 
For Dose Escalation phase using PF-02341066 with PD-0325901:  
Analysis of plasma samples for the determination of PF-02341066 (crizotinib) 
and PD-0325901 (and its carboxylic acid metabolite, PD-0315209, M15) will be 
carried out to ensure that the putative target level to inhibit p-cMET and pERK1/2 
is met when PF-02341066 is combined with PD-0325901. 
Blood samples will be centrifuged to generate plasma. Plasma concentrations of 
PF-02341066, PD-0325901 and M15 will be determined using a validated HPLC-
MS/MS assay following solid-phase extraction of the plasma sample. 
For Dose Escalation phase and Dose Expansion phase using PF-02341066 
with Binimetinib: 
Analysis of plasma samples for determination of PF-02341066 and Binimetinib 
will be carried out to ensure that the putative target level to inhibit p-cMET is met 
when PF-02341066 is combined with Binimetinib. 
Plasma concentrations of PF-02341066 and Binimetinib will be determined using 
a validated HPLC-MS/MS assay following solid-phase extraction of the plasma 
sample. 
Pharmacodynamic 
assays: 
We will investigate the impact of the MEK and MET inhibitors on established 
histological markers.  
a. In both dose escalation phases, only, a PBMC/plasma sample for PD 
assessment will be obtained on cycle 1 on days 1, 2, 15 and 16. The inhibitory 
effect of PD-0325901/Binimetinib on pERK, the only known substrate for MEK, 
will be assessed in PBMCs. 
b. In both dose escalation and dose expansion phase a plasma sample for PD 
assessment will be obtained on cycle 1 on days 1, 2, 15 and 16.  The plasma 
sample: plasma levels of HGF Scatter factor and soluble c-Met ectodomain will 
be assessed at baseline and following treatment with PF-02341066. 
c. Fresh skin biopsy for PD assessment is mandatory for both dose escalation 
phases as well as for an initial cohort of 10 patients in the dose expansion phase 
of the study. We will analyse pERK1/2 and pMETY1234/1235 by Western blotting  in 
skin biopsy at pre-dose and on cycle 1 day 15, 3-6 hours following dosing. In 
addition, We will also study pAKT and other markers of proliferation and 
apoptosis such as KI67 and caspase3.  
d. Tumour biopsy for PD analysis is mandatory in the expansion phase only and 
optional in both of the dose escalation phases. A further metastatic tumour 
biopsy is an optional sample taken at disease progression in the dose expansion 
phase only.  In the dose escalation and dose expansion phase we will analyse 
pERK1/2 and pMETY1234/1235 by IHC in tumour biopsy pre-dosing and on cycle 1 
day 15, 3-6 hours following dosing. In addition, we will also study pAKT and other 
markers of proliferation and apoptosis such as KI67 and caspase3.  
 
 
 
 
Biomarker/translational endpoints 
 Dose Expansion Phase: In order to identify molecular signatures of sensitivity 
and resistance to PF-02341066 and Binimetinib treatment in the a) RASMT CRC 
and b) RASWT/c-METmut/amplified CRC and c) RASWT/c-MET over-expressed 
CRCgroups, a biopsy from a representative metastasis (minimal 2 cores: one for 
FFPE and one for fresh frozen (FF) material) will be obtained prior to treatment. 
An H&E section will be obtained from each formalin-fixed paraffin embedded 
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(FFPE) core to histologically confirm CRC metastasis. Total c-MET expression 
levels will be determined by IHC on section of FFPE core. Computerised image 
analysis as well as conventional scoring will be carried out on the IHC samples. 
RAS mutational analysis will be determined on primary tumour.  In addition, we 
will also use a commercially available platform from MTP (Multiplicom) to detect 
mutations in RAS, BRAF, NRAS, PTEN, EGFR, PI3KCA, ERBB2, PIK3R1, MET 
and MEK. Exome sequencing and miRNA profiling will be performed to identify 
molecular signatures of response and resistance to combined MEKi/METi 
treatment. A whole blood sample for germline DNA and ctDNA analyses will be 
obtained prior to treatment. Patients who demonstrate a response to PF-
02341066 and Binimetinib (as determined by RECIST 1.1), but then develop 
secondary resistance, will undergo a second biopsy (2 cores for fresh frozen and 
1 core for FFPE material) from a metastasis. Additional plasma samples for 
ctDNA analyses will be collected every 4 weeks during the course of treatment, 
and after patients acquire resistance to therapy.  We will use next generation 
sequencing (NGS) to detect and monitor specific genetic markers present in 
ctDNA that have been identified in the mandatory baseline biopsies that are 
scheduled upon enrolment in the trial. 
 
Histopathology: 
Dose Escalation Phase: patients will have histologically or cytologically  
confirmed solid tumour 
Dose Expansion Phase: patients will have histologically confirmed colorectal 
cancer. An H&E section will be obtained from each formalin-fixed paraffin 
embedded (FFPE) core to histologically confirm CRC metastasis.c-MET 
expression levels (Ventana, 790-4430) will be measured in CRC metastases and 
primary tumour.  
No. of Study Site(s) 
5 for dose escalation cohorts, increasing to 8 -10 in total for the expansion 
cohorts. 
End of study 
Last patient last visit (LPLV) 
Early closure of 
recruitment 
Recruitment to the trial closed on 23Oct2018 with 82 patients recruited 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 TMG with the support of the FP7 
consortium members and trial sponsor, the University of Oxford. 
Publication policy 
The results of this study will be published in a peer-reviewed scientific journal 
and presented in academic research meetings as outlined in the grant agreement 
of the EU commission. 
 
 
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SUMMARY SCHEDULE OF EVENTS 
Note:  The Schedule of Events table for the Dose Escalation phase using PF-02341066 with PD-0325901 is located in Appendix 9 
Dose Escalation Phase - Schedule of Events for PF-02341066 and Binimetinib 
 
a To include neurological examination. 
Visit Description 
Screenin
g 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
onwards 
End of  
Treatment p 
Post end of 
treatment  
 
Follow 
Up 
Visit No 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
17 
19 
20 
Repeat 
cycle 3 
and 4 
 
 
Day 
-28 to 1 
 
D1 
D2 
D8 
D15 
D16 
D21 
D22 
D1 
 
D8 
D15 
D21 
D1 
 
D8 
D15 
D21 
D1 
 
D8 
D15 
D21 
 
D 28-30 after 
last dose 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics & History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medication 
X 
X 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECOG 
X 
X 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical examination a 
X 
X 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Tumour Assessment b 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Vital signs  c  
X 
X 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Height & Weight d 
X 
X 
 
X 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
Ophthalmic Exam  e 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
Haem & Clin Chem Bloods f 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
Urinalysis 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
Pregnancy test  g 
X 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
12 lead ECG 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
Echocardiography/MUGA -h 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumour marker  i 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
PK 24 hours profile j 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK trough k 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
PD PBMC/plasma l 
 
X 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE review 
 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Binimetinib administration  
 
Continuous administration or Days 1-21 every 28 days 
 
PF-02341066 administration  
 
 
Continuous administration 
 
 
 
Survival data (PFS and OS) 
 
 
 
X 
X 
Biomarker studies 
 
 
 
 
Archival tumour sample 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sample germline DNA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD skin biopsy m 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD tumour biopsy n  
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma soluble biomarkers o 
 
X 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
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b CT includes chest, abdomen and pelvis. Measurements using modified RECIST 1.1. At screening and after 2nd, 4th, 6th cycle, and every 2 cycles thereafter until intolerable toxicity or progressive disease. 
c To include pulse and systolic/diastolic blood pressure, body temperature. Blood pressure is to be measured after resting for 5 minutes in a sitting position. 
d Height measured only at screening. 
e Ophthalmic exam at baseline, and Day 21of cycles 2, 4, 6 and 9 and every third cycle (12 weekly) after this and also as clinically indicated. Time window for examination allowable +/- 2 days 
f To include FBC with differential and platelets, Na, K, Ca, phosphate, urea, creatinine, total protein, albumin, bilirubin, alk phos, AST and /or ALT, LDH, coagulation screen,  APTT, PT, CK, Troponin,  
(validity period of blood samples is 3 days). 
g  Serum pregnancy test to be performed at screening and urine pregnancy test required every 3-4 weeks for women of child-bearing potential 
 Echo or MUGA at baseline and at Day 21 of cycles 1, 3, 5, 8 and every third cycle (12 weeks) afterwards and also repeated as clinically indicated. For non-UK territories: if ECHO cannot be performed, a 
MUGA scan may be performed in compliance with local policy, applicable national legislation and relevant approvals. Cardiac ejection fraction must be determined as measured by echocardiogram (ECHO) 
in the UK. 
i For patients with relevant tumour types, tumour marker (CEA, CA-125, PSA or CA19-9 as relevant) will be checked during screening and after 2nd, 4th, 6th cycle, and every 2 cycles thereafter 
 j Serum PK measurements will be taken as specified in the protocol (section 7.3). 
k PK trough sample pre-dose (morning) and 2 hours post dose Day 21 of cycles 2, 4, 6, 8, 10 and 12. 
l PD PBMC/Plasma samples  will be taken as specified in the protocol (section 7.4) 
m At screening and Day 15 +/- 7 days. 
n At screening and Day 15 +/- 7 days. Optional biopsy if separate consent obtained. 
 o At each sampling point 4ml of plasma is obtained. 
p Disease progression, intolerance or withdrawal. 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Dose Expansion Phase - Schedule of Events for PF-02341066 and Binimetinib 
 
 
Visit Description 
Pre-
Screen 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
onwards 
End of 
Treatment r 
Post end 
of 
treatment  
Follow 
up 
Visit No 
0 
1 
2 
 
3 
4 
 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
Repeat 
cycle 3 
and 4 
 
Day 
 
-28 to -1 
D1 
 
D8 
D15 
 
D21 
D22 
D1 
D8 
D15 
D21 
D1 
D8 
D15 
D21 
D1 
D8 
D15 
D21 
 
D 28-30 
post dose 
 
Informed Consent 
X a 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics & History 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medication 
 
X 
X 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECOG 
 
X 
X 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical examination b 
 
X 
X 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Tumour Assessment c 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Vital signs  d  
 
X 
X 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Height & Weight e 
 
X 
X 
 
X 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
Ophthalmic Exam   f 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
Haem & Clin Chem Bloods g 
 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
Urinalysis 
 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
Pregnancy test  h 
 
X 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
12 lead ECG 
 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
Echocardiography/MUGA i 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumour marker j 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
PK 24 hours profile k 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK trough l 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE review 
 
 
X 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Binimetinib  administration   
 
X 
Continuous administration or Days 1-21 every 28 days 
 
PF-02341066 administration 
 
 
X 
Continuous administration 
 
 
 
Survival data (PFS and OS)  
 
 
 
 
X m 
Biomarker studies 
 
 
 
 
 
Archival tumour sample 
X a 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumour (CRC Mets)sample 
X a 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sample germline DNA 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD skin biopsy n 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD tumour biopsy o 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X s 
 
Plasma soluble biomarkers  p 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
Plasma sample for ctDNA q 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
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a Pre-trial screening for c-MET and RAS status  
 
b To include neurological examination.  
c CT includes chest, abdomen and pelvis. Measurements using modified RECIST 1.1. At screening and after 2nd, 4th, 6th cycle, and every 2 cycles thereafter until intolerable toxicity or progressive disease 
d to include pulse and systolic/diastolic blood pressure and body temperature (Blood pressure to be measured after resting for 5 minutes in a sitting position.)  
e Height to measured only at screening. 
f Ophthalmic exam at baseline, and at Day 21 cycles 2, 4, 6 and 9 and every third cycle (12 weekly) after this and also as clinically indicated.  This has an allowed time window of +/- 2 days 
g To include FBC with differential and platelets, Na, K, Ca, phosphate, urea, creatinine, total protein, albumin, bilirubin, alk phos, AST and /or ALT, LDH, coagulation screen, APTT, PT, CK, Troponin (validity 
period of bloods is 3 days). 
h Serum pregnancy test at screening and serum or urine pregnancy testing required every 3-4 weeks for women of child-bearing potential. 
i Echo/MUGA at baseline and at Day 21of cycles, 1, 3, 5, 8 and every third cycle (12 weeks) afterwards and also repeated as clinically indicated. For non-UK territories: if ECHO cannot be performed, a 
MUGA scan may be performed in compliance with local policy, applicable national legislation and relevant approvals. Cardiac ejection fraction must be determined as measured by echocardiogram (ECHO) 
in the UK. 
j Tumour markers (CEA, CA-125, PSA or CA19-9 as relevant) will be checked during screening and after 2nd, 4th, 6th cycle, and every 2 cycles thereafter 
k Serum PK measurements will be taken as specified in the protocol (section 7.3) 
l PK trough sample pre-dose (morning) and 2 hours post dose  day 21 of cycles 2, 4, 6, 8, 10 and 12  
m Survival status to be updated every 3 months post end of trial until death notification 
n At screening and Day 15 +/- 7 days for initial cohort of 10 patients only 
o At screening and Day 15 +/- 7 days. Also optional biopsy of metastases at disease progression 
p At each sampling point 4ml of plasma obtained. 
q Blood samples for the detection of ctDNA will be obtained every 4 weeks until disease progression. 
r Disease progression, intolerance or withdrawal. 
s Optional. Within 28 days following radiological confirmation of disease progression 
 
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ABBREVIATIONS 
AE 
 
Adverse Event 
ADL 
 
Activities of Daily Living 
ADR 
 
Adverse Drug Reaction 
ALT 
 
Alanine Transaminase 
ANC 
 
Absolute Neutrophil Count 
AST 
 
Aspartate Transaminase 
AUC 
 
Area Under the Curve 
BAL 
 
Bronchoalveolar Lavage 
 
BD 
 
Bi Daily 
BHSCT  
Belfast Health and Social Care Trust 
BNP 
 
B-type Natriuretic Peptide 
BRAT  
Mnemonic for bananas, rice, apple and toast 
CCRCB 
Centre for Cancer Research and Cell Biology 
CEA 
 
Carcinoembryonic Antigen 
CHF 
 
Congestive Heart Failure 
CI 
 
Chief Investigator 
CK 
 
Creatinine Kinase 
CML 
 
Chronic Myeloid Leukaemia 
CNS 
 
Central Nervous System 
CR 
 
Complete Response 
CRC 
 
Colorectal cancer 
CRF 
 
Case Report Form 
CSR 
 
Central Serous Retinopathy 
CT 
 
Computerized Tomography 
ctDNA  
Circulating tumour DNA 
CTA 
 
Clinical Trials Authorisation 
CTA 
 
Clinical Trial Agreement 
CTCAE  
Common Toxicity Criteria Adverse Events 
CTIMP  
Clinical Trial of an Investigational Medicinal Product 
DLT 
 
Dose Limiting Toxicity 
DNA 
 
Deoxyribonucleic Acid 
DSMC  
Data & Safety Monitoring Committee 
DSUR  
Development Safety Update Report 
ECG 
 
Electrocardiogram 
eCRF  
Electronic Case Report Form 
ELISA  
Enzyme-Linked ImmunoSorbant Assay 
EMA 
 
European Medicines Agency 
EGFR  
Epidermal growth factor receptor 
EP 
 
Early Progression 
ERK 
 
Extracellular-Signal-Regulated Kinases 
EU 
 
European Union 
FBC 
 
Full Blood Count 
FDA 
 
Federal Drug Administration 
FDG-PET 
Fluorodeoxyglucose Positron Emission Tomography 
FFPE  
Formulin-fixed Paraffin Embedded 
GAPs  
GTPase Activating Proteins 
GCP 
 
Good Clinical Practice 
GEPs  
Guanine Nucleotide Releasing Factors 
GI 
 
Gastro-Intestinal 
GMP 
 
Good Manufacturing Practices 
Hb 
 
Haemoglobin 
HCG 
 
Human Chorionic Gonadotrophin 
HDPE  
High-density PolyEthylene 
HGF 
 
Hepatocyte growth factor 
HGFR  
Hepatocyte growth factor receptor 
HIV 
 
Human Immunodeficiency Virus 
HTA 
 
Human Tissue Act 
IB 
 
Investigator Brochure 
IC50 
 
50% Inhibitory Concentration 
 
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IEPTOC 
Independent Early Phase Trial Oversight Committee 
IHC 
 
Immunohistochemistry 
ILD 
 
Interstitial Lung Disease 
IMP 
 
Investigational Medicinal Product 
IMPD 
 
Investigational Medicinal Product Dossier 
iV 
 
Intravenous 
RAS 
 
Rat Sarcoma 
KPS 
 
Karnofsky Performance Score 
LVEF 
 
Left-Ventricular-Ejection-Fraction 
LDH 
 
Lactate Dehydrogenase 
LPLV 
 
Last Patient Last Visit 
mCRC  
Metastatic Colorectal Cancer 
MEK 
 
Mitogen Activated Protein Kinase 
MHRA  
Medicines and Healthcare products Regulatory Agency 
MoABs  
Monoclonal Antibodies 
MRI 
 
Magnetic Resonance Imaging 
MTD 
 
Maximum Tolerated Dose 
MU 
 
Mazaryk University 
MUGA  
Multigated Acquisition 
NCI 
 
National Cancer Institute 
 
NE 
 
Not Evaluable 
NGS 
 
Next Generation Sequencing 
NHS 
 
National Health Service 
NIMP 
 
Non-Investigational Medicinal Product 
NSCLC  
Non-Small cell Lung Cancer 
OCTO   
Oncology Clinical Trials Office 
OCTRU 
Oxford Clinical Trials Research Unit 
OD 
 
Once Daily 
ORB 
 
Oxford Radcliffe Biobank 
OS 
 
Overall survival 
PD 
 
Pharmacodynamic or Progressive Disease 
PDUM  
Paris Descartes Universite Medecine 
PFS 
 
Progression Free Survival 
PI 
 
Principal Investigator 
PK 
 
Pharmacokinetic 
PBMC  
Peripheral blood mononuclear cells 
PO 
 
Per Os 
PR 
 
Partial Response 
QP 
 
Qualified Person 
QT 
 
QT interval 
QTc 
 
Corrected QT interval 
QUB 
 
Queen’s University Belfast 
REC 
 
Research Ethics Committee 
RECIST 
Response Evaluation Criteria In Solid Tumours 
RPII 
 
Recommended phase II dose 
RR 
 
Response Rate 
RVO 
 
Retinal Vein Occlusion 
SAE 
 
Serious Adverse Event 
SD 
 
Stable Disease 
SOP 
 
Standard Operating Procedure 
SmPC  
Summary of Product Characteristics 
SUSAR  
Suspected Unexpected Serious Adverse Reaction  
Tdp 
 
Torsades De Pointes 
TPN 
 
Total Parenteral Nutrition 
TSC 
 
Trial Steering Committee 
ULN 
 
Upper Limit of Normal 
UNITO  
Italian Università degli Studi di Torino 
USS 
 
Ultrasound Scan 
UZA 
 
Universitair Ziekenhuis Antwerpen 
VHIO 
 
Vall Hebron Institute of Oncology 
WBC 
 
White Blood Count 
 
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1 
INTRODUCTION 
1.1 
Background  
Disease background 
Colorectal cancer (CRC) is a significant health issue for men and women worldwide, with > 1 million cases 
and over 680,700 deaths each year (Malvezzi et al., 2011). In the European Union (2008), 334,092 new 
patients (151,478 women / 182,614 men) were diagnosed with CRC and 149,159 patients (68,999 
women/80,160 men) died of the disease http://globocan.iarc.fr) (Jemal et al., 2010). Approximately 450,000 
new cases of CRC will be diagnosed within Europe and 143,460 in the US in 2012 (Siegel et al., 2013). In 
addition, with an estimated 232,000 deaths in 2012 (Europe) and approximately 51,690 deaths (US), CRC 
remains the second most common cause of cancer death within the Western world (Siegel et al., 2013). The 
incidence increases significantly with age, with >80% of cases occurring in the 60 years or older population. 
Given the ageing population in Europe, CRC’s already considerable health and societal burden is expected 
to increase significantly. Metastatic colorectal cancer (mCRC) is a malignancy with a dismal overall survival 
(OS) rate. Due to its asymptomatic nature, CRC is frequently diagnosed only after cancer has spread to the 
lymph nodes (stage III) and/or distant organs (stage IV), eg liver, lung, peritoneum. 
 
Treatment background 
Standard chemotherapy for advanced CRC include combination of 5-Fluorouracil (5-FU) with Irinotecan 
(FOLFIRI) or Oxaliplatin (FOLFOX). Resistance to chemotherapy, either intrinsic or acquired, ultimately 
results in treatment failure for the majority of CRC patients. Approximately 50% of CRC patients eventually 
develop metastases (stage IV disease, mCRC) and receive systemic chemotherapy, with 5-year OS rates 
lower than 5%. For chemotherapy-naive mCRC patients, response rates (RR) are ∼40%-50% (FOLFOX, 
FOLFIRI) while median OS are ∼16-19 months (de Gramont et al., 2000; Douillard et al., 2000). When 
FOLFIRI/FOLFOX is given as 2nd line treatment, RR is 10-15%, progression-free survival (PFS) is 4 months 
and OS is 10-11 months respectively (Guglielmi and Sobrero, 2007).   
Recently, the treatment paradigm for mCRC has evolved to include targeted therapeutics. The Epidermal 
growth factor receptor (EGFR) signalling pathway is of key importance for the survival of CRC and other 
cancer cells (Laurent-Puig et al., 2012; Peeters et al., 2010; Van Schaeybroeck et al., 2005). These findings 
have led to the development of therapeutic monoclonal antibodies (MoAbs) (eg. chimeric MoAb cetuximab 
and fully human MoAb panitumumab), that inhibit ligand binding to the EGFR and subsequently EGFR 
activation and downstream signalling. Cetuximab and panitumumab have significantly improved PFS and OS 
when combined with FOLFIRI in patients with chemo-naive metastatic stage IV CRC patients (Berlin et al., 
2007; Van Cutsem et al., 2011).  Historically, “one-size-fits-all” approaches have been standard practice in 
CRC treatment, but with the increased understanding of the molecular/genetic heterogeneity of CRC, it is 
clear that novel treatments must be developed and tested in selected subgroups to maximize the benefit of 
these new developments. 
 
RAS as a predictive biomarker in CRC 
The RAS guanosine triphosphate (GTP)-ases act as critical “on-off” switches in cellular growth and survival 
(Ramjaun and Downward, 2007). RAS is activated by several receptor tyrosine kinases (RTKs), and is 
regulated by guanine nucleotide releasing factors (GEFs) and GTPase-activating proteins (GAPs). Active 
GTP-bound RAS interacts with a range of effectors to activate multiple downstream pathways, most notably 
the RAF/MEK/ERK and PI-3 kinase pathways. The RAS sub-family consists of three proto-oncogenes: c-
Harvey (H)-ras, c-Kirsten (K)-ras, and c-Neuroblastoma (N)-ras (Reuther and Der, 2000). RAS functions 
downstream of EGFR and is a critical mediator of EGFR induced signalling. RAS genes become oncogenic 
by single point mutations, which alter the guanine nucleotide binding region, rendering RAS unresponsive to 
GAPs and resulting in constitutive RAS activation, aberrant downstream signalling, increased proliferation 
and survival.  
 
The presence of activating RAS/NRAS mutations abolishes the ability of anti-EGFR drugs to inhibit cell 
survival signalling in cancer cells. RAS is mutated in 40%-45% of CRC (RASMT), and RAS mutations are 
associated with poorer survival in CRC (Richman et al., 2009). Several phase III studies, led by members of 
MErCuRIC, have shown that patients harbouring activating RAS and NRAS mutations (found in 4%-5% of 
CRC) do not benefit from anti-EGFR therapies (Maughan et al., 2011; Peeters et al., 2012; Peeters et al., 
2010). These therapies represent a personalized medicine approach in CRC, as patients are stratified 
according to their RAS mutational status. The European Medicines Agency (EMA), the US Food and Drug 
Administration (FDA) and the American Society for Clinical Oncology (ASCO) now recommend that all 
mCRC patients who are candidates for anti-EGFR therapy should be tested for RAS mutations and, if a 
mutation is detected, they should not receive anti-EGFR therapies (Allegra et al., 2009).  
 
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The need for new therapeutic approaches in mCRC 
Studies have also suggested that activating mutations in BRAF, NRAS and PIK3CA, loss of PTEN and 
expression of EGFR ligands epiregulin and amphiregulin, likewise correlated with resistance to anti-EGFR 
targeted therapies (Khambata-Ford et al., 2007; Perrone et al., 2009). Since its approval, cetuximab has 
become a €855 million p.a. drug, and > 50% of CRC patients are currently treated with anti-EGFR MoAb 
therapies (http://www. Firstwordpharma.com/node/1017862). Nevertheless, between 50%-60% of RAS Wild 
Type (RASWT) or indeed quadruple WT patients (i.e. KRAS, NRAS, BRAF, PI3KCA WT with high levels of 
epiregulin and amphiregulin and no loss of PTEN) will not benefit from the addition of an EGFR MoAb to 
standard chemotherapy (De Roock et al., 2010). Hence, novel treatment strategies are urgently needed for 
RASMT patients and >50% of RASWT CRC patients, especially in second line where responses to standard 
chemotherapy are relatively low. 
RASMT mCRC patients have few therapeutic options post-chemotherapy failure. Inhibitors of farnesyl 
protein transferase (resulting in impaired RAS membrane localization and activity) as single agents failed to 
show significant activity in unselected patient groups in CRC and NSCLC (Adjei et al., 2003; Rao et al., 
2004). Chemical library screens using isogenic RASWT and MT cell lines have identified compounds 
exhibiting greater lethality in tumour cells harbouring mutations in RAS (Guo et al., 2008; Ji et al., 2009). 
Translation of these studies into the clinical setting has been impeded by the difficulty in identifying the 
protein target for these compounds, a prerequisite for further drug development. More recently, genome wide 
shRNA screens have unravelled novel biology associated with oncogenic RAS, but these studies have yet to 
be translated into the clinic (Barbie et al., 2009; Luo et al., 2009).  
 
MErCuRIC is a pan-European collaboration to use a personalised medicine clinical trial strategy to target two 
key proteins, MEK and MET, which are deregulated in both RAS WT and RAS MT mCRC. The trial 
hypothesis is that inhibition of both MEK and MET in combination (MEKi)/METi), will improve PFS and 
ultimately OS in the stratified mCRC cohort. The comprehensive scientific dissection of disease biology will 
not only provide new insights on efficacy, but will also underpin development of new diagnostic and 
predictive tools to combat mCRC. The clinical trial has unique characteristics of (i) employing a novel 
treatment strategy targeting the biology of the disease; (ii) using next generation sequencing (NGS), miRNA 
and companion diagnostics strategies to identify/stage CRC patient subgroups who will maximally benefit 
from this novel treatment strategy and (iii) deploying (a) non-invasive detection tools (b) relevant preclinical 
models to underpin novel stratified solutions for patients with acquired drug-resistance. 
1.2 
Investigational Medicinal Products used in the study 
The Investigational Medicinal Products (IMPs) in this trial are PF-02341066, PD-0325901 and Binimetinib.  
PF-02341066 (Crizotinib); Pfizer) has a Marketing Authorisation in the EU for the indication of previously 
treated ALK+ NSCLC 
(http://www.medicines.org.uk/EMC/medicine/27168/SPC/Xalkori+200mg+and+250mg+hard+capsule/) but is 
not authorised for use in colorectal cancer. PD-0325901 is a new chemical agent developed by Pfizer and is 
provided in capsule form.  Binimetinib is a new chemical agent developed by Array Biopharma and is 
provided in tablet form. 
 
PF-02341066 (Crizotinib) 
PF-02341066 (Crizotinib) is a selective ATP-competitive small-molecule oral inhibitor of the anaplastic 
lymphoma kinase (ALK), c-Met/hepatocyte growth factor receptor (HGFR), Recepteur d’Origine Nantais 
(RON), and ROS receptor tyrosine kinases (RTKs) and their oncogenic variants (e.g., c-Met/HGFR 
mutations and ALK or ROS fusion proteins). PF-02341066 demonstrated a mean Ki value of 0.5 nM for 
inhibition of recombinant human ALK and a mean Ki value of 0.62 nM for inhibition of recombinant human c-
Met/HGFR. PF-02341066 also demonstrated a mean Ki value of 9.1 nM for inhibition of the RON RTK which 
was approximately 20-fold higher than the Ki for inhibition of ALK.  
 
PF-02341066 inhibited cell proliferation (EC50 = 54 nM) and induced apoptosis (EC50 = 110 nM) at 
concentrations comparable to those required to inhibit EML4- ALK phosphorylation (EC50 = 63 nM) in 
NCIH3122 lung adenocarcinoma cells expressing EML4-ALK variant 1. PF-02341066 also inhibited 
proliferation of Karpas 299 or SU-DHL-1 ALCL cells that express an NPM-ALK fusion protein due to a t(2;5) 
chromosomal translocation. Growth inhibition by PF-02341066 in these NPM-ALK positive lymphoma cells 
was associated with G0/G1 cell cycle arrest and induction of apoptosis. PF-02341066 has also been found 
to inhibit potently HGF (ligand for cMET)-stimulated human NCI-H441 lung carcinoma cell migration and 
invasion through a matrigel matrix (IC50 values of 11 nM and 6.1 nM, respectively), and HGF-stimulated 
MDCK cell motility/scattering (IC50 = 16 nM). PF-02341066 inhibited cell proliferation (EC50 = 59 nM) at 
concentrations comparable to those required to inhibit ROS phosphorylation (EC50 = 44 nM) in HCC78 lung 
 
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adenocarcinoma cells expressing the SLC34A-ROS fusion variant. In vivo PF-02341066 inhibited xenograft 
growth in a variety of models while inhibiting ALK or cMET activity.   
 
PF-02341066 has a long t1/2 (42 hrs), takes 15 days to reach steady-state and has stable exposure 
unaffected by body weight, gender, age, and race. PF-02341066 is excreted by the faecal route and is both 
a CYP3A substrate and inhibitor. The extent and duration of inhibition of c-MET is directly linked to its 
antitumor efficacy - near complete inhibition (>90%) of c-MET activity during the entire treatment period is 
necessary to achieve robust antitumor effects. PK/PD analyses established the target efficacious free 
plasma concentration range of 8.1 to 12.8 nM (40 – 62 ng/mL in human plasma) for c-MET (and 
approximately 2-fold greater for ALK inhibition). Vision disorders are seen in >50% (98% mild) of patients, so 
there is a need for baseline ophthalmic assessment which is repeated if patients become symptomatic. 
Expected toxicities (usually mild) include nausea, vomiting, diarrhoea, constipation, peripheral oedema, 
fatigue and rashes and oesophageal-related disorders, and significant myelosuppression is rare. Responses 
have been seen in c-MET aberrant tumours. 
 
In a phase I study in patients with ALK-positive non-small-cell lung cancer, dose-limiting fatigue in the cohort 
receiving 300mg BD led to the establishment of a regimen of 250mg BD as the MTD (Camidge et al., 2012; 
Kwak et al., 2010). As a single agent for ALK+ve NSCLC, PF-02341066 is licensed for use at 250mg BD. If 
this is not tolerated, the suggested dose reductions are 200mg BD, then 250mg once daily (OD), then to 
permanently discontinue. Available capsule sizes are 200mg and 250mg, with no current availability for the 
previous 150mg formulation. Doses of 200 mg or more once daily resulted in a mean plasma trough 
concentration of more than 60 ng per milliliter, the pre-clinically predicted effective concentration to inhibit c-
MET (J Clin Oncol 27:15s, 2009 (suppl; abstr 3509). Hence, 250mg OD will be the lowest concentration tested in 
combination with PD-0325901. Inhibition of c-MET activity is critical, so the dose of PF-02341066 will be 
increased initially in cohort 2. Doses that will be explored for PF-02341066 to be used in combination with 
PD-0325901 are 250mg OD and 200mg BD. The highest dose to be evaluated is 200mg BD in combination 
with PD-0325901 8mg BD. If this is the Maximum Tolerated Dose we have put the provision to check the 
lower PF-02341066 dose (250mg OD) with the higher dose of PD-0325901 (8mg BD see below). We will not 
explore a higher dose of PF-02341066 (eg. 250mg BD) in combination with MEK inhibitor PD-0325901 for 
the following reasons (1) the PF-02341066 target trough dose needed to inhibit our target (c-MET) is 
approximately 50% of that needed to inhibit ALK, (2) a consistent increase in toxicity is seen, albeit at 
acceptable frequency and severity, with escalation of the monotherapy PF-02341066 dose level from 200mg 
BD to 250mg BD, and (3) our experience and that of others over the last few years has been that combining 
oral targeted agents in oncology clinical trials  has been rarely achievable with both compounds at full 
monotherapy doses, with lower dosing needed of one or both and/or a change to alternative schedules with 
less frequent dosing. Within the restrictions of available capsule size and known single dose tolerability, our 
current design explores the full range of possible doses. PF-02341066 in combination with PD-0325901 will 
be administrated in this phase I dose escalation and dose expansion until disease progression, intolerance 
or withdrawal. 
 
PF-02341066 is approved in the United States for the treatment of patients with locally advanced or 
metastatic NSCLC that is ALK-positive as detected by an FDA-approved test. PF-02341066 is also approved 
in the Republic of Korea for the treatment of patients with ALK-positive locally advanced or metastatic 
NSCLC. PF-02341066 has been authorised in the European Union under an EMA ‘conditional approval’ 
scheme, which means that further evidence on this medicinal product is awaited, and is indicated for the 
treatment of adults with previously treated ALK-positive NSCLC. 
 
Randomized phase 3 studies of single-agent PF-02341066 vs. standard chemotherapy are ongoing in the 
first- and second-line ALK-positive advanced NSCLC treatment settings. Other indications under study with 
single-agent PF-02341066 treatment include but are not limited to MET-amplified NSCLC, ROS-positive 
NSCLC, ALK-positive anaplastic large cell lymphoma, ALK-positive inflammatory myofibroblastic tumor, and 
ALK-positive neuroblastoma. Clinical trials of PF-02341066 in combination with EGFR TKI in advanced 
NSCLC patients are ongoing. PF-02341066 is also under investigation in advanced cancer patients with 
various degrees of hepatic impairment, subjects with severe renal impairment, and pediatric cancer patients. 
 
 
 
PD-0325901 
PD-0325901 is a highly specific non-ATP-competitive inhibitor of MEK1 and MEK2. The Kiapp of PD-0325901 
for an activated form of MEK1, MEK1-S218D/S222D, was 1.1±0.2 nM, while the Kiapp of PD-0325901 for an 
activated form of MEK2, MEK2-S222D/S226D was 0.79±0.2 nM. Specificity of PD-0325901 was also 
 
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evaluated against a panel of 27 kinases. This panel, which was comprised of tyrosine kinases as well as a 
multitude of serine/threonine kinases, was completely refractory to inhibition by PD-0325901 at a 
concentration of 10 µM. Therefore, PD-0325901 appears to be exquisitely specific for MEK1/2. 
 
In vitro studies have shown that PD-0325901 inhibits phosphorylation of ERK of colon 26 (murine), HCT-116 
colon (human), and MDCK (dog) cells with IC50 values of 0.34, 0.28, and 0.31 nM, respectively. In vivo, PD-
0325901 has been found to inhibit potently phosphorylation of ERK in 2 human tumour xenograft models 
(HT-29 colon, and MiaPaCa2 pancreatic). Oral administration of 25 mg/kg PD-0325901 resulted in 79% and 
93% inhibition of pERK expression 24 hours after dosing, as measured in excised HT-29 and MiaPaCa2 
tumours, respectively. 
 
Four studies evaluating the safety, efficacy, and/or PK of PD-0325901 have been undertaken. Study 
A4581001 was a phase 1/2 study in cancer patients, with 79 patients dosed (66 in Phase 1 (LoRusso et al., 
2010) and 13 in Phase 2). The phase I component evaluated the toleration of alternate treatment regimens 
[eg, intermittent (3 wk on treatment/1 wk off), continuous (daily (OD), and continuous with breaks (5 d on/2 d 
off treatment). 5 days on/2 days off dosing). Doses ≥2 mg BD, the dose level at which the plasma 
concentration of PD-0325901 exceeded the target inhibition based on xenograft mouse models (16.5-53.5 
ng/mL), consistently caused >60% suppression of pERK in melanoma samples from patients. The most 
frequently reported treatment-related AEs on all treatment schedules were rash, diarrhoea, fatigue, nausea, 
and visual disturbances/eye disorders, a toxicity profile consistent with those observed for other MEK 
inhibitors. The maximum tolerated dose (MTD), based on first cycle dose-limiting toxicities, was 15 mg BD 
continuously. However, 10 and 15 mg BD continuous dosing and 10 mg BD 5 days on/2 days off schedules 
were associated with delayed development of RVO; thus, further enrolment to this trial was stopped. 
Intermittent dose scheduling between 2 and 10 mg BD should be explored to identify a recommended dose 
with long-term PD-0325901 use. 
 
Study A4581002 was a phase 2 study in patients having advanced non small cell lung cancer (NSCLC) (N = 
34) (Haura et al., 2010). PD-0325901 was initially administrated orally 15mg BD on an intermittent schedule 
(3 wk on/1 wk off; schedule A). This schedule was not well tolerated. Consequently the same dose 15mg BD 
was administrated with additional weekends “off treatment” (i.e. 5 d on/2d off for 3 wk, followed by 1 wk off, 
schedule B). The introduction of treatment breaks was thought more likely to improve patient safety. 
Treatment related toxicities included diarrhoea, fatigue, rash, vomiting and nausea. There was a substantial 
decrease in the incidence of visual disturbances with schedule B, neurologic events were similar between 
the 2 schedules. Visual disturbances include blurred vision, halo vision, photopsia and diplopia. There were 
no objective responses. Conclusion was that further studies should focus on PD-0325901, rational 
combination strategies and enrichment of patient selection based on the mode of action.  
 
Study B1271002, is an ongoing phase 1, open label, triple-arm, multi-centre, dose escalation study of two 
dual PI3K/mTOR inhibitors, PF-04691502 and PF-05212384, each in combination with irinotecan or PD-
0325901 in patients with advanced cancer. In this study PD-0325901 has been explored in combination with 
PF-04691502 in RAS or RAF mutated tumours (N = 7). In addition, a formal food effect study (A4581004) in 
healthy subjects (N = 23) evaluated the effect of food on plasma pharmacokinetics of PD-0325901. Doses 
have been administered on an intermittent (i.e., 3 weeks on/1 week off) or continuous daily dosing schedule. 
Study B1271002 is a Phase 1b study that explores two PI3K/mTOR inhibitors (PF-04691502 and PF-
05212384) in combination with either PD-0325901 or irinotecan in patients with advanced cancer. This is the 
first clinical trial exploring PD-0325901 in combination, in this case with the oral PI3K/mTOR inhibitor, PF-
04691502. However because PF-05212384 when combined with irinotecan showed a better safety profile 
and higher antitumor activity than the combination of PF-04691502 and irinotecan, the arm assessing the 
combination of PD-0325901 with PF-04691502 will be closed and a new arm combining PD-0325901 with 
PF-05212384 will be explored. Once identified the recommended phase 2 dose (RP2D) of the combination 
an expansion cohort will be conducted in up to 20 patients with advanced, RAS mutated, colorectal cancer. 
 
As of 20 June 2012, six patients were diagnosed with significant findings on eye examinations. These 
included 3 cases of retinal vein occlusion, 2 cases of optic neuropathy, 1 case of optic atrophy and 1 case of 
iridocyclitis and retinal detachment. The case of retinal detachment was reported in study B1271002. 
In humans, the plasma pharmacokinetics of PD-0325901 was characterized by rapid absorption, with peak 
concentrations occurring within 1 to 2 hours of dosing, generally dose proportional changes in exposures, 
and an average elimination half-life of 8.6 hours (range 5 to 18 hours across dosing cohorts). Food appeared 
to reduce PD-0325901 peak plasma concentrations, but the effect on AUC was variable. The plasma half-life 
of the carboxylic acid metabolite PD-0315209 was longer than that for the parent. 
 
 
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Dose of PD‐0325901 at 4mg inhibits pERK1/2 for >12 hours in xenograft mouse models. We will start with 
the suggested dose from the xenograft model of 4mg BD and then define a cohort taking 8mg BD. Dose 
levels of 8mg BD or lower (continuous and intermittent) are safe and did not result in any CNS toxicity or 
retinal vein occlusion/thrombosis. We therefore have no desire to exceed 8mg BD on safety grounds and as 
this is a dose that will inhibit the target of MEK1 and MEK2. 
 
Based on in vitro studies, PD-0325901 and its circulating metabolite, PD-0315209, have a low potential to 
inhibit CYP2D6, CYP3A4, CYP1A2, and CYP2C19. However, the metabolite (PD-0315209) has the potential 
to inhibit CYP2C8 and CYP2C9. Caution should be exercised when co-administering PD-0325901 with 
drugs that are substrates for CYP2C8 or CYP2C9. Patients taking concomitant phenytoin and/or warfarin 
should be monitored on a regular basis.  
 
During the dose escalation phase of this trial studying the combination of PF-02341066 and PD-0325901, a 
decision was made by Pfizer that they would not pursue clinical development of PD-0325901 whilst 
continuing to be fully supportive of the underlying rationale for this trial. Pfizer retained their commitment to 
use of PF-02341066 as a cMET inhibitor in all components of the clinical trial. It was agreed that we would 
proceed to completion of the dose escalation phase of the trial using the combination of PF-02341066 and 
PD-0325901, but that the investigators should explore the use of an alternate MEK inhibitor in combination 
with PF-02341066.An abbreviated dose escalation combination trial was considered suitable for the PF-
02341066 and Binimetinib combination as Binimetinib is further on its research development than the MEKi 
PD-0325901, thus providing good evidence for the choice of dosage level to be studied in this trial. The new 
combination of PF-02341066 and Binimetinib will then be used for the dose expansion phase of this trial. 
The MEK inhibitor Binimetinib has proceeded through phase I-III clinical trials as both monotherapy (in phase 
III trials in low-grade serous ovarian cancer, BRAF-mutant melanoma and NRAS-mutant melanoma, with the 
latter indication likely to proceed to registration filing in 2016) and in combination with various cytotoxics and 
other novel agents in phase I and II trials and was agreed as the preferred combinatorial partner with PF-
02341066for this trial. Array BioPharma have agreed to provide Binimetinib for use in the MErCuRIC trial in 
combination with PF-02341066. 
 
Binimetinib 
Binimetinib (also known as MEK162 or ARRY-438162) is an orally bioavailable, selective and potent 
mitogen-activated protein (MAP) kinase kinase (MEK) 1 and MEK 2 inhibitor. Binimetinib is currently being 
investigated as a single agent and in combination with a variety of additional compounds including paclitaxel, 
and inhibitors of PI3K, RAF, EGFR, PKC, CDK4/6 and IGF-1R in patients with selected advanced or 
metastatic solid tumors, including, among other tumors, melanoma, biliary, colorectal, and ovarian cancers. 
The clinical development program of binimetinib encompasses patients with selected advanced or metastatic 
solid tumors, including NRAS- and BRAF-mutant melanoma, BRAF- and KRAS- mutant NSCLC, high-grade 
platinum-resistant ovarian cancer, low-grade serous ovarian cancer, biliary, colorectal, and pancreatic 
cancers. 
 
Binimetinib is an ATP-uncompetitive inhibitor of MEK1/2. In cell-free systems, binimetinib inhibits MEK1/2 
with an IC50 of 12 nM. In vitro, binimetinib potently inhibits MEK- dependent phosphorylation of ERK in 
human BRAF-mutant melanoma cell lines as well as NRAS-mutant melanoma lines. In vivo, Binimetinib 
treatment results in dose- and time-dependent inhibition of phosphorylation of ERK in the HT-29 human 
colorectal carcinoma xenograft.  Similarly, levels of both pERK and DUSP6 mRNA (a target gene of 
phosphorylated ERK) are reduced in the A375 melanoma xenograft. Lastly, in ex vivo experiments, 
Binimetinib reduces pERK levels in human whole blood cells. In vitro, Binimetinib potently inhibits the 
proliferation of human cancer cell lines. Binimetinib is particularly active in cells harboring activating 
mutations in the BRAF, NRAS and KRAS genes, although activity is also observed in cell lines that lack such 
mutations. Synergistic interactions with the RAF inhibitor encorafenib and PI3K inhibitors BEZ235 (pan-
PI3K/mTOR), buparlisib and BYL719 (PI3Kα) have been observed in subsets of melanoma, colorectal, 
pancreatic and lung-derived cancer cell lines. In vivo, single-agent Binimetinib inhibits the growth of tumours 
in numerous xenograft models, including  those  derived  from  colorectal,  non-small  cell  lung,  pancreatic  
and  melanoma cancers. Binimetinib is also active in primary human explant models derived from several 
cancer types including colorectal. Combining Binimetinib with a variety of standard chemotherapy agents 
such as cisplatin, gemcitabine, taxanes or 5-FU/oxaliplatin resulted in enhanced anti-tumour activity in 
numerous in vivo tumour models. Similarly, combinations of Binimetinib with a variety of targeted agents 
have shown activity in vivo in multiple tumour models. In subsets of xenograft models of CRC, NSCLC and 
pancreatic cancer, anti-tumour effects have been observed when Binimetinib was combined with a variety of 
PI3K inhibitors. 
  
 
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As of 07-January-2015, a total of 2430 healthy subjects and patients have been enrolled in Binimetinib 
studies and 1945 of whom received at least one dose of Binimetinib, and have been evaluated for safety, 
including 204 healthy subjects, 6 liver dysfunction patients, 164 patients with rheumatoid arthritis and 1571 
patients with advanced cancer. As of the data-cut off Binimetinib experience as a single agent in 705 cancer 
patients includes 6 studies: 
• 
[ARRAY-162-111]: phase I, dose-escalation study in patients with advanced solid tumours followed 
by expansion cohorts in patients with advanced or metastatic biliary cancer or KRAS- or BRAF-mutant 
metastatic colorectal cancer (CCR). 
• 
[CMEK162X2201]: phase II study in patients with locally advanced and unresectable or metastatic 
malignant cutaneous melanoma, harbouring BRAFV600 or NRAS mutations. 
• 
[CMEK162X1101]: phase I, dose escalation study in Japanese patients with advanced solid tumours 
with the expansion part in patients whose tumours harbour RAS or BRAF mutations. 
• 
[CMEK162A2301]: phase III, two-arm, randomized study in patients with advanced unresectable or 
metastatic NRAS Q61 mutation-positive melanoma. 
 • 
[ARRAY-162-311]: phase III, two-arm, randomized study in patients with recurrent or persistent low-
grade serous carcinomas of the ovary, fallopian tube or primary peritoneum. 
•           [CMEK162AUS11]: phase II study in patients with RAS/RAF/MEK activated tumours. 
 
The study [ARRAY-162-111] was a phase I, open-label, dose-escalation of oral Binimetinib in patients with 
advanced solid tumours followed by expansion cohorts in patients with advanced or metastatic biliary cancer 
or KRAS- or BRAF-mutant metastatic CRC. A total of 93 patients received at least 1 dose of Binimetinib. 
Four dose levels were evaluated: 30 mg BID, 45 mg BID, 60 mg BID and 80 mg BID. Two of 4 patients 
receiving 80 mg BID experienced dose- limiting  toxicities  (DLTs),  thus  the  80  mg  BID  dose  was  
declared  non-tolerable.  Seven patients were enrolled at 60 mg BID and no DLTs were observed, therefore, 
60 mg BID was declared the MTD. Following completion of the Dose-Escalation Phase, a total of 74 patients 
were enrolled in the Expansion Phase. The dose of 45 mg BID was determined as the recommended phase 
II dose (RP2D) mainly due to the frequency of ocular AEs in patients at the 60 mg dose level. 
 
The study [CMEK162X1101] is an ongoing, phase I, open label, dose escalation study of Binimetinib in 
Japanese patients with advanced solid tumors with an expansion part in patients whose tumours harbour 
RAS or BRAF mutations. A total of 21 patients received at least 1 dose of Bnimetinib: 6 patients received 30 
mg BID and 15 patients received 45 mg BID. Eighteen patients (as of 10-February-2014) were discontinued 
from the study and 3 patients were still ongoing. Two patients in the 45 mg BID dose level cohort (dose 
escalation part) reported 2 
DLTs, both were recurrent Grade 2 detachment of retinal pigment epithelium. Therefore, 45 mg BID was 
declared the MTD in Japanese patients. No DLT was reported in patients enrolled in the expansion part. 
 
The most frequently reported AEs suspected to be related to Binimetinib, regardless of grade and 
Binimetinib dose were dermatological events (rash, dermatitis acneiform), gastrointestinal (GI) events 
(nausea, vomiting, diarrhea), edema peripheral, fatigue and  CPK increased. The majority of these AEs were 
Grade 1 or 2 with less than 5% of cases Grade 3 or 4, with the exception of elevation of blood CPK, reported 
as 24% (44/183 patients) Grade 3 or 4 in [CMEK162X2201] and 17.2% (10/58 patients) in dose escalation 
and 16.6% (11/66 patients) in dose expansion [CMEK162X1101] studies. 
 
Binimetinib experience in combination with others agents include 866 patients in 13 studies: 
 
Five studies with RAF inhibitors Encorafenib or RAF265: 
• 
[CMEK162X2102]: phase II study of sequential, single-agent Encorafenib followed by a rational 
combination with targeted agents (including Binimetinib) after progression, to overcome resistance in adult 
patients with locally advanced or metastatic BRAFV600 melanoma. 
• 
[CMEK162X2110]: phase Ib dose finding, dose escalation study of Binimetinib in combination with 
encorafenib, in selected advanced solid tumors. 
• 
[CLGX818X2102]: phase II study of Binimetinib in combination with Encorafenib in patients with 
locally advanced or metastatic BRAFV600 mutant melanoma. 
• 
[CMEK162B2301]: phase III, randomized, 2-part study in patients with BRAFV600- mutant locally 
advanced unresectable or metastatic melanoma. 
• 
[CLGX818X2109]: phase II, open-label study of Encorafenib and Binimetinib, followed by a rational 
combination with targeted agents after progression on Encorafenib and Binimetinib, to overcome resistance 
in adult patients with locally advanced or metastatic BRAF V600 melanoma. 
 
 
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Three studies with PI3KC/AKT pathway inhibitors BEZ235 (pan-PI3K/mTOR) Buparlisib (pan-PI3K) or 
BYL719 (PI3Kα): 
• 
[CMEK162X2103], [CMEK162X2101] and [CMEK162X2109]: all three are phase Ib, dose escalation 
and expansion studies in selected advanced solid tumours. 
 
One study with PKC-selective inhibitor sotrastaurin 
• 
[CMEK162X2203]: phase Ib/II study in patients with metastatic uveal melanoma.  
 
One study with CDK4/6 inhibitor LEE011 
•    [CMEK162X2114]: phase Ib/II study, in patients with NRAS mutant melanoma. 
 
One study with IGF-1R monoclonal inhibitor Ganitumab 
• 
[CMEK162X2111]: phase Ib/II dose-escalation and expansion study in patients with selected 
advanced solid tumours. 
 
One study with EGFR inhibitor Panitumumab 
• 
[CMEK162X2116]: phase Ib/II, dose-escalation study in patients with mutant RAS or wild-type RAS 
metastatic CRC. 
 
One study with standard chemotherapy agent paclitaxel 
• 
[ARRAY-162-112] phase Ib, dose-escalation and expansion study in women with platinum-resistant 
or refractory epithelial ovarian, fallopian tube or primary peritoneal cancer. 
 
The target RP2D of Binimetinib for combination studies with targeted agents is 45 mg BID. Overall, the 
frequently reported AEs suspected to be related to Binimetinib in combination studies were found to be 
similar to those found in single-agent studies, which include GI events (diarrhea, nausea, vomiting), 
dermatological events (dermatitis acneiform, rash) CPK elevation and retinal events. The percentage of 
patients that discontinued study drug due to AEs regardless of relationship to Binimetinib ranged from 2.6% 
[CMEK162X2203] to 36% [CMEK162X2101]. A total of 52 DLTs were observed in the dose-escalation part 
of combination studies, as following: 10 DLTs in [CMEK162X2102], 6 DLTs in [CMEK162X2110], 7 DLTs in 
[CMEK162X2111], 6 DLTs in [CMEK162X2103], 13DLTs in [CMEK162X2101] and 10 DLTs in 
[CMEK162X2201] study. Of these 52 DLTs, 13 were reported in the [CMEK162X2101] study combining 
Binimetinib with the PI3K inhibitor Buparlisib. The most frequents DLTs reported were gastrointestinal 
events, followed by ocular and dermatological events. A total of 128 deaths were reported during the study 
or within 30 days of last dose of study drug in cancer patients, either in single-agent or combination studies 
(45 and 46 respectively). The most frequent cause of treatment discontinuation was disease progression and 
other events not related to study drug. Based on the experience from the 13 completed phase I studies (9 in 
healthy subjects , 3 in cancer patients, 1 in rheumatoid arthritis patients) and   1   completed   phase   II  
study  (in   rheumatoid   arthritis   patients),   Binimetinib   has demonstrated an acceptable and manageable 
safety profile with the majority of AEs Grades 1 or 2 of intensity and reversible. 
 
Currently one phase III study of Binimetinib at 45mg BID is being conducted in patients with unresectable or 
metastatic BRAFV600-mutant melanoma in combination with encorafenib [CMEK162B2301]. The exposure 
of Binimetinib when combined with Bncorafenib described by Cmax and AUC has the same ranges of values 
founded in the single agent studies. 
 
 
 
Binimetinib has demonstrated an acceptable safety profile in non-clinical toxicology and clinical studies. As 
with any new investigational drug, unexpected AEs may occur. Regarding reproductive toxicity 
(teratogenicity), there are no clinical data. However, Binimetinib must not be used in pregnant women or 
nursing women and the use of highly-effective contraception is recommended for male and female subjects 
participating in clinical trials. Patients with a history or current evidence of retinal vein occlusion (RVO) or risk 
factors for RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or 
hypercoagulability syndrome) should be excluded from studies with binimetinib. Patients with a medical 
history of deficient liver glucuronidation (Gilbert syndrome) should be excluded from the clinical studies.  
Strict attention should be given to cardiovascular comorbidities, specifically, coronary artery disease and 
hypertension. Before Binimetinib administration patients should have a baseline left ventricular ejection 
fraction (LVEF) evaluation. Investigators should follow specific recommendations for dose adjustments due 
to specific toxicities  like  dermatologic  events,  diarrhoea,  hepatic  abnormalities,  decrease  of  LVEF, 
increase in blood pressure (systolic and diastolic), retinal events and CPK elevation in blood. Supportive 
 
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therapy for the management of binimetinib associated toxicities should be based on Investigator experience; 
guidance is provided in the protocols. Patients reporting de-novo or worsening of visual symptoms should be 
referred to an ophthalmologist. Ocular coherence tomography should be used for diagnosis and monitoring 
of retinal events. Early intervention is recommended for skin toxicities (including prophylactic measures, 
topical and/or systemic treatment and referral to a specialist as necessary), and management of diarrhoea. 
 
 
1.3 
Other research interventions  
Fundamental to our approach is the evaluation of the effects of drug administration on tumour biology. This 
requires access to tumour and surrogate tissues for detailed molecular analyses. To identify molecular 
signatures of sensitivity to MEKi/METi treatment in the RASMT and RASWT/cMET+ subgroups, 2 core 
biopsies from representative metastases (one for fixation and one for fresh frozen material) will be obtained 
prior to treatment. In addition, a whole blood sample for germline DNA and ctDNA analyses will be obtained 
prior to treatment. Patients who demonstrate a response to MEKi/METi (as determined by RECIST 1.1), but 
then develop secondary resistance, will undergo a second biopsy (2 cores fresh frozen and 1 for fixation) 
from a metastasis. At the time of trial enrolment, 20 mL of whole blood will be collected from each patient for 
extraction of cell free circulating DNA.  
1.4 
Rationale for the study 
Scientific Rationale:  
We have employed a systems biology approach, comprising gene expression profiling, metacore pathway 
analysis and siRNA screening, to identify novel targets/pathways critical for the survival of KRASMT 
tumours, both basally and following MEK inhibitor treatment. We found that JAK1/2-STAT3 and the upstream 
receptor tyrosine kinase c-MET are important pro-survival signals in KRASMT CRC (Van Schaeybroeck et 
al, Cancer Cell, in revision). Further studies indicated that c-MET is acutely activated following MEK1/2 
inhibition in KRASMT CRC cells. c-MET silencing (using different siRNA sequences and/or the small 
molecule inhibitor crizotinib (PF-02341066) strongly decreased basal and MEK1/2-induced c-MET and 
JAK/STAT3 activity and resulted in potent increase in cell death when combined with the MEK1/2 inhibitor 
AZD6244 in KRASMT CRC cells. Importantly, combining PF-02341066 with the MEKi AZD6244 resulted 
in synergistic reduction in tumour growth in KRASMT xenograft models. These preclinical in vitro and in vivo 
data support the further clinical evaluation of combined MEKi/METi treatment to combat metastases in 
RASMT CRC patients (Figure 1).  
 
 
Figure 1(as above). Preclinical in vitro and in vivo data of combined treatment with MEK inhibitor 
AZD6244 and c-MET inhibitor crizotinib in KRASMT CRC models. (A) KRASMT CRC cell lines, LS174T 
and GP5D (mutations in codon 12), were co-treatment with AZD6244 and crizotinib for 24 hours and 
apoptosis (cell death) was determined by Western blotting for PARP and caspase 3 cleavage. These data 
show a synergistic increase in cell death with combined AZD6244/crizotinib treatment in both models. (B) 
Growth rate of RASMT HCT116 (upper panel) and SW620 (lower panel) xenografts in BALB/c SCID mice. 
 
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Mice were treated with vehicle, AZD6244, crizotinib or combined AZD6244/crizotinib treatment. Differences 
in growth were determined using Student’s t test and by calculating subsequent P values. ***, P < 0.001. 
These data show a synergistic reduction in tumour growth in mice treated with combination of AZD6244 and 
crizotinib. 
Clinical rationale: Evidence underpinning the scientific rationale: 
Functional dysregulation of c-MET in cancer  
Under normal conditions, c-MET activation is tightly regulated by ligand activation on the cell surface, ligand-
activated receptor internalization/degradation and paracrine ligand delivery. Despite these controls, pathway 
deregulation occurs in multiple cancers. Binding of the physiological ligand HGF induces c-MET 
autophosphorylation on the tyrosine residues Y1234 and Y1235 at the tyrosine kinase domain c-MET, which 
leads to autophosphorylation of the carboxy-terminal bidentate substrate-binding site (Tyr 1349 and Tyr 
1356) of MET (Ponzetto et al., 1994; Weidner et al., 1996). Various cytoplasmic effector proteins, including 
GAB1, GRB2, phospholipase C and SRC are directly recruited to this site and become phosphorylated on 
tyrosine residues, resulting in a diversity of cellular responses such as cell survival, cell proliferation, 
migration, invasion and epithelial-to-mesenchymal transition (Birchmeier et al., 2003; Zeng et al., 2008). A 
number of reports have shown the role of c-MET in metastatic progression (Moshitch-Moshkovitz et al., 
2006).  
 
MEK as a potential therapeutic target in mCRC 
Inhibition of MEK1/2, a downstream effectors of RAS, is an attractive treatment strategy for RASMT CRC 
(Van Schaeybroeck et al., 2011). A number of preclinical in vivo models have shown that the MEKi 
(AS703026 and AZD6244) could inhibit RASMT CRC tumour growth (Little et al., 2011; Yoon et al., 
2011). 37 A phase II study of the MEKi AZD6244 in highly pre-treated unselected mCRC patients showed 
similar efficacy compared to oral 5-FU (capecitabine). However, acute activation of pro-survival pathways 
and other resistance mechanisms such as driver oncogene amplification can cause resistance, limiting its 
success as a single agent in the clinic (Little et al., 2011).  
 
c-MET mediates resistance to anti EGFR therapies in mCRC 
c-MET is overexpressed in ∼50%-60%, amplified in ∼10% and mutated in ∼5% of CRC (Di Renzo et al., 
1995; Fumagalli et al., 2010). A number of studies have shown that activation of c-MET is an important 
resistance mechanism following treatment with EGFR inhibitors in NSCLC and head and neck cancers 
(Wheeler et al., 2008; Yano et al., 2008). Ectopic overexpression of the MET receptor or paracrine activation 
of c-MET using its ligand HGF in quadruple WT CRC cells, conferred resistance to cetuximab or 
panitumumab to a degree equivalent to that triggered by mutant RAS. Notably, the ability of WT c-MET to 
drive resistance to EGFR was abolished by concomitant treatment with the anti-cMET inhibitor, JNJ-
38877605 (Bardelli et al, Cancer Discovery, submitted). These studies highlight the role of c-MET in 
mediating primary and secondary resistance to anti-EGFR targeted therapies in CRC. A recent retrospective 
study in 73 mCRC patients, suggested that c-MET overexpression may have a role in resistance to anti-
EGFR targeted therapies in RASWT CRC (Inno et al., 2011). All these studies indicate that patients with 
RASWT tumours with aberrant c-MET (RASWT/c-MET+) expression do not respond to EGFR targeted 
therapies and may benefit from anti-c-MET targeted therapies. 
 
 
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Figure 2. The HGF-c-MET axis signalling network and targeted therapies strategies.                                
The pathway which transduces invasive growth signals from mesenchymal to epithelial cells is activated by 
HGFA. C-MET kinase activation results in auto-phosphorylation and binding of adaptor proteins, forming 
scaffolds for recruitment and activation of signalling proteins. Activation of downstream signalling results in 
increased proliferation, survival, migration and metastasis. 
 
Targeting c-MET in colorectal cancer, rationale and progress.  
The tight regulation of HGF and MET signalling that is observed in development and regeneration is lost in 
cancer at multiple levels. Functional crosstalk of c-MET with the receptor tyrosine kinases EGFR, ERBB2, 
ERBB3 or insulin-like growth factor 1 receptor has been reported in several systems and has emerged as a 
major mechanism for cancer progression and resistance to therapy (Engelman et al., 2007). Recent data, 
including studies from this consortium, indicate that c-MET overexpression correlates with poor overall 
survival and resistance to cetuximab in RASWT CRC (Inno et al., 2011). These data further suggest that                     
c-MET is an attractive target in a significant subpopulation of CRC patients. Currently, multiple agents 
targeting HGF or c-MET are in phase I-III clinical trials. These targeted therapies can be HGF-competitive 
analogs (competing for ligand for receptor binding), decoy c-MET compounds, antibodies against HGF (eg. 
Rilotumumab, Ficlatuzumab, TAK-701), antibodies against cMET (eg. MetMab or Onartuzumab, LY-
2875358) and small molecule tyrosine kinase inhibitors (eg. Crizotinib, tivantinib, foretinib) (Figure 2). With 
respect to CRC, a phase Ib/II trial in patients with RASWT CRC, found that the combination of panitumumab 
plus rilotumumab was superior in term of response rate to panitumumab alone (31% versus 21%) (Eng et al. 
J Clin.Oncol. 29 (Suppl.), abstract 3500).  
 
Patient selection for treatment with HGF-cMET axis inhibitors.  
“One-size-fits-all” approaches have been standard practice in CRC treatment, but with our increased 
understanding of the molecular/genetic heterogeneity of CRC, it is clear that novel treatments must be 
developed and tested in selected subgroups to maximize the benefit of this new knowledge. In Chronic 
Myeloid Leukaemia (CML), the anti-apoptotic BCR-ABL fusion protein provides a disease specific target for 
the tyrosine kinase inhibitor imatinib mesylate. Since its introduction in 2001, Imatinib Mesylate and second 
and third generation TKIs directed against BCR-ABL have become the gold standard therapy in CML, 
replacing allogeneic stem cell transplantation (Kantarjian et al., 2002). In Non-Small Cell Lung Cancer 
Figure 2. The HGF-c-MET axis signalling network and targeted therapies strategies.                          
The pathway which transduces invasive growth signals from mesenchymal to epithelial cells is 
activated by HGFA. C-MET kinase activation results in auto-phosphorylation and binding of adaptor 
proteins, forming scaffolds for recruitment and activation of signalling proteins. Activation of 
downstream signalling results in increased proliferation, survival, migration and metastasis. 
 
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(NSCLC), tumours harbouring an EGFR mutation are selected for gefitinib treatment, (Lynch et al., 2004) 
while recent exciting data has demonstrated that patients carrying an EML4-ALK fusion gene respond to 
small molecule TKIs such as crizotinib, again demonstrating how molecular stratification informs state-of-the-
art treatment in patients with poor prognosis disease (Camidge et al., 2012). In this regard, the c-MET-HGF 
axis represents a viable target for molecular stratification, with a number of retrospective studies indicating 
benefit from molecularly targeted agents, particularly in patients whose tumour has high expression (amd/or 
amplification) of c-MET (Okamoto et al., 2012). Investigators of the randomized phase Ib/II study of 
rilotumumab with panitumumab versus panitumumab alone found that CRC tumours that overexpressed 
MET were more likely to respond to the combination of rilotumumab and panitumumab. Other studies in 
NSCLC and gastric cancer with Moab directed against MET and rilotumumab respectively have also 
indicated that the best responses are observed in patients expressing high levels of c-MET in the tumour 
(Spigel et al. J Clin Oncol: suppl; abstract 7505).  
 
Recent pilot data from the consortium (QUB, BHSCT)1 has led to an increased understanding of aberrant 
MET in RASWT CRC patients, which can be used to better define cohorts in the MErCuRIC clinical trials. 
This data indicates: (1) there is discordance between MET expression status as defined by 
immunohistochemistry (IHC) and RNA scope, (2) the prevalence of high MET (3+) defined with combination 
of IHC and RNA scope is ∼ 1%, (3) MET amplification is not always associated with high MET measured by 
IHC or RNA scope, and (4) there is clear evidence that MET amplified patients might benefit from crizotinib 
treatment, however the data for high MET IHC or RNA scope as predictive markers for anti-cMET therapies 
is less clear. In addition, new data2 has arisen over the last year showing the role of c-MET mutations (exon 
14 skipping) as a determinant of response to anti c-MET targeted therapies in Non-Small Cell Lung 
Carcinoma (NSCLC). Thus, there remains uncertainty as to which precise molecular alterations in cMET will 
drive sensitivity: is a structural alteration in the gene by mutation or copy number amplification required, or is 
over-expression as measured at RNA or protein level an acceptable biomarker?  In this study, we will 
therefore enter patients into two parallel cMET altered cohorts defined as below. 
1.5 
Primary hypothesis of the trial 
Combined MEK/MET inhibitor treatment is well tolerated and results in superior response and progression 
free survival of patients with either  
a) RASMT CRC or  
b) RASWT CRC with amplification or mutation  c-MET gene or 
c) RASWT CRC with over-expression of c-MET on protein or mRNA 
compared to standard chemotherapy treatment.  
 
This study, which is the first component of the overall MErCuRIC programme, will evaluate safety, toxicity, 
and anti-tumour activity of the combination of PD-0325901 with PF-02341066, as well as the combination of 
Binimetinib with PF-02341066.  
 
Expansion phases will be undertaken in the three molecular cohorts to determine clinical activity measured 
by response to combined Binimetinib with PF-02341066:  
a) RASMT CRC or  
b) RASWT CRC with amplification or mutation c-MET gene or 
c) RASWT CRC with over-expression of c-MET on protein or mRNA 
 
The outputs from this trial will inform a further study to compare the effect of combined MEKi/METi treatment 
(experimental arm) with standard therapy in any of these molecular cohorts where sufficient activity to 
warrant further investigation as defined in the statistical plan is observed.  
 
As part of this clinical trial we will develop, validate and apply a comprehensive diagnostic assay for 
assessing c-MET dysregulation. This will enable us to apply “smart recruiting” protocols for selection of 
future trial participants. Based on NGS data obtained during the trial, the MErCuRIC Consortium will also 
develop a customised NGS-CRC gene assay to predict response/resistance to combination MEKi/METi.  
 
 
 
1 Bradley et al. Transcriptional upregulation of c-MET is associated with invasion and tumor budding in colorectal cancer 
Oncotarget DOI: 10.18632/oncotarget.12933 
2 Frampton et al. Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers 
clinical sensitivity to MET inhibitors. Cancer Discov. 2015 Aug;5(8):850-9 
 
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2 
TRIAL DESIGN 
2.1 Outline  
This is a phase I combination study of the MET inhibitor PF-02341066 with the MEK inhibitors PD-0325901 
or Binimetinib. There was an initial dose escalation phase using patients with advanced solid tumours 
receiving the combined study treatment of PF-02341066 with PD-0325901.  Following the discontinuation of 
PD-0325901, the study design has been updated to include a further short dose escalation phase using 
patients with advance solid tumours receiving the combined study treatment of PF-02341066 with 
Binimetinib. This will be followed by a dose expansion phase recruiting patients with RASMT and 
RASWT/cMET over-expressing metastatic CRC.  
In the initial dose escalation study using PF-02341066 with PD-0325901, 25 patients were recruited. In the 
further dose escalation study using PF-02340166 in combination with Binimetinib, 20 patients were recruited. 
In the dose expansion phase an additional 42-98 patients with biopsiable metastatic disease will be treated 
at the RPII dose to further evaluate safety, PK, PD and treatment response. In the dose expansion phase 
additional biopsy and blood samples will be obtained to define mechanisms of response/resistance to PF-
02341066/Binimetinib therapy. 
Early closure of recruitment: Recruitment to the trial closed on 23Oct2018 with a total of 82 patients 
recruited, 45 patients to the dose escalation phases and 37 patients to the dose expansion phase.  
Significant difficulties were encountered in recruiting to the RAS WT CRC patient cohorts and it was decided 
that the dose expansion phase patient recruitment target of 42-98 patients was non-feasible within the 
constraints of the EU grant supporting the trial.  The decision was made with the support of the TMG, FP7 
consortium members and trial sponsor, the University of Oxford. 
2.2 
 Treatment Schedule and duration 
2.2.1 Dose escalation phase of study using PF-02340166 in combination with PD-0325901. 
In this first dose escalation phase of the study, patients with advanced solid tumours will be recruited.  It is 
anticipated that 12-24 patients will be required for the dose escalation phase of the study, which uses a 
rolling six design. This method minimises delays in the dose escalation phase and up to six patients can be 
enrolled concurrently onto the study. Accrual to the study will only be suspended when awaiting data from six 
patients and/or a decision from the Trial Management Group. Decisions as to whether to enrol a new patient 
onto the current, next highest, or next lowest dose level will be made based on available data at the time of 
new patient enrolment. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Figure 3.  Schema for dose levels in the escalation phase using PF-02341066 in combination with PD-
0325901 
 
 
 
 
Dose levels 
Dose levels are summarised in the table below, and may include an intermediate dose level dependent on 
the emergent clinical data and dose limiting toxicities. Dose levels 2a and 3a may only be investigated if 
either dose level 2 or dose level 3 respectively is determined to be the MTD. 
 
Dose Level 
PD-0325901 
PF-02341066 
1 
2mg BD 
250mg OD 
2 
2mg BD 
200mg BD 
2a 
4mg BD 
250mg OD 
3 
4mg BD 
200mg BD 
3a 
8mg BD 
250mg OD 
4 
8mg BD 
200mg BD 
 
Dose level assignment will be based on the number of patients currently enrolled in the cohort, the number 
of dose limiting toxicities (DLTs) observed, and the number of patients at risk for developing a DLT (i.e. 
patients enrolled but who are not yet evaluable for toxicity ) . For example, when three patients are enrolled 
onto a dose cohort, if toxicity data are available for all three when the fourth patient enters and there are no 
DLTs, the dose will be escalated and the fourth patient will be enrolled to the subsequent dose level. If data 
are not yet available for one or more of the first three patients, or if one DLT has been observed, the new 
patient will be entered at the same dose level. Lastly, if two or more DLTs have been observed, the dose 
level will be de-escalated.   The process will be repeated for patients five and six. When patients are non-
evaluable for toxicity, they will be replaced with the next available patient if escalation or de-escalation rules 
have not been fulfilled at the time the next available patient enrols in the study. Once the maximum tolerated 
dose (MTD) has been exceeded the cohort at the next lowest dose level will be expanded to six patients. If 
the MTD is not defined at the highest dose level to be explored (Dose Level 4, Figure 3), then this dose level 
will be defined as the RPII dose. The definition of MTD is outlined in the protocol section 8.4.2 and will be 
discussed and agreed at regular teleconferences throughout the dose escalation phase of the study. Once 
the MTD has been defined, dosing at a higher level must not occur. 
 
 
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2.2.2 Dose escalation phase of study using PF-02341066 in combination with Binimetinib. 
In this second dose escalation phase of the study, patients with advanced solid tumours will be recruited.  It 
is now anticipated that up to 25 patients will be required for this dose escalation phase of the study to 
provide for exploring the tolerability of the combination at intermediate dose levels from those previously 
envisaged, based upon the emerging tolerability and safety profile. The rolling six design is the method that 
minimises delays in the dose escalation phase and up to six patients can be enrolled concurrently onto the 
study. Accrual to the study will only be suspended when awaiting data from six patients and/or a decision 
from the Trial Management Group. Decisions as to whether to enrol a new patient onto the current, next 
highest, or next lowest dose level will be made based on available data at the time of new patient enrolment. 
 
Figure 4.  Schema for dose levels in the escalation phase using PF-02341066 in combination with 
Binimetinib 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dose levels 
Dose levels are summarised in the table below.  PF-02341066 250mg BD is the recommended dose level 
and dose level 7 has been included in this dose escalation phase as we wish to extend dosing to that level if 
the toxicity profile permits.  Dose levels 5a and 6a may be explored if BD dosing of the combination drug 
treatment is not well tolerated. There may also be a requirement to reduce the frequency of the Binimetinib 
dosing schedule from continuous dosing throughout the study period to days 1 to 21 every 28 days 
dependent on emergent clinical data.  
 
 
Dose Level 
 
Binimetinib 
PF-02341066 
5 
30mg BD 
200mg BD 
5a 
30mg BD 
250mg OD 
6 
45mg BD 
200mg BD 
6a 
45mg BD 
250mg OD 
7 
45mg BD 
250mg BD 
 
Dose level assignment will be based on the number of patients currently enrolled in the cohort, the number 
of dose limiting toxicities (DLTs) observed, and the number of patients at risk for developing a DLT (i.e. 
patients enrolled but who are not yet evaluable for toxicity ) . For example, when three patients are enrolled 
onto a dose cohort, if toxicity data are available for all three when the fourth patient enters and there are no 
DLTs, the dose will be escalated and the fourth patient will be enrolled to the subsequent dose level. If data 
are not yet available for one or more of the first three patients, or if one DLT has been observed, the new 
patient will be entered at the same dose level. Lastly, if two or more DLTs have been observed, the dose 
level will be de-escalated.   The process will be repeated for patients five and six. When patients are non-
evaluable for toxicity, they will be replaced with the next available patient if escalation or de-escalation rules 
 
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Note:  Simon staging is further explained in the protocol 
sample size sec 15.1 
have not been fulfilled at the time the next available patient enrols in the study. Once the maximum tolerated 
dose (MTD) has been exceeded the cohort at the next lowest dose level will be expanded to six patients. If 
the MTD is not defined at the highest dose level to be explored (Dose Level 7,), then this dose level will be 
defined as the RPII dose. The definition of MTD is outlined in the protocol section 8.4.2 and will be discussed 
and agreed at regular teleconferences throughout the dose escalation phase of the study. Once the MTD 
has been defined, dosing at a higher level must not occur. 
 
2.2.3 Dose expansion phase of study 
Once the RPII dose has been identified, up to 40 patients with biopsiable RASMT CRC or up to 29 with 
biopsiable RASWT CRC with amplification or mutation in the MET gene or 29 patients with biopsiable 
RASWT CRC with over-expression of c-MET protein or mRNA 
will be enrolled in the dose expansion phase to further evaluate the safety, PK, PD and treatment response.  
 
Figure 5: Schema for dose expansion phase 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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All patients in the RASWT group will receive full c-MET testing prior to recruitment to detect: (a) 
overexpression at protein level (IHC), (b) overexpression at mRNA level (RNAscope), (c) MET amplification, 
and (d) MET mutation. This would allow us to assess the potential correlation between MET amplification or 
mutation and MET protein/mRNA overexpression, and, importantly, to assess initial benefit from this 
treatment in each of two different molecular groups independently: Cohort  (b) RASWT CRC with 
amplification or mutation in the-MET gene or Cohort c) RASWT CRC with over-expression of c-MET on 
protein or mRNA) 
2.3 
Projected Number of Subjects 
 
The study will be conducted in 4-5 EU centres for the dose escalation phase, increasing to 8-10 for the dose 
expansion phase. It was anticipated that 12-24 patients would be required for the initial dose escalation 
phase of the study.  25 patients were actually recruited for this initial dose escalation phase using PF-
02341066 in combination with PD-0325901.  In the further dose escalation study using PF-02341066 in 
combination with Binimetinib it was anticipated that up to 25 patients would be required.  20 patients were 
actually recruited as required for the the exploration of the tolerability of the combination at intermediate dose 
levels from those previously envisaged, based upon the emerging tolerability/safety profile. For the dose 
expansion phase of the study it was anticipated that 42 - 98 patients would be required, bringing the 
expected total patient number for the trial to between 92 and 148, not counting any replacements.  This 
target patient number will now not be realised for lack of feasibility of recruiting to the specific RAS WT CRC 
patient cohorts. 
2.4 
Replacement of Subjects 
In the dose escalation phase if a patient comes off treatment due to a DLT they will not be replaced. If 
however, they withdraw for reasons other than safety before completing the first treatment cycle they will 
need to be replaced. Patients withdrawing will not receive further PF-02341066 or PD‐0325901, in the initial 
dose escalation phase, nor will they receive any further PF-02341066 or Binimetinib in the further dose 
escalation phase. These patients will be followed up for progression free and overall survival unless they 
withdraw their consent to do so. If the protocol mandated skin and tumour biopsies in the dose escalation 
and expansion phases cannot be completed for whatever reason, then the patient will be replaced.  
2.5 
Post-trial care and follow-up 
Following the end of study visit, patients will receive subsequent standard active, clinical trial, supportive and 
palliative care as appropriate. All patients will be followed up for post-progression survival (PFS and OS), 
with details of further lines of treatment.   
 
 
 
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3 
OBJECTIVES AND ENDPOINTS 
 
 
Primary Objective  
(Dose Escalation) 
Endpoints or  
Outcome Measures 
To assess the safety and toxicity profile of PD-
0325901 /PF-02341066 or Binimetinib/ PF-
02341066 combinations in patients with advanced 
solid tumours using the NCI CTCAE V4.03, and 
determine the maximum tolerated dose (MTD). 
Maximal tolerated dose (MTD) of PD-0325901 or 
Binimetinib with PF-02341066 according to toxicities 
graded by NCI CTCAE V4.03 in cycle 1 of treatment. 
Primary Objective  
(Dose Expansion) 
 
To investigate the response to treatment with RPII 
dose of PF-02341066 in combination with 
Binimetinib in patients with a) RASMT CRC or b) 
RASWT/c-METmut/amplified CRC or c) 
RASWT/c-MET over-expressed CRC. 
Clinical and radiological response to Binimetinib with 
PF-02341066 as defined by stable, partially or 
completely responding disease using RECIST 
version 1.1. 
Secondary Objectives  
(Dose Escalation) 
 
To define the recommended phase II (RPII) dose 
and schedule of PD-0325901 or Binimetinib in 
combination with PF-02341066. 
Recommended phase II (RPII) dose and schedule, 
guided by safety, PK and PD data.  
To investigate the pharmacokinetics (PK) of PD-
0325901 or Binimetinib with PF-02341066 when 
administrated in combination. 
Determine plasma Cmax, Cmin, AUC, oral clearance 
and t1/2 etc for PF-02341066, PD‐0325901 (and its 
metabolite) and Binimetinib. 
To investigate pharmacodynamic (PD) biomarkers 
of PD-0325901 or Binimetinib with PF-02341066 in 
paired skin biopsies, tumour biopsies (where 
possible), in serum and PBMCs. 
ELISA for soluble c-MET and HGF in plasma; ERK 
phosphorylation (pERK) in PBMC; 
Immunohistochemistry (IHC) for pERK1/2, c-
METY1234/1235 in (mandatory) skin and (optional) 
tumour biopsies. 
To preliminarily assess the efficacy of RPII dose of 
PF-02341066 in combination with PD‐0325901 or 
Binimetinib. 
Objective response using CT scan and modified 
RECIST version 1.1 and progression free and overall 
survival. 
Secondary Objectives  
(Dose Expansion) 
 
To assess the efficacy of RPII dose of PF-
02341066 in combination with Binimetinib in 
patients with a) RASMT CRC or b) RASWT/c-
METmut/amplified CRC or c) RASWT/c-MET over-
expressed CRC. 
Progression free survival using RECIST version 1.1. 
and overall survival. 
To further investigate the safety and toxicity 
profile/tolerability of Binimetinib/ PF-02341066 
combinations. 
Adverse events according to NCI CTCAE v4.03 
across all treatment cycles. 
To investigate pharmacokinetic (PK) biomarkers of 
PF-02341066 and Binimetinib in blood. 
Determine plasma Cmax, Cmin, AUC, oral clearance 
and t1/2 etc. for PF-02341066 and Binimetinib. 
To measure pharmacodynamic (PD) effect of PF-
02341066 in combination with Binimetinib in paired 
skin biopsies, tumour biopsies (where possible), 
plasma and PBMCs. 
ELISA for soluble c-MET and HGF in plasma; 
Western blotting for pERK1/2 in skin ( 10 patients). 
Tertiary and  
Exploratory Objectives 
 
To identify molecular signatures of response and 
resistance to combined PD-0325901 /PF-02341066 
or Binimetinib/ PF-02341066 treatment.   
Whole exome sequencing and miRNA profiling on 
tumour biopsies taken prior to treatment and upon 
resistance to PF-02341066 and PD‐0325901 or 
Binimetinib treatment.   
Develop a liquid biopsy platform for routine 
assessment of therapeutic efficacy 
Gene sequencing outputs from ctDNA in serially 
collected plasma samples from mCRC patients in the 
dose expansion phase 
 
 
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4 
PATIENT SELECTION 
Written informed consent must be obtained before any study specific procedures are performed. The 
Investigator will determine patient eligibility based on the following criteria.  
 
Dose escalation: Adult patients with pathologically proven advanced solid tumours. This will include 
patients with any solid tumour for whom the drug combination is considered a reasonable treatment option in 
the opinion of the clinical investigator.  
 
Dose expansion: Adult patients with pathologically proven colorectal cancer with a) RASMT CRC or b) 
RASWT/c-METmut/amplified CRC or c) RASWT/c-MET over-expressed CRC in a metastatic lesion. This will 
include CRC patients who received prior lines of cytotoxic drug treatment or targeted therapies. 
 
Subjects must meet all the inclusion/exclusion criteria listed below. 
4.1 
Inclusion Criteria 
(Inclusion criteria for the completed initial dose escalation phase using PF-02341066/PD-0325901 is listed in 
Appendix 7.) 
 
A patient will be eligible for inclusion in this study if all of the following criteria apply. 
 
4.1.1 All patients 
• 
Age ≥ 16 years 
• 
ECOG performance status 0-1 (Appendix 1) 
• 
Adequate respiratory function on clinical assessment. 
• 
Left ventricular ejection fraction (LVEF) ≥ 50% as determined by a multigated acquisition (MUGA) 
scan or echocardiogram. 
• 
Able to give informed consent prior to any screening procedures being performed and be capable of 
complying with the protocol and its requirements. 
• 
Haematological and biochemical indices within the ranges shown below: 
o 
Haemoglobin (Hb) ≥ 9g/dl (transfusion to achieve this allowed),  
o 
Neutrophils≥ 1,500/µl,  
o 
Platelet count ≥ 100,000/µl,  
o 
AST or ALT ≤ 2.5 x ULN, patient with liver metastases ≤ 5 ULN, Alkaline phosphatase ≤ 5 x 
ULN, 
o 
Serum Bilirubin ≤ 1.5 x ULN,  
o 
Creatinine Clearance ≥ 50ml/min (Calculated by Cockcroft Gault equation, or by EDTA) 
(Appendix 2) 
• 
Able to swallow oral medication 
• 
Life expectancy of at least 3 months. 
 
4.1.2 Dose escalation phase 
• 
Patients with any advanced solid tumours  
• 
Patients for whom the combination of PF-02341066 with Binimetinib is a reasonable option. 
 
4.1.3 Dose expansion phase  
Patients will be eligible for pre-screening for MErCuRIC provided that: 
• 
They have given informed consent to screening. 
• 
They are willing to undergo a biopsy for assessment of tumour RAS mutation status and c-MET 
assessment 
 
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• 
The Investigator anticipates that they are likely to satisfy the eligibility criteria for the trial.                     
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Eligibility for the trial, in patients passing pre-screening, requires: 
• 
Histologically confirmed colorectal adenocarcinoma that is either a) RASMT (KRAS codon 12, 13, 
61,117, 146; NRAS codon 12, 13, 61, 117, 146 mutations) or b) RASWT/c-MET mutated or amplified 
or c) RASWT/c-MET over-expressed with progressive disease on or within 6 months of completion 
of adjuvant therapy or after chemotherapy/targeted therapies for metastatic disease.  
• 
Prior treatment with an EGFR targeted monoclonal antibody for patients with RASWT/c-METmutated 
or amplified CRC or RASWT/c-MET over-expressed CRC. 
• 
No evidence for a mutation in BRAF at codon600 
• 
Metastases accessible for biopsy on 2-3 occasions 
• 
At least one other measurable lesion (according to RECIST v1.1). 
• 
Unsuitable for potential curative resection.  
 
┼For non-UK territories: if ECHO cannot be performed, a MUGA scan may be performed in compliance with local 
policy, applicable national legislation and relevant approvals. Cardiac ejection fraction must be determined as 
measured by echocardiogram (ECHO) in the UK. 
4.2 
Exclusion criteria 
(Exclusion criteria for the completed initial dose escalation phase using PF-02341066/PD-0325901 is listed 
in Appendix 7.) 
 
4.2.1 All patients 
• 
Unstable ischemic heart disease, cardiac dysrhythmias, coronary/peripheral artery bypass graft or 
cerebrovascular accident within 6 months prior to starting treatment.  
• 
Uncontrolled arterial hypertension despite medical treatment. 
• 
Ongoing congestive heart failure or cardiac dysrhythmias of NCI CTCAE Grade ≥2 or uncontrolled 
atrial fibrillation.  
• 
History of extensive disseminated/bilateral or known presence of Grade 3 or 4 interstitial fibrosis or 
interstitial lung disease, including a history of pneumonitis, hypersensitivity pneumonitis, interstitial 
pneumonia, interstitial lung disease (ILD), obliterative bronchiolitis, and pulmonary fibrosis. A history 
of prior radiation pneumonitis is allowed.  
• 
Any active central nervous system (CNS) lesion (i.e., those with radiographically unstable, 
symptomatic lesions) and/or leptomeningeal metastases. However, patients treated with stereotactic 
radiotherapy or surgery are eligible if the patient remained without evidence of CNS disease 
progression ≥ 3 months. Patients must be off corticosteroid therapy for ≥ 3 week 
• 
Patients who have neuromuscular disorders that are associated with elevated CK (e.g., inflammatory 
myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy); 
• 
Patients who are planning on embarking on a new strenuous exercise regimen after first dose of 
study treatment. NB: Muscular activities, such as strenuous exercise, that can result in significant 
increases in plasma CK levels should be avoided while on Binimetinib treatment 
• 
Spinal cord compression unless treated with the patient attaining good pain control and stable or 
recovered neurologic function.  
• 
Carcinomatous meningitis or leptomeningeal disease.  
• 
History of hypoalbuminaemia, or patients with peritoneal disease or pleural disease, where there is a 
requirement for ascitic or pleural taps. 
• 
History of retinal vein occlusion, intraocular pressure > 21 mmHg or patient considered at risk of 
retinal vein thrombosis (e.g. history of hyperviscosity or hypercoagulability syndromes). 
• 
History of retinal degenerative disease. 
• 
History of Gilbert’s syndrome. 
• 
Active infections (including chronic hepatitis type B or C and HIV infection if status known), severe 
immunologic defect, compromised bone marrow function 
• 
Other severe acute or chronic medical (including severe gastro-intestinal disorders e.g. partial bowel 
obstruction, malabsorption, active inflammatory bowel disease) or psychiatric conditions or 
 
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laboratory abnormalities that the investigator considers would make the patient a poor trial 
candidate, would impart excess risk associated with study participation or drug administration or 
could interfere with protocol compliance or the interpretation of trial results. 
• 
Patients who have undergone major surgery ≤ 3 weeks prior to starting study drug or who have not 
recovered from side effects of such procedure 
• 
Use of drugs or foods that are known potent CYP3A4 inhibitors or inhibitors or are CYP3A4 
substrates with narrow therapeutic indices (see Appendix 5)  
• 
Radiotherapy (except for palliative reasons), endocrine therapy, immunotherapy or chemotherapy 
during the previous four weeks (six weeks for nitrosoureas, Mitomycin-C) and four weeks for 
investigational medicinal products before treatment. Patients with prostate cancer may continue to 
receive endocrine therapy to maintain castrate levels of androgens. 
• 
Resting ECG with QTc >480msec at 2 or more time points within a 24h period (using Fredericia 
correction). 
• 
Requirement for medication known to prolong QT interval (see Appendix 5). 
• 
History of other malignancy less than 3 years before the diagnosis of current cancer, EXCLUDING 
the following: Non-melanoma skin cancer, in situ carcinoma of the cervix treated surgically with 
curative intent, other malignant tumours that have been treated curatively and patient is deemed 
disease-free  
• 
Women with the ability to become pregnant (or already pregnant or lactating).  However, those 
female patients who have a negative serum pregnancy test before enrolment and agree to use one 
highly effective form of contraception (oral, injected or implanted hormonal contraception or intra-
uterine device) in addition to condom plus spermicide, for four weeks before entering the trial, during 
the trial and for six months afterwards are considered eligible.  
• 
Male patients with partners of child-bearing potential unless they agree to take measures not to 
father children by using one form of highly effective contraception including: oral, injected or 
implanted hormonal contraception or intra-uterine device in addition to condom plus spermicide, 
during the trial and for six months afterwards).  Men with pregnant or lactating partners should be 
advised to use barrier method contraception (condom plus spermicidal gel) during the trial and for 
six months afterwards to prevent exposure to the foetus or neonate. 
• 
Prior exposure to any of a HGF, cMET or a MEK inhibitor. 
 
4.3 
Protocol deviations and waivers to entry criteria 
Protocol adherence is a fundamental part of the conduct of a clinical study.  Changes to the approved 
protocol need prior approval unless for urgent safety reasons. 
 
Systems for prospectively approving protocol deviations, in order to effectively widen the scope of a protocol 
should not be used.  Doing so might erode the scientific and ethical value of the protocol and its 
authorisation and might have an impact on the processes put in place for the care and safety of the study 
subjects.  
 
Investigators must contact the MErCuRIC Office to obtain guidance and/or clarification as necessary if 
unsure whether the patient satisfies all the entry criteria and to clarify matters of clinical discretion.  OCTO 
will contact the chief investigator or clinical coordinators as necessary. Investigators should not request a 
protocol waiver to enter a patient who does not satisfy the selection criteria.  
 
Investigators should not deviate from the protocol for the management of enrolled subjects deliberately 
unless essential to protect the rights or safety of the individual. Examples might include the addition or 
deletion of tests, dosing, duration of treatment etc. It may be necessary to withdraw the patient from further 
study.  All waivers and deviations should be fully documented/ justified and reported to the trial office without 
delay. 
 
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4.4 
Re-screening if patient does not meet inclusion/exclusion criteria first time round 
If a patient does not meet the list of key inclusion/exclusion criteria first time round, he/she can be re-
screened, as long as dose escalation or dose expansion phase is recruiting. Patients who fail at rescreening 
are ineligible and may not be rescreened. 
4.5 
Patient registration procedure 
Patients will be recruited from those referred to oncology services at participating sites for management of 
their advanced solid cancers (escalation phase) or colorectal cancer (expansion phase). A screening log 
must be kept of all patients considered for the study including any that are subsequently excluded; the 
reason for exclusion must be recorded on this form. A copy of the screening log should be sent to the trial 
office on request, but without patient identifiers. The original must be retained on site. 
 
Before entering a patient onto the study the Principal Investigator or designee will confirm eligibility. If in any 
doubt the Chief Investigator must be consulted before entering the patient. Details of the query and outcome 
of the decision must be documented on the registration/ eligibility checklist. 
 
After completing suitability checks, Informed Consent Form for trial participation and Informed Consent Form 
for blood and tissue sample collection, the site staff will scan and email the Registration Form, where 
applicable, to confirm the patient’s eligibility.  
 
Registration of patients  
 
OCTO Registration by email to octo-MErCuRIC.ox.ac.uk 
 
The patient will then be registered. Once the Investigator / research nurse has a study number for the 
patient, they will be asked to provide the original Registration Form along with c-MET and RAS mutation 
status report and a copy of the histology report (expansion phase) to the Trials office 
5 
TRIAL ASSESSMENTS AND PROCEDURES 
5.1 Pre-trial screening consent and procedure (dose-expansion phase only) 
Written informed consent will be obtained to perform RAS mutational status on archival tumour tissue (if not 
already known) and to perform a biopsy of representative CRC metastasis for c-MET status assessment 
(using mutation, amplification and immunohistochemistry) before seeking consent for the main study. The 
Investigator will explain the principles and rationale for evaluating c-MET and RAS mutational status using 
patient information and consent form A. Patients may give consent to c-MET and RAS screening testing 
without the usual 24 hour period for consideration if they wish. This is to reduce the time required to obtain c-
MET and RAS mutational status, and to minimise delays in evaluating patients’ suitability for the protocol.  
 
Once the patient has consented to tRAS and cMET screening demographic information and medical history 
will be recorded. No further study specific investigations will be made until the RAS and cMET status is 
known.  Patients whose RAS mutational status on primary tumour is already known do not require re-testing 
of primary tumour; however, these patients still require biopsy of CRC metastasis for c-MET status. The 
Investigator must ensure that a copy of the relevant test report is obtained and held in the medical record. 
 
Patients consenting to RAS and cMET trial screening tests must be logged with the trials office in order to 
obtain a screening number before the sample is dispatched (see 7.5). The responsible analytical laboratory 
will provide the Investigator with a written report within 5 working days of receipt of a suitable sample. The 
study site will maintain a log of all patients screened for RAS and c-MET status along with details of the 
outcome and date of the test result. A copy of this log must be provided to the trial office on request.  
 
Patients will only be eligible for the main study if the RAS mutational status and cMET report confirms a RAS 
mutant or RASWT/c-MET+ status. If the result is inconclusive the patient is not eligible for the dose 
expansion phase.  Note that the responsible laboratory will assess the sample quality and perform the assay 
and any re-test in accordance with their internal standard operating procedures. Hence any inconclusive 
result is final and no further re-testing will be done for the trial. 
 
Once the patient RAS and c-MET status is confirmed to be a) RAS mutant, b) RASWT/c-MET mutated or 
amplified or c) RASWT/c-MET over-expressed status the trial entry procedures detailed below (for the dose 
expansion phase) may start.  
 
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5.2 Informed consent for main study 
Potential participants will be given a current, approved version of the patient information sheet. They will also 
receive clear verbal information about the study detailing no less than: the nature of the study; the 
implications and constraints of the protocol; the known side effects and any risks involved in taking part.  It 
will be explained that they will be free to withdraw from the study at any time, for any reason, without 
prejudice to future care, and with no obligation to give a reason for withdrawal. They will have at least 24 
hours to consider the information provided and the opportunity to question the Investigator, their GP or other 
independent parties before deciding whether to participate. 
 
The Investigator (or delegate) who obtains consent must be suitably qualified and experienced. All delegates 
working on behalf of the investigator must be authorised by the PI. The Investigator is responsible for 
ensuring that the trial consent procedures comply with current applicable GCP Regulatory and ethical 
requirements. Informed consent discussions and outcomes must be well documented in the medical record. 
The Investigator (or delegate) must be satisfied that the patient has made an informed decision before taking 
consent.  The patient and the Investigator (or delegate) must personally sign and date the current approved 
version of the informed consent form in each other’s presence. A copy of the information and signed consent 
form will be given to the participant. The original signed form will be retained in the Site File, whilst a copy is 
to be filed in the medical record. A copy of the signed and dated consent form is to be sent to the MErCuRIC 
Office, for the purpose of central monitoring.  If patients agree to donate samples to the licenced tissue bank 
a copy of the signed consent form is to be sent to the tissue bank. If local policies differ from the above, the 
site should discuss this at the stage of site activation before the trial is opened.  
 
Contraceptive/ Pregnancy counselling 
All participants must be advised on the need to use reliable methods of contraception during the study. The 
advice should include:  
(1) The acceptable methods, including: male or female sterilization, implants, injectables, combined oral 
contraceptives, some intrauterine devices (IUDs), and abstinence.  
(2) Male patients with partners of child-bearing potential unless they agree to take measures not to 
father children by using one form of highly effective contraception (oral, injected or implanted 
hormonal contraception or intra-uterine device) in addition to condom plus spermicide during the trial 
and for six months afterwards).  Men with pregnant or lactating partners should be advised to use 
barrier method contraception (condom plus spermicidal gel) during the trial and for six months 
afterwards to prevent exposure to the foetus or neonate.  A barrier method (condom with 
spermicide) should be used in addition to a highly effective form of contraception. 
(3) Males should continue to take these precautions for a minimum 6 months after the last dose of study 
drug.  
(4) Females should continue to take these precautions a minimum of 6 months after the last dose of 
study drug. 
(5) That any pregnancy (also applies to females partners of male trial subjects) occurring within six 
months of the last administration of study drug / other trial intervention will be followed up and the 
outcome of all pregnancies (spontaneous miscarriage, elective termination, normal birth or 
congenital abnormality) will be reported and followed up even if participant is discontinued from the 
study.  
5.3 Informed consent for translational sub-studies 
Patients, who agree to participate in the dose escalation part of the trial, will also be informed of the 
MErCuRIC translational studies. Subjects who agree to donate samples for the sub-study will have these 
taken during the screening period, and a biopsy of a representative metastasis taken upon developing 
resistance to either the PF-02341066/PD-0325901 or PF-02341066/Binimetinib treatment.  The translational 
component is fundamental to the dose expansion part of the trial and participation is therefore mandatory.  
 
Note: Study procedures 5.4 – 5.8 below refer to participants treated with the combination of PF-
02341066 with Binimetinib. For participants treated with PF-02341066 with PD-0325901, these study 
procedures are detailed separately in Appendix 8. 
 
 
 
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5.4 Main screening: pre-dosing evaluations 
 
The following must be performed/obtained within the 28 days before the patient receives the first 
administration of study drug.  
 
All patients  
• 
Written informed consent 
• 
Demographic details 
• 
Medical history (including prior diagnosis, prior treatment, concomitant diseases, concomitant 
medications, therapies received by patient within 28 days prior to cycle 1, day1, known 
ophthalmologic medical history). 
• 
ECOG Performance Status (PS) 
• 
Full physical examination 
• 
Clinical and radiological (CT chest/abdomen/pelvis or CT chest with MRI abdomen/pelvis) disease 
assessment  
• 
Vital signs (systolic/diastolic blood pressure, pulse, body temperature), height and weight. 
• 
Ophthalmic assessment, including visual acuity, pressure, perimetry, slit lamp examination, 
fundoscopy with digital photography, optical coherence tomography (OCT).   
• 
Safety blood laboratory examination Haematology: haemoglobin, white blood cells (WBC) with 
differential count and platelets; Clinical chemistry: sodium, potassium, calcium, phosphate, urea, 
creatinine, total protein, albumin, bilirubin, alkaline phosphatase (alk phos), AST and/or ALT and 
LDH; Coagulation screen: APTT, PT) 
• 
Blood for assessment of tumour markers (if appropriate) 
• 
Cardiac muscle/enzymes levels - CK and troponin  
• 
Urinalysis 
• 
Serum pregnancy test for women of childbearing potential. 
• 
12-lead electrocardiogram 
• 
Echocardiography or MUGA 
• 
Review of inclusion and exclusion criteria 
  
Dose escalation phase  
• 
Obtain archived tumour tissue for biomarker analysis  
• 
Draw blood sample for germline DNA  
• 
Obtain fresh skin biopsy for PD assessment 
• 
Obtain fresh tumour biopsy for PD assessment, where additional consent has been given. 
 
Dose expansion phase 
• 
Obtain archived tumour tissue for biomarker analysis 
• 
Draw blood sample for germline DNA  
• 
Obtain fresh skin biopsy for PD assessment (first 10 patients only) 
• 
Obtain fresh biopsy of metastases for biomarker assessment 
 
5.5    Evaluations during dosing 
 
Cycle 1 day 1 
All patients  
• 
ECOG PS 
• 
Record of concomitant medications 
• 
Full physical examination  
• 
Vital signs (systolic/diastolic blood pressure, pulse, body temperature) and weight. 
• 
ECG (12-lead) 
 
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• 
Blood for assessment of haematology, clinical chemistry, cardiac/muscle enzymes - CK and troponin 
status and coagulation status, 
• 
Urinalysis 
• 
Serum or urine Human Chorionic Gonadotropin (HCG) pregnancy test for women of childbearing 
potential. 
• 
Plasma samples for biomarkers; blood draws as per section 7.4. 
• 
Assessment of adverse events  
• 
Start dosing with PF-02341066 and Binimetinib. 
 
Dose expansion phase only 
• 
Obtain blood sample for ctDNA as per section 7.5. 
 
 
Cycle 1 day 8 
• 
ECOG PS 
• 
Record of concomitant medications 
• 
Full physical examination  
• 
Vital signs (systolic/diastolic blood pressure, pulse, body temperature) and weight. 
• 
Assessment of adverse events  
• 
Dosing with PF-02341066 and Binimetinib. 
 
Cycle 1 day 15  
• 
ECOG PS 
• 
Record of concomitant medications 
• 
Full physical examination  
• 
Vital signs (systolic/diastolic blood pressure, pulse, body temperature) and weight. 
• 
ECG (12-lead) 
• 
Blood for assessment of haematology, clinical chemistry, cardiac/muscle enzymes – CK and 
troponin status and coagulation status 
• 
Urinalysis 
• 
Plasma samples for biomarkers; blood draws as per section 7.4. 
• 
Assessment of adverse events  
• 
Dosing with  PF-02341066 and Binimetinib 
• 
3-6 hours post-dose fresh skin biopsy for PD assessment (for dose escalation phase and initial 
cohort of 10 patients in dose expansion phase) 
• 
3-6 hours post-dose fresh tumour biopsy for PD assessment (for patients in the dose expansion 
phase and those patients who have consented to the biopsy in the escalation phase). 
 
 
Cycle 1 day 21 
• 
ECOG PS 
• 
Record of concomitant medications 
• 
Full physical examination  
• 
Vital signs (systolic/diastolic blood pressure, pulse, body temperature) and weight. 
• 
Echocardiography or MUGA  
• 
PK sampling: blood draws as per section 7.3. 
• 
Assessment of adverse events  
• 
Dosing with PF-02341066 and Binimetinib. 
 
 
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Cycle 1 day 22 
• 
PK sampling (24 hour sample) 
• 
Dosing with PF-02341066 only and Binimetinib (if continuous dosing) 
 
Cycle 2 day 1  
All patients 
• 
ECOG PS 
• 
Record of concomitant medications 
• 
Full physical examination  
• 
Vital signs (systolic/diastolic blood pressure, pulse, body temperature) and weight. 
• 
ECG (12-lead) 
• 
Blood for assessment of haematology, clinical chemistry, cardiac/muscle enzymes – CK and 
troponin status and coagulation status 
• 
Plasma samples for biomarkers; blood draws as per section 7.4. 
• 
Serum or urine Human Chorionic Gonadotropin (HCG) pregnancy test for women of childbearing 
potential. 
• 
Urinalysis 
• 
Assessment of adverse events  
• 
Dosing with PF-02341066 and Binimetinib 
Dose expansion phase only 
• 
Blood sample for ctDNA  
 
Cycle 2 onwards, Day 8 assessments 
• 
ECOG PS 
• 
Record of concomitant medications 
• 
Full physical examination  
• 
Vital signs (systolic/diastolic blood pressure, pulse, body temperature). 
• 
Assessment of adverse events  
• 
Dosing with PF-02341066 and Binimetinib 
  
Cycle 2 onwards, Day 15 assessments 
• 
ECOG PS 
• 
Record of concomitant medications 
• 
Full physical examination  
• 
Vital signs (systolic/diastolic blood pressure, pulse, body temperature). 
• 
Assessment of adverse events  
• 
Plasma samples for biomarkers; blood draws as per section 7.4 (cycle 2 only). 
• 
Dosing with PF-02341066 and Binimetinib 
 
Cycle 2 onwards, Day 21 assessments 
• 
ECOG PS 
• 
Record of concomitant medications 
• 
Full physical examination  
• 
Vital signs (systolic/diastolic blood pressure, pulse, body temperature). 
• 
PK sampling: blood draws as per section 7.3 (trough level and 2h after morning dosing, cycles 2, 4, 
6, 8, 10 and 12). 
• 
Assessment of adverse events  
 
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• 
Ophthalmic assessment, including visual acuity, pressure, perimetry, slit lamp examination, and 
fundoscopy with digital photography 
• 
Dosing with PF-02341066 and Binimetinib 
 
Cycle 3 onwards Day 1 asessments 
All patients 
• 
ECOG PS 
• 
Record of concomitant medications 
• 
Full physical examination  
• 
Clinical and radiological (CT chest/abdomen/pelvis or CT chest with MRI abdomen/pelvis) disease 
assessment  
• 
Vital signs (systolic/diastolic blood pressure, pulse, body temperature) and weight. 
• 
ECG (12-lead) 
• 
Blood for assessment of haematology, clinical chemistry, cardiac/muscle enzymes - CK and troponin 
status and coagulation status 
• 
Serum or urine Human Chorionic Gonadotropin (HCG) pregnancy test for women of childbearing 
potential. 
• 
Blood for assessment of tumour markers (if appropriate) 
• 
Plasma samples for biomarkers; blood draws as per section 7.4. 
• 
Urinalysis 
• 
Assessment of adverse events  
• 
Dosing with PF-02341066 and Binimetinib 
Dose expansion phase 
• 
Blood sample for ctDNA  
 
Cycle 3 onwards: Day 21 assessments 
• 
Echocardiography or MUGA  
5.6   End of treatment evaluations 
All patients 
• 
ECOG PS 
• 
Record of concomitant medications 
• 
Full physical examination  
• 
Assessment of adverse events  
• 
Vital signs (systolic/diastolic blood pressure, pulse, body temperature) and weight. 
• 
ECG (12-lead) 
• 
Urinalysis  
• 
Serum or urine Human Chorionic Gonadotropin (HCG) pregnancy test for women of childbearing 
potential. 
• 
Blood for cardiac/muscle enzymes - CK and troponin status 
• 
Blood for assessment of haematology, clinical chemistry, and coagulation status 
• 
Blood for assessment of tumour markers (if appropriate) 
• 
Ophthalmic assessment, including visual acuity, pressure, perimetry, slit lamp examination, 
fundoscopy with digital photography, optical coherence tomography and fluorescin angiography 
(OCT and flourescin angiography only if required). 
• 
Tumour assessment: CT scan chest/abdomen/pelvis (or CT chest with MRI abdomen/pelvis) using 
RECIST v1.1. 
 
 
 
 
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Dose expansion phase 
• 
Blood for ctDNA  
• 
Biopsy of representative metastases for molecular profiling (optional) 
5.7 Post treatment follow-up - evaluations 
All patients 
• 
Assessment of adverse events  
• 
Record of post-trial therapy 
• 
Patients will be followed up every 3 months for survival status until death or study closure, whichever 
happens first. 
Dose expansion phase 
• 
Tumour biopsy (optional)  
5.8 Evaluations on early withdrawal 
 
If the patient is withdrawn from treatment, for any of the reasons indicated in section 6, a final off-study visit 
assessment should be performed 28 - 30 days after the last administration of PF-02341066 and Binimetinib. 
The following assessments will be done: 
• 
ECOG PS 
• 
Record of concomitant medications 
• 
Full physical examination  
• 
Assessment of adverse events  
• 
Vital signs (systolic/diastolic blood pressure, pulse, body temperature) and weight. 
• 
ECG (12-lead) 
• 
Urinalysis  
• 
Blood for cardiac/muscle enzymes - CK and troponin status  
• 
Blood for assessment of haematology, clinical chemistry, and coagulation status 
 
If the patient is withdrawn from the trial and declines attendance for a final off-study visit, then a withdrawal 
assessment should be performed, if possible on the day the decision is made to take the patient off-study or 
as soon as possible. Telephone review is permitted in these circumstances. These patients will be followed 
up for progression and overall survival.  
6.  EARLY PATIENT WITHDRAWAL 
6.1 Treatment Withdrawal 
During the course of the trial, a patient may withdraw early from treatment.  This may happen for a number of 
reasons, including: 
• 
Unacceptable toxicity, including but not limited to:  
- Life threatening grade 4 toxicity. 
- Repetition of non-life threatening grade 4 toxicity despite per protocol dose reduction. 
- Delay of a treatment cycle for more than 3 consecutive weeks beyond the due date 
• 
Objective evidence of progressive disease as determined by CT scan and/or X-ray and/or ultrasound 
and/or clinical examination 
• 
Clinical decision by the investigator that continued participation in the trial is contrary to the patient’s 
best interests 
• 
Patient decision to discontinue treatment (as opposed to participation in all aspects of the study) 
 
When a patient stops treatment early, an ‘End of Treatment’ Form should be completed, and any other 
relevant form (for example a SAE Form).  The reason for withdrawing from treatment early should be clearly 
documented in the medical records. An off-study visit assessment should be performed and the results of the 
evaluations and observations reported in the CRF.  
 
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6.2 Withdrawal of Consent  
Withdrawal of consent means that a patient has expressed a wish to withdraw from the study altogether.  
Under these circumstances, the site needs to document all relevant discussions in the patient notes and 
notify the Trials Office. Under these conditions, ongoing SAEs require follow up until resolution. 
6.3 Patient evaluability and replacement 
In the dose escalation phase, if a patient comes off treatment due to a DLT, they will not be replaced. If 
however, a patient withdraws, for reasons other than safety/toxicity, prior to the end of cycle 1, they will need 
to be replaced and will not receive any further PF-02341066/PD‐0325901 or PF-02341066/Binimetinib. All 
withdrawn patients will no longer receive the study drugs and will be followed up for progression free and 
overall survival unless they withdraw their consent. 
 
In the dose expansion phase patients who are non-evaluable for the primary end-point of response to 
treatment will be replaced. This does not include patients who progress early on treatment so as to be 
unable to undergo cross-sectional imaging, who will be classified as progressing on treatment. 
 
 
• SAMPLES FOR LABORATORY ANALYSIS 
7.1 Samples to be analysed in local laboratories 
Diagnostic Laboratories 
Samples for haematology, biochemistry and coagulation analysis will be labelled with standard patient 
identifiers and sent to the local hospital diagnostic laboratory. Results will be processed in the standard way 
and entered into the routine hospital reporting system. Samples will be stored, held, reported and 
subsequently destroyed in accordance with standard local laboratory practice. 
 
Pathology 
The routine diagnostic pathology samples taken at participating centres will also be labelled, processed and 
reported according to local hospital protocols.  With regard to the dose expansion study, an H&E section will 
be obtained from each FFPE core of each of the 2-3 tumour biopsies prior to and during treatment and also 
upon resistance (where consent provided) to confirm the presence of tumour.  
 
RAS mutational analysis –dose expansion phase 
RAS mutational analysis will be determined on primary tumour using the applicable local technique 
according to local policies. 
7.2 Samples to be sent to and analysed in a Central Laboratory 
Details of sample preparation, labelling and despatch are provided in the sample handling manual for the 
MErCuRIC1 protocol. 
 
The following samples will be sent to the CCRCB Molecular pathology lab (Prof Manuel Salto-Tellez): 
• 
Block of FFPE core from the pre-screening biopsy, during treatment and end of treatment biopsy 
(optional) to evaluate cMET expression, amplification and mutation  (only in dose expansion study) 
• 
Pharmacodynamic FF tumour and skin samples for pERK1/2 by Western blotting 
• 
Pharmacodynamic blood samples to measure soluble HGF and MET 
• 
Fresh frozen cores for DNA extraction and molecular profiling. DNA extraction will be performed by 
QUB NI-MPL and DNA send to PDUM lab for analysis of MET amplification and mutational status.  
• 
Blood samples for germ-line DNA 
 
The following blood samples will be sent according to the procedures described in the sample handling 
manual:  
• 
Pharmacokinetic studies for PF-02341066, PD-0325901 and M15, Binimetinib 
• 
Pharmacodynamics blood samples to measure soluble c-MET 
 
Blood samples for ctDNA analysis will be sent to Professor A. Bardelli’s lab (UNITO). 
 
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7.3 Pharmacokinetic assays  
PF-02341066 in combination with PD-0325901 
 
Analysis of plasma samples for the determination of PF-02341066, PD‐0325901, M15 will be carried out to 
ensure that the putative target levels to inhibit cMET and ERK1/2 signalling pathways respectively are met 
when PF-02341066 is combined with PD‐0325901. 
Blood samples for the determination of PF-02341066 and PD‐0325901, and M15 levels will be collected pre-
dose, 1, 2, 4, 6, 8, 10 and 24 hours post morning dose of PF-02341066 and PD‐0325901 on cycle 1 days -
1/1,  cycle 1 days 21/22 and cycle 1 days 28/29 (cycle 2 day 1). The levels being determined at the various 
time points are summarised in the table below: 
 
 
Pre-dose 
and, 1, 2 , 4, 
6, 8, 10 
(hours post-
morning 
dose) Cycle 
1 
Day -1 
24 hours 
(pre-
morning 
dose) 
Cycle 1 
Day 1 
Pre-dose, 1, 
2 , 4, 6, 8, 10 
(hours post-
morning 
dose) 
Cycle 1 
Day 21 
24 hours 
(pre-
morning 
dose) 
Cycle 1 
Day 22 
Pre-dose, 1, 
2 , 4, 6, 8, 10 
(hours post-
morning 
dose) 
Cycle 1 
Day 28 
24 hours  (pre-
morning dose) 
Cycle 1 Day 
29/Cycle 2 Day 1 
PF-02341066 
 
 
X 
X 
X 
X 
PD-0325901 + 
M15 
X 
X 
X 
X 
 
 
 
PK trough samples will also be collected pre-dose and 2 hours post morning dose of PF-02341066 and PD‐
0325901 on cycle 2 day 21, cycle 4 day 21, cycle 6 day 21, cycle 8 day 21, cycle 10 day 21 and cycle 12 day 
21. 
 
Blood samples will be centrifuged to generate plasma. Plasma concentrations of PF-02341066, PD‐0325901 
and M15 will be determined using validated HPLC-MS/MS assays following solid-phase extraction of the 
plasma sample.  
 
Pharmacokinetic assays for PF-02341066 in combination with Binimetinib 
 
Analysis of plasma samples for the determination of PF-02341066 and Binimetinib will be carried out to 
ensure that the putative target levels to inhibit cMET and ERK1/2 signalling pathways respectively are met 
when PF-02341066 is combined with Binimetinib. 
Blood samples for the determination of PF-02341066 and Binimetinib levels will be collected pre-dose, 1, 2, 
4, 6, 8, 10 hours post morning dose of PF-02341066 and Binimetinib on cycle 1 day 21 and immediately 
prior to dosing on the morning of day 22. Further PK profiling on Cycle 1 Day 28/29 is not required for the 
dose escalation  and dose expansion phases using PF-02341066 with Binimetinib  as the study drugs are 
being taken together. The levels being determined at the specified time points are summarised in the table 
below: 
 
  
Pre morning dose Cycle 1 day 21,  
And at  1, 2 , 4, 6, 8, 10 hours 
post morning dose on 
Cycle 1 Day 21 
24 hours (pre morning dose)  
On Cycle 1 Day 22 
PF-02341066 
               X 
             X 
Binimetinib 
               X 
             X 
 
PK trough samples will also be collected pre-dose and 2 hours post morning dose of PF-02341066  and 
Binimetinib on cycle 2 day 21, cycle 4 day 21, cycle 6 day 21, cycle 8 day 21, cycle 10 day 21 and cycle 12 
day 21. 
 
Blood samples will be centrifuged to generate plasma. Plasma concentrations of PF-02341066 and 
Binimetinib will be determined using validated HPLC-MS/MS assays following solid-phase extraction of the 
plasma sample.  
 
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7.4 Pharmacodynamic assays 
 
Pre-dose and post-dose fresh skin biopsy. Samples will be collected at site and the sections will be 
forwarded to the central laboratory where the Western Blotting technique will be used for for analysis of 
pERK1/2. These samples will be collected at screening and Cycle 1, day 15 (+/- 7 days) during the Dose 
Escalation phase and from the first 10 patients during the Dose Expansion phase. 
 
Pre-dose and post-dose fresh tumour biopsy.  
 
Samples will be fixed in formalin and paraffin embedded at site. Sections will be forwarded to QUB, where 
immunohistochemistry for pERK1/2 and pcMETY1234/1235 will be performed. These will be collected at 
screening and Cycle 1, day 15 (+/- 7 days) as mandatory for the Dose Expansion phase, but optional for the 
Dose Escalation phase. A further optional metastatic tumour biopsy will be collected at disease progression 
during the Dose Expansion phase only.  
 
Plasma sample for soluble biomarkers. c-MET ectodomain and HGF scatter factor will be analysed using 
commercially available Invitrogen ELISAs. Blood samples will be collected to assess biomarkers  pre-dose 
and 6 hours post-dose (morning dose) on days 1 and 15 of Cycle 1; pre-dose and 6 hours post-dose 
(morning dose) on day 1 and 15 of Cycle 2; pre-dose and 6 hours post-dose (morning dose) on day 1 of 
cycles 3 through to 6.  
7.5 Samples for molecular analysis and patient derived xenografts 
Fresh frozen cores from pre-dose and post-dose fresh tumour biopsies will be processed for DNA 
extraction and molecular profiling. Where sufficient material exists fresh frozen cores may also be used to 
develop xenografts. Blood samples will be processed for germ-line DNA and ctDNA. 
7.6 Summary of samples/assays to be taken during the study 
Assay/sample handling and storage will be managed according to separate written instructions. The 
following summarises the arrangements for collection, close to patient handling, timings, and analytical 
laboratories responsible.  Research assays will be performed according to separate laboratory SOPs. 
7.7 Samples for Biobanking 
Participants in this trial will be invited to permit the long term retention of samples left over after protocol-
specified analyses for use in possible other future research linked to trial data. Consent to participate in this 
aspect of the trial is optional and not a requirement of participation in the main study.  
7.8 Labelling and confidentiality of samples sent 
All samples sent to analytical laboratories will be labelled with the trial code, trial patient number, dosing 
cohort and date/time taken.  Should a laboratory receive any samples carrying unique patient identifiers the 
recipient must immediately obliterate this information and re-label the samples. The study site will be 
informed of their error. 
7.9 Clinical reporting of exploratory research assay results 
The results of the MErCuRIC trial research assays are exploratory and are not intended to influence the 
individual patient’s medical care. Findings for exploratory research assays will not be reported routinely in 
real time to the responsible clinician.  
7.10 Trial sample retention at end of study 
The Chief Investigators have overall responsibility for custodianship of the trial samples. Laboratories are 
instructed to retain any surplus samples pending instruction from the Chief Investigators on use, storage or 
destruction.  It is possible that new or alternative assays may be of future scientific interest. At the end of the 
research study any surplus samples may be retained for use in other projects that have received ethical 
approval.  Hence, any surplus study samples may be transferred to a licensed tissue bank where they will be 
managed in accordance with applicable host institution policies and the Human Tissue Act (HTA) 
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7.11 Withdrawal of consent for sample collection and/or retention 
A patient may withdraw consent to provide samples for research at any time without giving a reason. The 
Investigator must ensure that their wishes are recorded in the medical record and will inform the trials office 
accordingly. The investigator should discuss with patients the valuable use of samples that have already 
been provided and under circumstances where these samples have already been processed and 
anonymised, it would not be possible to destroy such samples. 
• INVESTIGATIONAL MEDICINAL PRODUCTS (IMPS)  
8.1  Name of IMPs 
PF-02341066 (Crizotinib) 
PD-0325901 
Binimetinib (MEK162) 
8.2  Treatment dose 
Dose escalation phase: PF-02341066 in combination with PD-0325901  
PF-02341066 (Crizotinib): 250mg orally, once a day or 200mg orally, twice a day continuously. 
PD-0325901: 2mg orally, twice a day to 8mg orally twice a day. Run-in day -7 to day -1, then days 1 to 21 
every 28 days. 
 
Dose escalation phase: PF-02341066 in combination with Binimetinib 
PF-02341066 (Crizotinib): 250mg orally once or twice a day or 200mg orally twice a day, continuously. 
Binimetinib: 30mg orally, twice a day or 45mg orally twice a day continuously or for 1 to 21 days every 28 
days. 
 
Dose expansion phase:  
PF-02341066 (Crizotinib) at recommended phase II dose continuously. 
Binimetinib at recommended phase II dose either continuously or for 1- 21 days every 28 days.. 
8.3  Duration of treatment 
Treatment will be given continuously until  
• 
Disease progression 
• 
Intercurrent illness that in the judgment of the investigator would affect patient safety, the ability to 
deliver treatment or the primary study endpoints. 
• 
In case of unacceptable toxicity 
• 
At the patient’s request.   
• 
Physician’s decision for any other reasons (which should be clearly justified or documented) 
8.4  Management of drug administration 
Dose escalation phase: PF-02341066 in combination with PD-0325901 
Patients will receive the morning dose of PF-02341066 and/or PD-0325901 without regard to meals. . 
Patients should take the capsules at approximately the same time each day. For BD evening dosing PF-
02341066 will be administered approximately 12 hours following the morning dosing. 
In case of BD administration, doses of PF-02341066 and PD-0325901 should be taken approximately 12 
hours apart. Wherever possible doses should not be missed but if a dose is missed then the next dose 
should be taken at the allotted time and the missed dose should not be made up. If the patient vomits shortly 
after taking PF-02341066 or PD-0325901, the dose should be replaced only if the vomited capsules can 
actually be seen and counted. Compliance with PF-02341066and PD-0325901 dosing will be evaluated by 
capsule count during scheduled visits to the trial site by pharmacy staff. 
 
 
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Dose escalation phase and dose expansion phase using PF-02341066 in combination with 
Binimetinib: 
Patients will receive the morning dose of PF-02341066 and Binimetinib. In case of BD administration, doses 
of PF-02341066 and Binimetinib should be taken approximately 12 hours apart and, wherever possible, at 
approximately the same time every day, without regard to meals.  Doses should not be missed, but, if a dose 
is missed, then the next dose should be taken at the allotted time and the missed dose should not be made 
up. If the patient vomits shortly after taking PF-02341066 or Binimetinib, the dose should be replaced only if 
the vomited capsules or tablets can actually be seen and counted. Compliance with PF-02340166 and 
Binimetinib dosing will be evaluated by capsule/tablet count during scheduled visits to the trial site by 
pharmacy staff. 
8.4.1  Dose limiting Toxicity (DLT) 
PF-02341066 in combination with PD-0325901 or Binimetinib 
The dose limiting toxicity (DLT) and maximum tolerated dose (MTD) are defined using the National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. DLTs identified 
during the first cycle will inform the decision to dose escalate through the increasing dose levels. 
A DLT is defined as an almost certainly or probably drug-related adverse event to PF-02341066 and/or                   
PD-0325901 or Binimetinib. 
• 
neutropenia Grade 4 for ≥5 days duration *(See note) 
• 
febrile neutropenia (without clinically or microbiologically documented infection) with an absolute 
neutrophil count  <1000/mm3 and a single temperature of >38.3˚C or a sustained temperature of  
≥38˚C for more than one hour.  
• 
infection (documented clinically or microbiologically) with Grade 3 or 4 neutropenia (ANC <1.0 x 
109/L) 
• 
thrombocytopenia Grade 4:  
a) for ≥5 days duration * (See note), or  
b) associated with active bleeding, or  
c) requiring platelet transfusion. 
• 
CK elevation ≥ Grade 3 associated with an increase in creatinine ≥ 1.5 × the patient’s Baseline 
screening creatinine. 
• 
Grade 2 pneumonitis  
• 
Total bilirubin Grade ≥ 3 
• 
AST or ALT Grade ≥ 3 in conjunction with total bilirubin Grade ≥ 2 of any duration 
• 
AST or ALT Grade 3 for > 7 consecutive days 
• 
AST or ALT Grade 4 
• 
Serum creatinine Grade ≥ 3 
• 
Grade 3 or 4 toxicity to organs other than the bone marrow but including Grade 3 and Grade 4 
biochemical AEs EXCLUDING: 
a) Grade 3 nausea in patients who have not received optimal treatment with anti-emetics 
b) Grade 3 or 4 vomiting in patients who have not received optimal treatment with anti-emetics 
c) Grade 3 or 4 diarrhoea in patients who have not received optimal treatment with anti-
diarrhoeals and Grade 2 diarrhoea for more than 7 days in patients who have received 
optimal treatment with anti-diarrhoeals. 
d) Grade 3 fatigue, unless there is an increase by at least two grades from baseline 
• AE with a fatal outcome 
* Note: In the event of a Grade 4 neutropenia or Grade 4 thrombocytopenia, a full blood count 
must be performed at least on Day 5 after the onset of the event to determine if a DLT has 
occurred.  The Investigator must continue to monitor the patient closely until resolution to 
Grade 3 or less. 
 
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Should any change be made to the grade or causality of an AE during the trial that may alter its DLT status, 
OCTO must be informed immediately as this may affect dose escalation decisions. 
 
8.4.2  Maximum Tolerated Dose (MTD) 
PF-02341066 in combination with PD-0325901 
If two out of up to six patients at the same dose level experience a DLT in the first cycle of PF-02341066 in 
combination with PD-0325901, the Maximum Tolerated Dose (MTD) will be determined as the dose level 
below this.  This dose will be determined following discussion of all the relevant toxicity data between OCTO 
and the TMG.  Once the MTD has been defined, dosing at a higher dose must not occur.  With the 
introduction of Binimetinib as the alternative MEKi to PD-0325901, the data accrued from the initial dose 
escalation phase will not now be used for determining the phase II recommended dose.   
 
PF-02341066 in combination with Binimetinib  
If two out of up to six patients at the same dose level experience a DLT in the first cycle of PF-02341066 in 
combination with Binimetinib, the Maximum Tolerated Dose (MTD) will be determined as the dose level 
below this.  This dose will be determined following discussion of all the relevant toxicity data between OCTO 
and the TMG.  Once the MTD has been defined, dosing at a higher dose must not occur.  The PF-02341066 
and Binimetinib recommended phase II dose to be used in the expansion phase and subsequent phase II/III 
evaluation will be determined based on the MTD, observed safety profile, PK and pharmacodynamic data, 
but may include drug-related toxicities experienced in sustained dosing after cycle 1 after discussion with the 
TMG. 
 
8.5  Dose modification  
a. 
PF-02341066 in combination with PD-0325901 
Every effort should be made to administer trial treatment on the planned schedule. The toxicity of each cycle 
of PF-02341066 and PD-0325901 must be recorded before the administration of the next one and graded 
according to the current version of the Common Terminology Criteria for Adverse Events (CTCAE Version 
4.03). If individual patients experience treatment related toxicity, subsequent trial treatment may be delayed, 
omitted and/or dose modified according to the worst toxicity observed during the previous cycle as described 
below. Dose reductions are permanent (no intra-patient dose re-escalation is permitted). The following 
outlines provide guidance for the management of toxicities for patients treated with PF-02341066 and/or PD-
0325901. 
If > 2/3 or > 2/6 DLTs occur during cycle 1 in the first patient cohort (ie defined as exceeding the MTD), then 
the planned schedule of PF-02341066  on continuous dosing and/or PD-0325901 on day 1 – 21 every 28 
day dosing will be discontinued.  In that case, we need to explore:  
• 
alternate intermittent schedules of both oral agents in combination, whereby a substantial 
amendment will be submitted to the MHRA prior to administering the proposed new dosing 
schedule. 
• 
use of a monoclonal antibody directed against HGF (e.g. from AVEO or AMGEN), the ligand of 
cMET or the ectodomain of c-MET (eg MetMAb from Roche/Genentech) instead of PF-02341066 
For grade 3, grade 4 or intolerable grade 2 toxicities, the treatment will be interrupted until recovery to 
<grade 2 or to base line (in the judgement of the investigator). If the patient fails to recover to this extent 
within 3 weeks, then trial treatment will be discontinued. If a patient cannot tolerate treatment after two 
successive dose reductions, trial treatment will be discontinued.  This trial investigates the use of combined 
cMET and MEK inhibition, and so complete cessation of either drug will result in the patient discontinuing all 
trial treatment.  In any of these circumstances, patients then will undergo end of treatment evaluation as per 
section 5.6 and will be followed up at the end of study visit at day 28-30 following the last treatment. Patients 
will then be monitored for progression and survival as per section 5.7. 
 
 
b. 
PF-02341066 in combination with Binimetinib 
 
Every effort should be made to administer trial treatment on the planned schedule. The toxicity of each cycle 
of PF-02341066 and Binimetinib must be recorded before the administration of the next one and graded 
according to the current version of the Common Terminology Criteria for Adverse Events (CTCAE Version 
4.03). If individual patients experience treatment related toxicity, subsequent trial treatment may be delayed, 
 
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omitted and/or dose modified according to the worst toxicity observed during the previous cycle as described 
below. Dose reductions are permanent (no intra-patient dose re-escalation is permitted). The following 
outlines provide guidance for the management of toxicities for patients treated with PF-02341066 and/or  
Binimetinib. 
If > 2/3 or > 2/6 DLTs occur during cycle 1 in the first patient cohort (i.e. defined as exceeding the MTD), 
then the planned schedule of PF-02341066 on continuous dosing and/or Binimetinib on either continuous 
dosing or day 1 – 21 every 28 day dosing, will be discontinued.  In that case, we need to explore alternate 
intermittent schedules of either or both oral agents in combination, whereby a substantial amendment will be 
submitted to the MHRA prior to administering the proposed new dosing schedule. 
For grade 3, grade 3 CPK rise associated with creatinine increase of 50% over baseline, grade 4 or 
intolerable grade 2 toxicities, the treatment will be interrupted until recovery to <grade 2 or to base line (in 
the judgement of the investigator). If the patient fails to recover to this extent within 3 weeks, then trial 
treatment will be discontinued. If a patient cannot tolerate treatment after two successive dose reductions, 
trial treatment will be discontinued.  This trial investigates the use of combined cMET and MEK inhibition, 
and so complete cessation of either drug will result in the patient discontinuing all trial treatment.  In any of 
these circumstances, patients then will undergo end of treatment evaluation as per section 5.6 and will be 
followed up at the end of study visit at day 28-30 following the last treatment. Patients will then be monitored 
for progression and survival as per section 5.7. 
 
Comprehensive information on recommended guidelines for dose modification for Binimetinib is included in 
Appendix 6 and updated in Appendix 6A. 
8.5.1  Non Haematological Toxicities: 
 
Skin toxicities: 
Maculopapular erythematous (acneiform) rash, similar to that described in patients with EGFR inhibitors, has 
been noted with MEK inhibitors (LoRusso et al., 2010). While most often of mild or moderate severity, grade 
3 rash (associated with pain, ulceration, disfiguration or desquamation) has been noted. Patients should be 
informed about the frequent related cutaneous adverse reactions associated with PD-0325901 or Binimetinib 
and the need to avoid the exposure to extreme temperatures, the use of lotions (since lotions can contain 
alcohol) and direct sunlight (or tanning beds). The employment of preventive topical treatments, such as 
bathing techniques using bath oils or mild moisturizing soaps and bathing in tepid water may help to prevent 
the appearance of cutaneous toxicity or reduce its intensity. The use of regular moisturizing creams is also 
recommended to keep an appropriate skin hydration and humidity, which is useful to reduce the symptoms in 
case of rash appearance. 
Rash, including erythematous, macular, papular, and pruritic rash, has been reported in 47 (7%) patients 
treated with single-agent PF-02341066. All of these cases were Grade 1 or 2 in severity. 
 
Grade of AE 
Maculo-
Papular rash 
Rash severity 
Management of rash 
Alterations to  IMP doses 
Grade 1 
Localised 
Minimally symptomatic 
No impact on activities of 
daily living (ADL) 
No sign of superinfection 
Initiate prophylactic 
regimen if not already 
started.  Consider using 
moderate strength topical 
steroidsa 
PD-0325901: no change 
Binimetinib: no change 
PF-02341066: no change 
Reassess after 2 weeks; if rash 
worsens or does not improve, 
proceed as for Grade 2. 
Grade 2 
Generalized  
Mild symptoms (e.g. 
pruritis, tenderness) 
Minimal impact on ADL 
No sign of superinfection 
Initiate prophylactic 
regimen if not already 
started, using moderate 
strength topical steroidsa 
PD-0325901 
or 
Binimetinib: 
Hold until < grade 1, then 
restart at the same dose level. 
PF-02341066: no change 
Reassess after 2 weeks, if rash 
worsens or does not improve, 
proceed as for Grade 3. 
Grade 3 
Generalized 
Severe symptoms (e.g., 
pruritis, tenderness) 
Significant impact on 
ADL 
Initiate prophylactic 
regimen if not already 
started, using moderate 
strength topical steroidsa 
plus methylprednisone 
PD-0325901 or Binimetinib: 
Hold until < grade 1, then 
resume with -1 dose level. 
PF-02341066: Hold until < 
grade 1, then resume with 
 
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Sign of, or potential for, 
superinfection 
dose pack. 
Consider obtaining 
dermatology consultation.  
Manage rash per 
dermatologist’s 
recommendation. 
same dose level. 
 
If rash worsens or does not 
improve in 2 weeks, 
permanently discontinue PD-
0325901/Binimetinib and PF-
02341066. 
a Hydrocortisone 2.5% cream or fluticasone proprionate 0.5% cream. 
 
The need for oral or topical antibiotics (e.g., clindamycin cream, oral minocycline or doxycycline etc) and 
higher strength topical steroids is a clinical decision of the investigator. Oral or topical retinoids are not 
recommended.   
It is strongly recommended that subjects who develop rash or other skin toxicities have a consultation with a 
dermatologist to determine appropriate management. 
• 
For pruritic lesions, the use of cool compresses and oral antihistamine agents may be helpful. 
• 
For fissuring, the use of Monsel’s solution, silver nitrate, or zinc oxide cream is advised. 
• 
For desquamation, thick emollients and mild soap are recommended. 
• 
For paronychia, antiseptic bath and local potent corticosteroids, in addition to oral antibiotics, are 
recommended.  If no improvement is seen, a dermatology or surgery consultation is recommended. 
For infected lesions, bacterial and fungal culturing followed by the appropriate culture-driving systemic or 
topical antibiotics is indicated. 
 
Fatigue: 
Fatigue has been reported as a common side effect for PD-0325901, Binimetinib and PF-02341066, with the 
majority of these cases of grade 1 or 2 in severity. 
Grade of 
event 
 Clinical presentation 
Alterations to   IMP doses 
Grade 1 
Fatigue relieved by rest 
PD-0325901: no change 
Binimetinib: no change 
PF-02341066: no change 
Grade 2 
Fatigue not relieved by rest; limiting 
instrumental ADL 
PD-0325901: no change  
Binimetinib: no change  
PF-02341066: no change 
Grade 3 
Fatigue not relieved by rest, limiting self 
care ADL 
Hold until grade 1 – resume -1 dose level PD-
0325901/Binimetinb 
Grade 4 
- 
Off protocol; STOP all study drug agents 
 
Diarrhoea: 
Diarrhoea has been reported as a common side effect for all 3 IMPs. The majority of these cases were grade 
1 or 2 in severity and can be symptomatically managed with loperamide 2mg PRN. 
Grade of 
event 
Diarrhoea Severity 
Adverse Event 
Management 
guidelines 
Alterations to  IMP doses 
Grade 1 
Uncomplicated 
diarrhoea 
 
Increase of <4 stools 
per day over baseline; 
mild increase in 
colostomy output 
compared to baseline. 
Diet: Stop all lactose-
containing products; eat 
small meals, BRAT diet 
(bananas, apples, rice, toast) 
is recommended. 
Hydration: 8 to 10 large 
glasses of clear liquids per 
day (e.g., Gatorade or broth) 
Loperamide: initially 4mg, 
followed by 2mg every 4 
hours or after every 
unformed stool, to a 
maximum of 16mg/ day. 
PD-0325901: no change 
Binimetinib: no change 
PF-02341066: no change 
Grade 2 
Uncomplicated 
diarrhoea 
 
Increase of 4-6 stools 
per day over baseline; 
moderate increase in 
colostomy output 
compared to baseline. 
PD-0325901: no change 
Binimetinib: no change 
PF-02341066: no change 
 
If diarrhoea is Grade 2 for >48 
hours, interrupt study treatment 
 
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Continue until diarrhoea-free 
for 12 hours. 
Diarrhoea > 24 hours: 
Loperamide 2mg every two 
hours to a maximum of 
16mg/ day. Consider adding 
oral antibiotics. 
Diarrhoea >48 hours:  
Loperamide 2mg every two 
hours to a maximum of 
16mg/ day. Add budesonide 
or other 2nd line therapies 
(otreotide, or tincture of 
opium) and oral antibiotics. 
until resolution to ≤ Grade 1. 
 
Restart study treatment at the 
current dose level. 
 
Grade 3 
Any 
complicated 
diarrhoea. 
 
Increase of ≥7 stools 
per day over baseline; 
incontinency; 
hospitalization 
indicated; severe 
increase in colostomy 
output compared to 
baseline; Limiting self- 
care ADL. 
Clinical evaluation is 
mandatory. 
Loperamidec: initially 4mg, 
followed by 2mg every 4 
hours or after every 
unformed stool, to a 
maximum of 16mg/ day. 
Continue until diarrhoea-free 
for 12 hours. 
Oral antibiotics and 2nd line 
therapies should be 
implemented if clinically 
indicated. 
Hydration: intravenous fluids 
should be administered if 
clinically indicated. 
Antibiotics (oral or iV) should 
be administered if clinically 
indicated. 
Interventions should be 
continued until the patient is 
diarrhoea-free for ≥ 24 hours. 
Intervention may require 
hospitalisation for patients at 
risk of life-threatening 
complications. 
Interrupt study treatment until 
diarrhoea recovers to ≤ Grade 
1. 
Restart study treatment with a 
one dose level reduction.   
If 3 dose reductions of study 
treatment are clinically 
indicated, permanently 
discontinue study treatment. 
 
Grade 4 
Life threatening 
consequences; urgent 
intervention indicated. 
Off protocol; STOP all study 
drug agents 
Other, frequent causes for diarrhoea including concomitant medications (e.g., stool softeners, laxatives, 
antacids, etc.), infections by C. difficile or other pathogens, partial bowel obstruction, etc., should be clinically 
excluded.  Guidelines regarding management and dose reduction for diarrhoea considered to be related to 
study treatment by the investigator are provided in this Table. 
 
- Uncomplicated diarrhoea is defined by the absence of symptoms such as cramping, nausea/vomiting 
≥Grade 2, decreased performance status, pyrexia, sepsis, neutropenia ≥Grade 3, frank bleeding, and/or 
dehydration requiring iV fluid substitution. 
 
- Complicated diarrhoea is defined by the presence of symptoms such as cramping, nausea/vomiting ≥Grade 
2, decreased performance status, pyrexia, sepsis, neutropenia ≥Grade 3, frank bleeding, and/or dehydration 
requiring iV fluid substitution. 
 
- Loperamide should be made available to the patient prior to the start of study treatment so that loperamide 
administration can begin at the first signs of diarrhoea. 
 
- Escalation of study treatment to the previous dose level is allowed after consultation with the trial 
coordination team in the absence of another episode of complicated or severe diarrhoea in the 4 weeks 
subsequent to dose reduction. 
 
 
 
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Nausea/vomiting:  
Nausea has been reported as a common side effect for all 3 IMPs. The majority of these cases were grade 1 
or 2 in severity and can be symptomatically managed. Standard anti-emetics such as cyclizine may be used 
for the treatment of vomiting. Taking PF-02341066 with food may reduce nausea. Prophylactic anti-emetics 
may be used. 
 
Grade of 
event  
Clinical presentation 
Alterations to  IMP doses 
Grade 1 
Nausea: Loss of appetite without 
alteration in eating habits 
Vomiting: 1-2 episodes (separated by 5 
minutes) in 24h 
PD-0325901: no change 
Binimetinib: no change PF-02341066: no 
change 
Grade 2 
Nausea: Oral intake decreased without 
significant weight loss, dehydration or 
malnutrition 
Vomiting: 3-5 episodes (separated by 5 
minutes) in 24 h 
PD-0325901: no change 
Binimetinib: no change 
PF-02341066: no change 
Grade 3 
Nausea: Inadequate oral caloric or fluid 
intake; tube feeding, TPN, or 
hospitalization indicated 
Vomiting: ≥6 episodes (separated by 5 
minutes) in 24 hrs; tube feeding, TPN or 
hospitalization indicated 
Hold until < grade 1 – resume -1 dose level  
Grade 4 
Life-threatening consequences; urgent 
intervention indicated  
Off protocol; STOP all study drug agents 
 
Visual disturbances/retinal vein occlusion (RVO): 
Grade 1-2 visual symptoms, such as blurred vision, photopsia, and halos, generally with preservation of 
acuity, have been reported for PD-0325901 and also for Binimetinib. All episodes of RVO with PD-0325901 
presented quite late, after 13, 15 and 36 weeks of therapy. A retrospective analysis of relevant visual 
episodes found predisposing factors for retinopathy (hypertension, diabetes, hypercholesterolemia, and 
glaucoma).   
Diplopia; photopsia; vision blurred; visual brightness; visual field defect; vitreous floaters; visual impairment, 
mostly grade 1 or 2 have been seen with PF-02341066 (Camidge et al., 2012).  
Baseline ophthalmologic examination including visual acuity, pressure, perimetry and slit lamp examination 
with fundoscopy and digital photography should be performed for all patients. Optical coherence tomography 
and fluorescin angiography should also be performed with PD-0325901, or if clinically indicated. If the patient 
develops new visual disturbances/symptoms suggestive of RVO, ophthalmologic investigation will be 
urgently repeated.  
 
Grade of 
event 
Eye disorder severity 
Alterations to  IMP doses 
Grade 1 
Asymptomatic 
or 
mild 
symptoms; 
clinical or diagnostic observations only; 
intervention not indicated. 
a. If the changes are clearly not due to retinal or 
retinal 
vein 
abnormalities 
or 
are 
clearly 
unrelated to study drug(s), (e.g., conjunctivitis), 
PD-0325901/Binimetinib and PF-02341066 may 
continue with close observation. 
b. If drug attribution or aetiology is unclear, 
immediately refer the patient for an ophthalmic 
exam. If an ophthalmic exam cannot be 
performed within 7 days of onset of the event, 
then interrupt PD-0325901/Binimetinib and PF-
02341066   until the exam can be performed. 
c. If a retinal abnormality is noted, interrupt  
PD-0325901/Binimetinib 
immediately 
and 
consider referral to a retinal specialist if 
available for further evaluation. 
d. If RVO is diagnosed, then report as SAE and 
permanently 
discontinue 
PD-
 
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0325901/Binimetinib. 
e. 
If 
CSR 
is 
diagnosed, 
then 
interrupt  
PD-0325901/Binimetinib 
until 
signs 
and 
symptoms 
have 
resolved. 
Resume 
PD-
0325901/Binimetinib with a 1 dose level 
reduction. 
f. If there is no evidence of RVO or CSR, then 
resume PD-0325901/Binimetinib at the same 
dose level. 
Grade 2 
Moderate, 
minimal, 
local 
or 
non-
invasive intervention indicated; limiting 
age-appropriate instrumental ADL. 
a. 
Immediately 
interrupt 
PD-
0325901/Binimetinib and                PF-
02341066 
and 
refer 
the 
patient 
to 
an 
ophthalmologist for evaluation. For all patients 
with findings consistent with RVO or CSR based 
on the ophthalmic exam, consider referral to a 
retinal 
specialist 
if 
available 
for 
further 
evaluation. 
b. If RVO is diagnosed, then report as SAE and 
permanently 
discontinue 
PD-
0325901/Binimetinib and PF-02341066 
c. 
If 
CSR 
is 
diagnosed, 
then 
interrupt  
PD-0325901/Binimetinib and until signs and 
symptoms 
have 
resolved. 
Resume 
PD-
0325901/Binimetinib with a 1 dose level 
reduction. 
d. If there is no evidence of RVO or CSR, 
interrupt 
PD-0325901/Binimetinib 
and 
PF-
02341066 until signs and symptoms have 
returned to Grade 1 or resolved. Resume PD-
0325901 or Binimetinib with a 1 dose level 
reduction, 
resume 
PF-02341066. 
 
MEK 
inhibition at the initial dose level may be 
considered if visual changes are clearly 
unrelated to PD-0325901/Binimetinib. 
Grade 3 
Severe or medically significant but not 
immediately 
sight-threatening; 
hospitalization 
or 
prolongation 
of 
existing 
hospitalization 
indicated; 
disabling; limiting self-care ADL 
Grade 4  
Sight-threatening consequences; urgent 
intervention 
indicated; 
blindness 
(20/200 or worse) in the affected eye. 
Off protocol; STOP all study drug agents; 
Repeat ophthalmic consultation 
For all visual changes, regardless of grade, a blood sample for pharmacokinetic analysis must be drawn as 
close as possible to the time of onset of the event. 
 
Neurologic toxicity: 
PD-0325901 has been associated with acute neurotoxicity (balance, gait disorders) in patients receiving 
≥15mg BD, regardless of the schedule. Nervous system disorders ( burning sensation; dizziness; dysgeusia; 
hypoesthesia; hypoaesthesia facial; neuralgia; neuropathy peripheral; paraesthesia; peripheral sensory 
neuropathy; peripheral motor neuropathy; sensory disturbance), usually grade 1 or 2 have also been seen 
with PF-02341066 (Appendix 3).  
 
Grade of event 
Neuro-sensory 
Neuro-motor 
Neuro-mood 
Neuro-cortical or 
cerebellar 
Clinical presentation 
(see also Appendix 3) 
Alterations to  IMP doses 
Grade 1 
Asymptomatic or mild symptoms; 
clinical or diagnostic observations only; 
intervention not indicated 
PD-0325901: no change 
Binimetinib: no change 
PF-02341066: no change 
Grade 2 
Moderate; minimal, local or 
Non-invasive intervention indicated; 
limiting age-appropriate instrumental 
ADL 
PD-0325901: no change 
Binimetinib: no change 
PF-02341066: no change 
 
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Grade 3 
Severe or medically significant 
but not immediately life threatening; 
hospitalization or prolongation of 
existing hospitalization indicated; 
disabling; limiting self-care ADL 
Hold until < grade 1 – resume -1 dose level  
Grade 4  
Life-threatening consequences; urgent 
intervention indicated 
Off protocol; STOP all study drug agents 
 
Transaminitis:  
Transient and mild (grade 1 or 2) elevation of ALT has been reported for  PD-0325901, Binimetinib and PF-
02341066 (Kwak et al., 2010; LoRusso et al., 2010). The following guidelines are recommended: 
 
Grade of event 
Alterations to  IMP doses 
Grade 1 
ALT, AST≤ 2.5 x N 
Bilirubin normal 
PD-0325901: no change 
Binimetinib: no change 
PF-02341066: no change 
Grade 2 
ALT, AST 2.6 - 5.0 xN 
Bilirubin <1.5 x N 
PD-0325901: no change 
Binimetinib: no change 
PF-02341066: no change 
Grade 3 
ALT, AST 5.1 - 20.0 xN 
Bilirubin   1.5 - 3.0 x N 
Withhold until toxicity is grade 1 or better, or has returned to baseline, then 
resume treatment  -1 dose level  
Grade 4  
ALT, AST > 20.0 x N 
Bilirubin    >  3.0 x N 
Off protocol; STOP all study drug  agents 
 
Pneumonitis:  
Pneumonitis and Interstitial Lung Disease (ILD) at <1% frequency has been associated with PF-02341066 
and Binimetinib. The following guidelines (in absence of disease progression, pulmonary embolism, positive 
cultures or radiation effect) are recommended: 
 
Grade of 
event 
Clinical presentation 
Alterations to  IMP doses 
Grade 1 
Asymptomatic; clinical or diagnostic 
observations only; intervention not 
indicated. 
PD-0325901: no change 
Binimetinib: no change 
PF-02341066: withhold dose until toxicity is 
grade 0, i.e. has returned to baseline, then 
resume treatment at the same dose. 
Discontinue permanently if pneumonitis recurs. 
Grade 2 
Symptomatic; medical intervention 
indicated; limiting instrumental ADL 
PD-0325901: no change 
Binimetinib:  withhold dose until improves to 
grade 0 or 1; then resume at lower dose; if not 
resolved within 3 weeks, permanently 
discontinue 
PF-02341066:  withhold dose until toxicity is 
grade 0, then resume treatment at the same 
dose. Discontinue permanently if pneumonitis 
recurs. 
Grade 3 
Severe symptoms; limiting self-care ADL; 
oxygen indicated. 
PD-0325901: no change 
PF-02341066 or Binimetinib: discontinue 
treatment and do not re-treat 
Grade 4  
Life-threatening respiratory compromise; 
urgent intervention indicated (e.g. 
tracheotomy or intubation). 
Off protocol; STOP all study drug agents 
 
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Investigators must evaluate thoroughly patients who demonstrate potential signs/symptoms of 
pneumonitis/pneumonia. If a patient has a potential diagnosis of pneumonitis or drug related lung injury the 
following evaluations/procedures should be considered to assist or exclude the diagnosis of pneumonitis 
during this period: 
• 
A sputum gram stain and culture (induced sputum if needed) bacterial, viral, fungal, protozoal, and 
mycobacteria 
• 
Blood culture should be performed in febrile patients 
• 
Thoracenthesis if pleural fluid is present (examined for same pathogens as sputum) 
• 
Bronchoscopy with bronchoalveolar lavage (BAL) if appropriate. The BAL fluid should be sent for 
culture and cytology (same pathogens as above). 
• 
Lung biopsy (e.g.open or thorascopic preferable, bronchoscopy with transbronchial biopsy) if 
appropriate. 
• 
A plasma sample for BNP (B-type Natriuretic peptide) to evaluate for evidence of CHF, 
• 
For Asian patients or any other in whom it is suspected, a blood sample for β-D-glucan to evaluate 
for the presence of protozoal pneumonia (e.g. Pneumocystis jerovicii) 
 
If clinically appropriate, high dose corticosteroid treatment should be initiated. Should the event be fatal an 
autopsy is highly recommended to confirm/exclude the diagnosis. For any case of suspected pneumonitis 
please contact the Sponsor. 
 
Left ventricular systolic dysfunctions:  
Decreases of the left-ventricular-ejection-fraction (LVEF) have been observed in subjects receiving                     
PD-0325901 and Binimetinib. LVEF changes are common and the severe, sometimes fatal, events can 
occur in patients treated with crizotinib. A review by European medicines regulators of data from clinical trials 
and reports of clinical practice has concluded that this side effect is common (i.e, occurs in between 1 in 10 
and 1 in 100 patients who take crizotinib). 
Up to 25 February 2015, about 14,700 patients worldwide have received crizotinib since licensing. Forty 
cases of cardiac failure have been reported in the post-marketing setting. In most cases cardiac failure 
occurred within 1 month of starting treatment with crizotinib, and affected patients with or without pre-existing 
heart disorders. The reports included some cases with evidence of symptoms of cardiac failure resolving on 
stopping crizotinib, and cases with evidence of symptoms reoccurring when it was reintroduced. 
 
 
 
Grade of event 
Clinical presentation 
Alterations to IMP doses 
Grade 1 
Asymptomatic absolute decrease 
of > 10% in LVEF compared to 
baseline and the LVEF is below 
the institutions’ LLN 
-Hold Binimetinib and  PF-02341066 and repeat 
LVEF within 2 weeks 
If LVEF recovers (defined as LVEF ≥ 50% or ≥ LLN 
and absolute decrease ≤ 10% compared to B/L) in 
≤ 21 days, reduce 1 dose level . Repeat 
ECHO/MUGA at 2 weeks after resuming 
Binimetinib and PF-02341066, then every 4 weeks 
for 12 weeks until resolution 
If the LVEF does not recover in ≤ 21 days, 
permanently discontinue Binimetinib and PF-
02341066. Closely monitor LVEF until resolution or 
for up to 16 weeks 
Grade 2 
Grade 3 resting 
LVEF 39-20% or 
>20% absolute 
reduction from 
baseline 
Symptomatic 
 
Permanently discontinue study treatment 
Consult with cardiologist 
Repeat ECHO/MUGA after 2, 4, 8, 12 and 16 
weeks or until resolution. 
 
Grade 4 resting 
LVEF <20% 
 
 
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Symptoms may include: dyspnoea, orthopnoea, and other signs and symptoms of pulmonary congestion and 
oedema. 
Prolonged QTc interval:  
Prolonged QTc interval has been reported as a common side effect in all 3 IMPs. 
Grade of event 
 
Alterations to  IMP doses 
Grade 1 
QTc 450-470ms 
PD-0325901: no change 
Binimetinib: no change 
PF-02341066: no change 
Grade 2 
QTc 470-500ms 
Assess electrolytes and concomitant medications. Correct any 
electrolyte or magnesium abnormalities. Continue study treatment 
at the same dose level. 
Grade 3 
QTc >500ms on at least 2 
separate ECG’s 
Interrupt both PF-02341066 and PD-0325901/Binimetinib until 
recovery to baseline. Assess electrolytes and concomitant 
medications. Correct any electrolyte or magnesium abnormalities. 
Resume treatment by reducing one dose level of either PF-
02341066/PD-0325901 or PF-02341066/Binimetinib if no other 
cause for QTc prolongation is found otherwise resume with the 
same dose level. 
Grade 4 
QTc >= 501 or >60 ms change 
from baseline and Torsade de 
pointes or polymorphic ventricular 
tachycardia or signs/symptoms of 
serious arrhythmia  
Off protocol; STOP all study drug treatment 
Based on an average QTc (Bazett’s) value of triplicate ECGs. For example, if an ECG demonstrates a 
prolonged QT interval, obtain 2 more ECGs over a brief period e.g. at least 2 minutes apart each, and then 
use the averaged QTc values of the 3 ECGs to determine if study treatments should be interrupted or 
discontinued. 
 
Bradycardia: 
For a heart rate <40 beats per minute, evaluate patient fully including an assessment of concomitant 
medications. Adjust the dosage of any medication known to be associated with bradycardia e.g. beta 
blockers. If the bradycardia is symptomatic at any time or does not improve within 7 days of adjusting the 
concomitant medications, hold PF-02341066 and Binimetinib dosing until recovery. Patient may continue 
treatment only with the agreement of both the sponsor and investigator 
 
CK Elevations: 
 
Serum CPK elevation has been observed in some patients receiving Binimetinib both as a single agent and 
also as part of a combined therapy. 
Grade of event 
Alterations to  IMP doses 
 
Grade 1 - 2 
total CK ≥ 3 × ULN 
 
Maintain dose level of Binimetinib and PF-02341066 
Measure CK, CK isoenzymes and myoglobin in blood or urine weekly for 3 
weeks and if total CK remains ≥ Grade 2, continue to assess CK, CK 
isoenzymes and myoglobin along with regularly scheduled clinical chemistry 
assessments 
Grade 3 
total CK ≥ 5 to 10 × ULN 
• If asymptomatic, maintain dose of Binimetinib and PF-02341066 but 
monitor closely 
Measure CK, CK isoenzymes and myoglobin in blood or urine weekly for 
3 weeks and if total CK remains ≥ Grade 3, continue to assess CK, CK 
isoenzymes and myoglobin along with regularly scheduled clinical chemistry 
assessments 
• 
If symptomatic (muscle pain/spasms), or asymptomatic with serum 
creatinine ≥ 1.5 x baseline creatinine, interrupt Binimetinib only until 
 
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resolved to Grade ≤ 1 and monitor closely, then: 
If resolved in ≤ 21 days, reduce 1 dose level of Binimetinib 
If not resolved in ≤ 21 days, permanently discontinue Binimetinib and PF-
02341066 
Grade 4 
total CK >10 x ULN  
• If asymptomatic  ,  hold  Binimetinib only until resolved to Grade ≤ 1 and 
monitor closely, then: 
o 
If resolved in ≤ 21 days, reduce 1 dose level of Binimetinib.  PF-
02341066 no change. 
• 
If symptomatic , or asymptomatic withserum creatinine ≥ 1.5 x 
baseline creatinine,  permanently discontinue Binimetinib and PF-
02341066 
If not resolved in  ≤ 21 days, permanently discontinue Binimetinib - Off 
protocol; STOP Binimetinib and PF-02341066 
. 
8.5.2 Haematological Toxicities:  
Haematological abnormalities have been observed with all 3 IMPs, are usually of grade 1 and 2 severity and 
occur in less than 5% of patients.  
Asymptomatic neutropaenia (ANC) 
Grade of event 
Alterations to  IMP doses 
≤1.5-≥1.0 
Continue both drugs, repeat ANC in 1 week 
<1.0 ≥0.5 
Withhold PF-02341066 and PD-0325901/Binimetinib until toxicity is ≤2, or 
has returned to baseline, then resume treatment at the same dose level.   
<0.5 
Withhold PF-02341066 and PD-0325901/Binimetinib until toxicity is ≤2, or 
has returned to baseline, then reduce dose level -1. 
 
Febrile neutropaenia/neutropenic sepsis: 
If ANC is ≤ 1.0 with a declining trend and is associated with temperature above 38.0° C on two separate 
occasions and or associated with signs or symptoms of sepsis, treatment with both drugs should be held. 
Patients should be assessed immediately and treated as in patients with intravenous antibiotics (in 
accordance with the local hospital neutropenic sepsis guidelines) and supportive treatment as deemed 
necessary. G-CSF support may be given as deemed appropriate by the physician and in keeping with 
institutional guidelines (and recorded as concomitant medication). 
Further treatment is issued after the patient has completely recovered from infection and ANC has resolved 
to ≥1.5, then reduce dose level -1. 
On subsequent events of neutropaenic sepsis, the same protocol as above is followed and the combination 
therapy is discontinued.  
Lymphopaenia: 
No dose modification of the combination therapy is necessary if other laboratory parameters are normal and 
the lymphocyte counts are ≥ 0.5 x 10 9/l (normal reference range 2.0-3.5 x 10 9/l). Consider dose reduction of 
PD-0325901/Binimetinib or PF-02341066 at physician’s discretion if lymphocyte count ≤0.5 x 10 9/l (grade 4). 
 
 
 
 
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Anaemia (Hb < 8g/dl or 80 g/l). 
Grade of event 
Alterations to  IMP doses 
≤10 g/dl > 8 g/dl, not 
symptomatic 
No change in dose. . 
≤ 8 g/dl > 6 g/dl 
Blood transfusion according to local guidelines. No change in dose. 
≤ 6g/dl > 5g/dl 
Blood transfusion according to local guidelines. Withhold till Hb > 8 g/dl. 
Dose reduction of PD-0325901 or Binimetinib. Continue PF-02341066  at 
same dose 
≤ 5g/dl 
Blood transfusion according to local guidelines. Withhold till Hb > 8 g/dl. Off 
protocol; STOP both agents. 
8.6 Compliance 
Patients will be instructed to keep a record of compliance with treatment, by means of using a “patient diary” 
that will be provided to them. 
8.7 Management of overdose 
In the event of a PF-02341066 or PD-0325901/Binimetinib overdose (defined as any dose above that 
specified in the protocol), the investigator should contact the OCTO and the Chief Investigator immediately 
and closely monitor the patient for AEs/SAEs and laboratory abnormalities. The investigator will use clinical 
judgment to treat any overdose. 
 
Information regarding the quantity of the excess dose as well as the duration of the overdosing should be 
documented in the eCRF for treatment. 
 
9 OTHER TREATMENTS (NON-IMPS) 
9.1   Supportive medication 
Local anti-emetic and anti-diarrhoeal drug policy may be followed.  
9.2  Concomitant medication and non-drug therapies 
Concomitant medication may be given as medically indicated. All patients will be asked to provide a 
complete list of prescription, over-the-counter and complementary and alternative medications that have 
been taken within the previous 4 weeks prior to the first treatment visit.  They must also inform the 
Investigator about any new medication started while in the trial. 
Details (including indication, doses, frequency and start / stop dates) of concomitant medication taken during 
the trial until the completion of the off-study visit must be recorded in the medical record and the appropriate 
CRF. 
9.3  Prohibited therapies 
Patients should not be prescribed any other anti-cancer or investigational therapies while participating in this 
study.  
9.4  (Potential) Drug Interactions 
PF-02341066  (Appendix 5) 
Agents That May Increase Crizotinib Plasma Concentrations  
Coadministration of PF-02341066 with strong CYP3A inhibitors may increase PF-02341066 plasma 
concentrations. The concomitant use of strong CYP3A inhibitors, including but not limited to atazanavir, 
clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, 
telithromycin, troleandomycin, and voriconazole, should be avoided. Grapefruit or grapefruit juice and Seville 
oranges, their juice and marmalade containing them may also increase plasma concentrations of crizotinib 
and should be avoided. Caution should be exercised with concomitant use of moderate CYP3A inhibitors.  
Agents That May Decrease Crizotinib Plasma Concentrations  
 
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Coadministration of crizotinib with strong CYP3A inducers may decrease crizotinib plasma concentrations. 
The concurrent use of strong CYP3A inducers, including but not limited to carbamazepine, phenobarbital, 
phenytoin, rifabutin, rifampin, and St. John’s Wort, should be avoided.  
Agents Whose Plasma Concentrations May Be Altered By Crizotinib  
PF-02341066 has been identified as an inhibitor of CYP3A both in vitro and in vivo. Coadministration of            
PF-02341066 with CYP3A4 substrates with narrow therapeutic indices associated with life-threatening 
arrhythmias including, but not limited to dihydroergotamine, ergotamine, pimozide, astemizole, cisapride, and 
terfenadine must be avoided during PF-02341066 treatment. In addition, caution must be exercised in 
patients receiving PF-02341066 in combination with other CYP3A4 substrates, particularly those with narrow 
therapeutic indices, including but not limited to alfentanil, cyclosporine, fentanyl, quinidine, sirolimus, and 
tacrolimus.  
In addition to drug interactions due to enzyme inhibition and induction, the possibility of an additive 
pharmacodynamic interaction of PF-02341066 and other negatively chronotropic medications (e.g., beta-
blockers and non-dihydropyridine calcium-channel blockers) should be considered. Co-administration of       
PF-02341066 with these medications may lead to significant decreases in heart rate. 
 
PD-0325901 
Drug interaction studies have not been conducted for PD-0325901 in humans. Based on in vitro studies, PD-
0325901 and its circulating metabolite, PD-0315209, have a low potential to inhibit CYP2D6, CYP3A4, 
CYP1A2, and CYP2C19. However, the metabolite (PD-0315209) has the potential to inhibit CYP2C8 and 
CYP2C9. Caution should be exercised when co-administering PD-0325901 with drugs that are substrates for 
CYP2C8 or CYP2C9. Patients taking warfarin should be switched to low molecular weight heparin for the 
duration of the study. Other interactions may exist that are as yet unknown. 
 
Binimetinib 
A human ADME study identified direct glucuronidation as a main metabolic pathway of Binimetinib, and in 
vitro studies identified UGT1A1 as the main enzyme mediating direct glucuronidation. The impact of 
UGT1A1 inhibitors or inducers has not been assessed to date; therefore, inhibitors or inducers of UGT1A1 
should be co-administered with caution. In vitro solubility data indicates that Binimetinib’s solubility is pH 
dependent. Currently, the impact of pH modifying agents (such as proton pump inhibitors) on the PK of 
Binimetinib is unknown. If a patient is prescribed a pH modifying agent, it is recommended that patients take 
the pH modifying agent at least two hours after Binimetinib administration. Binimetinib has been shown to be 
a substrate for P-gp and BCRP in vitro. The impact of P- gp/BCRP inhibitors on the PK of Binimetinib in vivo 
is unknown; therefore, it is recommended that P-gp and BCRP inhibitors are dosed with caution. Patients 
taking warfarin should be switched to low molecular weight heparin for the duration of the study. Other 
interactions may exist that are as yet unknown. 
 
10 DRUG MANAGEMENT 
10.1 
Drug supplies 
PF-02341066 will be provided as clinical stock by Pfizer.  PF-02341066 is formulated as capsules containing 
200 or 250 mg of study medication and packaged in HDPE bottles. 
 
PD-0325901 will be supplied as clinical stock by Pfizer. PD-0325901 is provided in 1 and 5 mg strength hard 
gelatin capsules (42 capsules per bottle). Both IMPs will be manufactured and QP released to the 
specifications of an existing IMPD (Investigational Medicinal Product Dossier) under strict GMP conditions.  
For both their IMPs, Pfizer provides these as bulk stock and repackaging, labelling, QP release and 
distribution to the local hospital pharmacies will be performed free of charge by Almac Clinical Services.   
 
Binimetinib will be provided as clinical stock by Array.  Binimetinib is provided in 15mg strength tablets and 
packaged in HDPE bottles (70 tablets per bottle).  Array provides this stock as bottled, labelled and QP 
released to Almac Clinical Services who will then store and distribute the stock, free of charge, to the 
participating site local pharmacies.  
 
All supportive medication is to be sourced and funded locally.  
Drugs will be prescribed, tracked, and dispensed according to the local policy for investigator initiated 
studies. 
 
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10.2 
Drug ordering 
Initial supplies of PF-02341066 and PD-0325901 or Binimetinib are distributed by Almac Clinical Services 
after they have been informed by the Trials office that all approvals are in place. Re-supply of PF-02341066, 
PD-0325901 and Binimetinib will be managed by the Trials office. If any supplies of PF-02341066, PD-
0325901 or Binimetinib are damaged the pharmacist should contact the Trials office for replacement patient 
supplies. 
10.3 
IMP Receipt 
Upon receipt of each drug delivery, the site must complete and return the scanned enclosed 
acknowledgement of receipt by email within 24 hours.  
If supplies are damaged on arrival, please contact OCTO promptly.  
10.4 
Handling and storage 
The investigator or an approved representative (e.g. pharmacist) will ensure that all study drugs are stored in 
a secured area, under recommended storage conditions in accordance with applicable regulatory 
requirements 
.  
PF-02341066 should be stored at room temperature (15°C - 30°C) and there are no specific restrictions. 
PD-0325901 capsules are stored at 15°C - 25°C and there are no specific restrictions.  
Binimetinib tablets are stored at 15°C - 25°C and there are no specific restrictions 
10.5 
Labelling  
PF-02341066, PD-0325901 and Binimetinib will be supplied to participating sites appropriately labelled in 
accordance with all applicable regulatory requirements. 
10.6 
Dosing dispensing 
PF-02341066 is formulated as capsules containing 200 or 250 mg of study medication and packaged in 
HDPE bottles and will be provided as 60 capsules per bottle for the 200mg strength and 60 capsules per 
bottle for the 250mg strength. 
 
PD-0325901 is formulated as 1 and 5 mg strength hard gelatin capsules and will be supplied as 42 capsules 
per bottle. The number of bottles to be dispensed must be sufficient for the cycle of treatment. Patient 
specific details and the number of capsules to be taken per day must be added to the label prior to 
dispensing. 
 
Binimetinib drug product is supplied as film-coated tablets in a-dosage strength of 15 mg. The film coated-
tablets consist of Binimetinib drug substance; colloidal silicon dioxide/silica colloidal anhydrous; 
croscarmellose sodium; lactose monohydrate; magnesium stearate; microcrystalline cellulose/cellulose, 
microcrystalline; and a commercial film coating. The tablets are yellow to dark yellow and capsule shaped. 
The number of bottles to be dispensed must be sufficient for the cycle of treatment.  Patient specific details 
and the number of tablets to be taken per day must be added to the label prior to dispensing. 
10.7 
Drug accountability 
Full drug accountability records must be maintained for PF-02341066, PD-0325901 and Binimetinib using 
the Drug Accountability Logs provided. Sites can use their own logs provided their use is approved in 
advance by the Trials office. 
 
The Drug Accountability Logs should be kept up to date and have to contain the following information; 
patient identifier, date and quantity received at site, date and quantity dispensed, date and quantity 
returned/destroyed at site. 
 
The Drug Accountability Logs must be available for inspection by the Sponsor or its representative at every 
monitoring visit. 
 
At the conclusion of the study the overall numbers of drug shipped to the centre, the number dispensed and 
the number destroyed or returned will be provided by the pharmacy. An account must be given of any 
discrepancy. 
 
 
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10.8 
Drug returns from patients 
Patients will be asked to return all bottles, whether empty or not, to the hospital. Unused PF-02341066, 
Binimetinib and PD-0325901 must be returned to pharmacy for counting and recording in the patient’s Drug 
Accountability Log. Returns must be retained until permission to destroy is given by the trial office at the end 
of the study. 
 
10.9 
Drug destruction 
Returned, unused and expired drugs should be destroyed only once permission has been granted by the 
Sponsor, as per the following table: 
Expired drug 
At the end of the study, once authorised to do so by the 
Sponsor, any unused drug should be destroyed by the site.   
A signed & dated Drug Destruction form must be completed 
scanned and emailed to OCTO. 
Drug left unused/not dispensed 
At the end of the study, once authorised to do so by the 
Sponsor, any unused drug should be destroyed by the site.   
A signed & dated Drug Destruction form must be completed 
scanned and emailed to OCTO. 
Patient returns 
Upon receipt, number of capsules returned to be recorded 
on patient’s Drug Accountability Log. 
At the end of the study, once authorised to do so by the 
Sponsor, any unused drug should be destroyed by the site.  
A signed & dated Drug Destruction form must be completed 
and scanned and emailed OCTO. 
10.10 Occupational safety 
The product is not expected to pose an occupational safety risk to site staff under normal conditions of use 
and administration. 
 
11 EVALUATION OF RESPONSE 
11.1 
Measurement of disease for solid tumour 
Objective disease response must be measured according to the RECIST version 1.1 criteria given in 
Appendix 4. 
In the dose escalation and expansion phase, radiological tumour response with CT scan 
chest/abdomen/pelvis will be evaluated prior to study entry and then after 2nd, 4th, 6th cycle, and every 2 
cycles thereafter, until intolerable toxicity or progressive disease.  
11.2 
Tumour assessment 
A clinical and CT-graphic evaluation of malignancy, as judged appropriate by the Investigator, and in line 
with the protocol, must be performed before starting the study treatment.  The same methods that detect 
lesions at baseline will be used to follow these lesions throughout the study.  To ensure compatibility, the 
radiological assessments used to assess response must be performed using identical techniques.   
 
11.2.1  Baseline evaluations 
These will include radiological measurements of the extent of disease by CT chest/abdomen/pelvis or CT 
chest with MRI abdomen/pelvis). All areas of disease present must be mentioned (even if specific lesions are 
not going to be followed for response) and the measurements of all measurable lesions must be recorded on 
the scan reports.  Any non-measurable lesions must be stated as being present.  For clinical measurements, 
documentation by colour photography including a ruler to estimate the size of the lesion is recommended to 
aid external independent review of responses.  
All patients with at least one measurable lesion are included in the trial. 
 
 
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11.2.2  Evaluations during treatment and at off-study 
Tumour assessment will be repeated as per the schedule of events given or more frequently if clinically 
indicated.  All lesions measured at baseline must be measured at subsequent disease assessments, and 
recorded on the scan reports.  All non-measurable lesions noted at baseline must be reported as present or 
absent. 
 
Investigators must ensure that their radiologists are aware of the requirement to follow up and measure 
every target lesion mentioned at baseline and comment on the non-target lesions in accordance with 
RECIST 1.1 criteria. 
11.3 
Tumour response 
All patients included in the study must be assessed for response to treatment, even if there is a major 
protocol treatment deviation or if they are ineligible, or not followed/re-evaluated. Each patient will be 
assigned one of the following categories: complete response, partial response, stable disease, progressive 
disease, early death from malignant disease, early death from toxicity, early death from other cause or 
unknown (not assessable, insufficient data). 
Response duration will be measured from the time measurement criteria for CR/PR (whichever is first 
recorded) are first met until the first date that recurrent or progressive disease is objectively documented. 
Date of progression is defined as the first day when RECIST (version 1.1) PD is observed. 
Early death is defined as any death occurring before the first per protocol time point of tumour re-evaluation. 
The responsible investigator will decide if the cause of death is malignant disease, toxicity or other cause. 
Patients for whom response is not confirmed will be classified as "unknown", unless they meet the criteria for 
stable disease (or the criteria for partial response in case of an unconfirmed complete response). Patients’ 
response will also be classified as "unknown" if insufficient data were collected to allow evaluation per these 
criteria. 
Should rapid tumour progression occur before the completion of 8 weeks treatment the patient will be 
classified as having early progression (EP). 
 
Tumour response should be classified as “not evaluable” (NE), only when it is not possible to classify it under 
another response category, e.g., when baseline and/or follow-up assessment is not performed or not 
performed appropriately.  
 
The applicable overall response category for each visit that includes disease assessment must be recorded 
in the medical record for inclusion in the appropriate CRF in OpenClinica. 
 
11.4 
Other definitions of outcome: 
Toxic death:   
Any death to which drug toxicity is thought to have a major contribution. 
Early death:  
 
Death during the first three weeks of treatment that is not a toxic death. 
 
12 ASSESSMENT OF SAFETY 
 
The Investigator will monitor each patient for clinical and laboratory evidence of adverse events on a routine 
basis throughout the study. Should an Investigator become aware of any study drug related SAEs following 
this period these must also be reported as stated below. Adverse event monitoring starts from the time the 
patient consents to the study until they complete the trial. All reportable AEs will be followed to a satisfactory 
conclusion. Any reportable AEs that are unresolved at the patient’s last visit in the study are followed up by 
the Investigator for as long as medically indicated, but without further recording in the CRF. 
 
All AEs reported to the trial office will be processed according to internal SOPs. The trial office may request 
additional information for any AE as judged necessary. 
12.1 
Adverse Event Definitions 
An Adverse Event or experience (AE) is any untoward medical occurrence in a study subject temporally 
associated with the administration of an investigational medicinal product (IMP) or a comparator product, 
 
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whether or not considered related to the IMP or a comparator product. An AE can therefore be any 
unfavourable and unintended sign, symptom, disease (new or exacerbated) and /or significant abnormal 
laboratory or physiological observation temporally associated with the use of a medicinal product. For 
marketed medicinal products, this also includes failure to produce expected benefits (i.e. lack of efficacy), 
abuse or misuse. This includes any newly occurring event, or a previous condition that has increased in 
severity or frequency since the administration of study drug. 
An abnormal laboratory value will not be reported as an AE unless that value leads to discontinuation or 
delay in treatment, dose modification, therapeutic intervention, or is considered by the investigator to be a 
clinically significant change from baseline. 
 
 
A Serious Adverse Event (SAE) is any AE, regardless of dose, causality or expectedness, that: 
 
•  Results in death 
 
 
•  Is life-threatening  
This refers to an event in which the subject was at risk of death 
at the time of the event.  It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
 
• Requires in-patient 
hospitalisation  
or prolongs existing inpatient 
hospitalisation  
 
In general, hospitalisation signifies that the subject has been 
admitted (usually involving at least an overnight stay) at the 
hospital or emergency ward for observation and/or treatment 
that would not have been appropriate in the physician’s office or 
out-patient 
setting. 
 
Complications 
that 
occur 
during 
hospitalisation 
are 
AEs. 
 
If 
a 
complication 
prolongs 
hospitalisation or fulfils any other serious criteria, the event is 
serious.  When in doubt as to whether hospitalisation occurred 
or was necessary, the AE should be considered serious. 
• Results in persistent or 
significant incapacity or 
disability 
This means a substantial disruption of a person’s ability to 
conduct normal life functions.  It does not include experiences of 
relatively minor medical significance or accidental trauma (e.g. 
sprained ankle), which does not constitute a substantial 
disruption. 
• Is a congenital anomaly or 
birth defect 
 
• Is 
any 
other 
 
medically 
important event 
Defined as an event that may jeopardise the patient or may 
require intervention to prevent one of the outcomes listed 
above. Any new primary cancer must be reported as an SAE. 
 
 
 
Clarification should be made between a serious AE (SAE) and an AE that is considered severe in intensity 
(Grade 3 or 4), because the terms serious and severe are NOT synonymous.  The general term severe is 
often used to describe the intensity (severity) of a specific event; the event itself, however, may be of 
relatively minor medical significance (such as a Grade 3 headache).  This is NOT the same as serious, 
which is based on patient/event outcome or action criteria described above, and are usually associated with 
events that pose a threat to a patient’s life or ability to function.  The seriousness criteria in the table above 
should be used to determine if the event is serious. 
 
An Adverse Drug Reaction (ADR) is a response to a medicinal product which is noxious and unintended. 
Response in this context means that a causal relationship between a medicinal product and an adverse 
event is at least a reasonable possibility. 
 
An Unexpected Drug Reaction is an adverse drug reaction, the nature or severity of which, is not 
consistent with applicable reference safety information section (referring to SPC or IB). 
 
 
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A Suspected Unexpected Serious Adverse Drug Reaction (SUSAR) is a serious adverse drug reaction, 
the nature or severity of which is not consistent with the applicable product information (e.g. Investigator’s 
Brochure for an unapproved investigational product or SPC for an approved product). 
12.2 
Clinical laboratory abnormalities and other abnormal assessments as AEs and SAEs 
Abnormal laboratory findings (e.g., clinical chemistry, haematology, urinalysis) or other abnormal 
assessments (e.g., ECGs, X-rays and scans) that are judged by the investigator as clinically significant will 
be recorded as AEs or SAEs if they meet the definitions given above.  
 
The investigator will exercise his or her medical and scientific judgment in deciding whether an abnormal 
laboratory finding or other abnormal assessment is clinically significant.  
12.3 
Determining adverse event causality 
The Investigator will assess and classify the relationship of an AE to the trial IMP ((PF-02341066 (Crizotinib) 
and PD-0325901 or PF-02341066 (Crizotinib) and Binimetinib)) as follows: 
 
Classification 
Relationship 
Definition 
 drug-related 
Definitely related 
 
• Starts within a time related to the study drug 
administration and 
• No obvious alternative medical explanation. 
 
Probably related 
 
• Starts within a time related to the study drug 
administration and 
• Cannot 
be 
reasonably 
explained 
by 
known 
characteristics of the patient’s clinical state. 
 
Possibly related 
 
• Starts within a time related to the study drug 
administration and 
• A causal relationship between the study drug and the 
adverse event is at least a reasonable possibility. 
 
not drug 
related 
Probably not 
related 
 
• The time association or the patient’s clinical state is 
such that the study drug is not likely to have had an 
association with the observed effect. 
 
Definitely not 
related 
 
• The AE is definitely not associated with the study drug 
administered. 
 
 
The Investigator must endeavour to obtain sufficient information to confirm the causality of the adverse event 
(i.e. relation to surgery, study drug, background treatment, other illness, progressive malignancy etc) and 
give their opinion of the causal relationship between each AE and study drug.  This may require instituting 
supplementary investigations of significant AEs based on their clinical judgement of the likely causative 
factors and/or include seeking a further specialist opinion. 
12.4 
Expected adverse events 
Section 6.2 of the IB for PD-0325901 lists all the expected side effects associated with the use of PD-
0325901. Section 6.0 of the IB for MEK 162 (Binimetinib) lists all the expected side effects associated with 
the use of Binimetinib. Section 4.8 of the SmPC for PF-02341066 lists all the expected side effects 
associated with the use of PF-02341066. A copy of the current, approved version of RSI documents for each 
IMP must be held in the Site File for reference.  Please note that the list of expected side effects for PF-
02341066 (Crizotinib) in the SmPC are those listed for advanced non-small cell lung carcinoma (NSCLC) 
patients. It should also be noted that the side effects for Binimetinib in the SmPC are those listed for 
 
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advanced unresectable or metastatic NRAS mutation-positive melanoma. It is therefore possible that in this 
study population other side effects may occur, or the patient might suffer a more severe reaction.  
12.5 
Suspected Unexpected Serious Adverse Drug Reactions (SUSARs) 
All SUSARs must be reported to the responsible Authority and main REC within very tight deadlines 
depending on the outcome, so it is imperative that sites report potential SUSARs to the trials office without 
delay.  OCTO will report SUSARs according to their SOPs. In addition, other safety issues qualify for 
expedited reporting where they might materially alter the current risk assessment of an IMP or be sufficient 
to change IMP administration or the overall conduct of the trial. Responsibility for expedited safety reporting 
will be assigned by the Sponsor. 
 
OCTO must ensure that all SUSARs are reported to the competent authorities of the EU countries in which 
the trial is taking place 
12.6 
Expedited reporting of SAEs 
The following SAE reporting requirements apply regardless of the Investigator’s assessment of the causality 
of the SAE (See section 12.9 for exceptions). All SAEs should be reported on the trial SAE report form (see 
SAE report form and instructions for completion). Please note that the SAE report form is a paper form and 
these data cannot be entered into the eCRF system (OpenClinica). 
 
The SAE form must be completed, scanned and emailed to the Oxford MErCuRIC Pharmacovigilance Team 
at OCTO: octo-safety@oncology.ox.ac.uk : 
 
    
SAE forms must be completed with all critical information as soon as possible and submitted within 24hrs of 
becoming aware of the event by scanning the report and sending as an attachment in email to: 
 octo-safety@oncology.ox.ac.uk. 
 
If the SAE has not been reported within the specified timeframe, a reason for lateness must be provided 
when sending the SAE Report Form. 
 
Investigators should also adhere to their local policy for incident and SAE reporting in research. 
 
Safety issues that qualify for expedited reporting where they might materially alter the current risk-benefit 
assessment of an IMP or be sufficient to change the IMP administration or the overall conduct of the trial.  
For instance:  
• 
Single case reports of an expected serious adverse reaction with an unexpected outcome.  
• 
An increase in the rate of occurrence of an expected serious adverse reaction, which is judged to be 
clinically important.  
• 
Post study SUSARS that occur after the patient has completed a clinical trial and are reported by the 
investigator to OCTO.  
• 
New event relating to the conduct of the trial or the development of the IMP likely to affect the safety 
of the subjects. 
 
OCTO will send all SAE reports to Pfizer (or designee) and Array Biopharma (or designee) within 24 hours of 
receipt as per any agreement.  
12.7 
Follow-up of Serious Adverse Events 
If new or amended information on a reported SAE becomes available, the Investigator should report this on a 
new SAE form or update the existing form, without obscuring any initial information.  All new data must be 
initialled and dated so that all changes are clearly identified. . .  
 
Follow up will continue until all the necessary safety data for the event has been gathered. Any SAE that is 
ongoing when a subject completes his/her participation in the trial must be followed until any of the following 
occurs: 
• 
The event resolves or stabilizes; 
• 
The event returns to baseline condition or value (if a baseline value is available); 
• 
The event is attributed to other agent(s) or to factors unrelated to study conduct. 
 
 
 
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AEs which are serious must be reported to OCTO from the first dose of PF-02341066 (Crizotinib) and 
PD-0325901 and up to and including 30 days after administration of the last dose of PF-02341066 
(Crizotinib) and PD-0325901 or PF-02341066 (Crizotinib) and Binimetinib .  Any SAE that occurs at any time 
after completion of PF-02341066 (Crizotinib) and PD-0325901 or PF-02341066 (Crizotinib) and Binimetinib 
treatment, or after the designated follow-up period that the investigator considers to be related to any study 
drug, must be reported. 
 
12.8 
Reporting Adverse Events on the CRF 
All AEs, including Serious AEs, occurring during treatment and within 30 days after the last protocol 
treatment must be recorded on the case report forms (CRF) for that patient. The information provided will 
include date of onset, event diagnosis (if known) or sign/symptom, severity, time course, duration and 
outcome and relationship of the AE to study drug.  Any concomitant medications or other any therapy used 
to treat the event must be listed. The Investigator will provide an “other” cause for serious AEs considered to 
be unrelated to the study drug. Sites should ensure data entered into the CRF is consistent with the SAE 
report information where applicable.   
 
Each separate AE episode must be recorded.  For example, if an AE resolves completely or resolves to 
baseline and then recurs or worsens again, this must be recorded as a separate AE. For AEs to be 
considered intermittent, the events must be of similar nature and severity. 
 
Adverse Events reporting requirements 
Subjects having adverse events will be monitored with relevant clinical assessments and laboratory tests as 
determined by the Investigator. All adverse events must be followed to satisfactory resolution or stabilization 
of the event(s) including the investigation for the likely causative factor. Any actions taken and follow-up 
results must be recorded in the subject's source documentation. Follow-up laboratory results should be filed 
with the subject's source documentation. For all adverse events which require the subject to be discontinued 
from the study, relevant clinical assessments and laboratory tests will be repeated, on at least a weekly 
basis, until final resolution or stabilisation of the event(s).  
 
 
12.9 
Events exempt from being reported as AE/ SAEs 
Abnormal findings associated with the disease being studied: 
 
Clinically significant abnormal laboratory findings or other abnormal assessments that are detected during 
the study or are present at baseline and significantly worsen following the start of the study will be reported 
as AEs or SAEs. However, clinically significant abnormal laboratory findings or other abnormal assessments 
that are associated with the disease being studied, unless judged by the investigator as more severe than 
expected for the patient’s condition, or that are present or detected at the start of the study and do not 
worsen, should not be reported as AEs or SAEs 
 
Progression of underlying disease 
Disease progression and resultant death will be captured on the CRF.  An event that is part of the natural 
course of the disease under study (i.e., disease progression or admission for standard treatment) should not 
be reported as an AE/SAE. However, if the progression of the underlying disease is greater than that which 
would normally be expected, or if the investigator considers that there may be a causal relationship between 
the IMP or protocol design/procedures and the disease progression, then it must be reported.   
 
Every effort should be made to document the objective progression of underlying malignancy.  In some 
cases, the determination of clinical progression may be based on symptomatic deterioration. For example, 
progression may be evident from clinical symptoms, but is not supported by tumour measurements. Or, the 
disease progression is so evident that the investigator may elect not to perform further disease assessments.  
 
Death on study 
Death due to disease under study is to be recorded on the Death CRF form providing the death is not 
unexpected or if a causal relationship suspected. The investigator must clearly state whether the death was 
expected or unexpected and whether a causal relationship to the study IMP or other protocol treatment 
intervention is suspected.  
 
 
 
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Elective admissions and supportive care 
Elective admissions to hospital for patient convenience or for planned procedures or investigations or 
treatment as specified in this protocol and standard supportive care are not SAEs, and do not require SAE 
reporting.  Hospital admission for the following supportive care procedures are considered standard for this 
patient group and should not be reported as SAEs: 
• 
insertion of stent 
• 
insertion of Port-A-Cath, PICC line etc. 
• 
admission for hydration 
• 
admission for transfusion 
12.10 Development Safety Update Reports 
DSURs will be co-ordinated by OCTO and prepared in collaboration with the CI and submitted in parallel to 
the regulatory authority and responsible Research Ethics Committee within 60 days of the anniversary of the 
date of regulatory approval.  A copy of each report will be provided to Pfizer, Array Biopharma and the 
sponsor. 
12.11 Informing Investigators of new safety information 
OCTO or the Chief Investigator will ensure that all investigators are kept informed in a timely manner, as new 
safety profile information becomes available. Investigators are responsible for briefing their study team and 
onward transmission to R&D office as appropriate. 
 
13 PREGNANCY AND BREAST FEEDING 
Pregnancies (in a participant or partner) occurring within 6 months of treatment dosing with PF-02341066, 
PD-0325901 or Binimetinib must be reported using the Pregnancy Notification Form which should be 
scanned and emailed to OCTO within 24 hours of receipt of information at octo-safety@oncology.ox.ac.uk. 
In the event that the pregnancy results in an abnormal outcome and meets the criteria for immediate 
classification as a serious adverse event, (i.e. spontaneous abortion, still birth, neonatal death or congenital 
anomaly), the investigator should follow the procedures for reporting serious adverse events. Note: 
Pregnancy itself is only considered an AE/SAE if there is reason to believe it may be the result of an 
interaction between the study IMP and the contraceptive used. 
 
Women who become pregnant should be withdrawn from treatment at the earliest opportunity. All reported 
pregnancies should be followed up until the outcome. Pregnancy outcome must be recorded in the medical 
record and in the follow-up section of the Pregnancy Notification Form. Any abnormal outcome (other than 
elective abortion) for the mother or child should also be reported as a SAE.  
 
Pfizer should also be informed by OCTO of any pregnancy arising in a study participant or his/her partner 
whilst taking part in the trial or during a stage where the foetus could have been exposed to the medicinal 
product. Following inclusion of the Binimetinib into this trial, Array Biopharma should also be informed by 
OCTO of any pregnancy arising in a study participant or his/her partner whilst taking part in the trial or during 
a stage where the foetus could have been exposed to the medicinal product. 
 
14 DEFINING THE END OF TRIAL  
For this study the end of the trial is defined as the last visit of the last patient undergoing the trial (LPLV).  
 
The study will be stopped when: 
• 
The stated number of patients to be recruited is reached. 
AND 
• 
All patients have discontinued treatment with either PD-0325901 in combination with PF-02341066 or 
Binimetinib in combination with PF-02341066.  
The sponsor, Chief Investigator in consultation with the trial committee, reserve the right to terminate the 
study earlier at any time. In terminating the study, they must ensure that adequate consideration is given to 
the protection of the participants’ best interests. 
 
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15 STATISTICAL CONSIDERATIONS  
15.1 
Sample size  
Phase I dose escalation using PF-02341066 in combination with PD-0325901 
Between 2 and 24 patients will be recruited to this phase I dose escalation part of the trial in a rolling 6 
design to establish an MTD as explained in earlier sections of the protocol.  The dose escalation is agreed 
between the CI’s at the recruiting centres based on the definitions in this protocol. 
 
Phase I dose escalation using PF-02341066 in combination with Binimetinib 
Up to 25 patients will be recruited to this phase I dose escalation part of the trial in a rolling 6 design to 
establish an MTD as explained in earlier sections of the protocol.  The dose escalation is agreed between 
the CI’s at the four recruiting centres based on the definitions in this protocol. 
 
Dose expansion 
a) RASMT expansion phase statistical plan: 
A Simon Minimax design was proposed for the RASMT patients, as these patients should be easier to recruit 
as they comprise 50% of the total CRC population and there is a shortage of competing therapeutic options. 
If 7/40 responders are observed in the RASMT group, we will continue to the randomised phase II trial 
(WP2).  
b) RAS WT/cMET amplified or mutated expansion phase statistical plan 
c) RAS WT/cMET overexpressed expansion phase statistical plan 
A Simon optimal design will be used for both the  RASWT/cMET+  groups. This design will give a rapid 
indication if an effect is not observed, allowing a timely decision to stop that group continuing in the trial 
(thereby involving fewer patient) or continue the trial (motivating further recruitment). RASWT/cMET patients 
are rare, hence recruitment to this group will be slower than RASMT. Due to the rarity of RASWT/cMET 
patients and delays in the project timelines due to replacement of PD-0325901 with Binimetinib with , 
consequential delays due to protocol amendment, ethics/regulatory approval, Binimetinib supply delay) and 
lengthy phase Ia dose escalation for Binimetinib/Crizotinib (higher than anticipated number of patients 
requiring replacement), inclusion of RASWT/cMET patients in the randomised phase II trial is not achievable. 
Nonetheless, this design will be the first study that aims to: (a) find these RASWT MET aberrant cases, and 
(b) define the role of MET inhibition in these two separate MET-dependent groups. 
 
 
 
Table 1 Sample size calculation for dose expansion phase design 
 
RAS MT 
RAS WT/cMET amplified   
RAS WT/cMET overexpressed  
Simon minimax: response 
then (conditionally) 
RCT: primary: PFS, secondary: OS 
Simon optimal: response 
 
Simon optimal: response 
            p1=0.1 
 
 
            p2=0.25  
    
Power=80% 
Alpha=5% 
 
Stage 1: If at least 2 responder in first 
22 patients, then continue to stage 2 
 
Stage 2: If at least 7 responders in 40 
patients, then continue to phase II  
 
 
p1*=0.1 
p2*=0.3 
Power=80% 
Alpha=5% 
 
Stage 1: If 2/10 responders, 
then continue to Stage 2 
 
Stage 2: If 6/29 responders, 
then continue to collect 
samples for MErCuRIC 
translational WPs and generate 
evidence for future clinical trials 
after MErCuRIC 
p1*=0.1 
p2*=0.3 
Power=80% 
Alpha=5% 
 
Stage 1: If 2/10 responders, 
then continue to Stage 2 
 
Stage 2: If 6/29 responders, 
then continue to collect 
samples for MErCuRIC 
translational WPs and generate 
evidence for future clinical trials 
after MErCuRIC 
40 patients 
29 patients 
29 patients 
 
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15.2 
Statistical analysis plan 
A statistical analysis plan written adhering to the current OCTRU standard operating procedures will be 
signed off for this trial prior to analysis of primary or secondary aims. 
 
Inclusion in analysis 
Toxicity analysis will be on all patients who received at least some of at least one of the treatments in the 
combination. 
 
Dose escalation for both combination IMPs 
All evaluable patients will be analysed for dose escalation, which is those completing cycle 1 or who 
withdraw early for experiencing a DLT. The variables that define the DLTs and safety variables will be 
summarized by descriptive statistics with patients grouped according to dose level received. Number (with 
percentages) of patient with and without DLT will also be presented according to dose level. 
 
Dose expansion 
 All patients recruited to the dose expansion phase will be analysed as intention to treat. 
This means that patients will be analysed as they are consented irrespective of the amount of treatment 
actually received. The intention-to-treat population will include all patients who have given their informed 
consent.  It is therefore important that every effort is made to encourage patients, including those patients 
who do not receive/complete their allocated treatment, to attend for follow-up clinic visits and complete tests 
to avoid bias in the analysis of the results. Results will be given separately for the three genetic subgroups. 
 
Subgroup analysis 
No subgroup analyses are planned beyond those inherent in the dose expansion cohort. 
 
Interim Analyses 
No interim analyses of primary or secondary endpoints are planned beyond those inherent in the rolling 6 
design. 
 
Procedures for reporting any deviation(s) from the original statistical plan 
Sites must report any deviations/violations to OCTO according to the procedure outlined during site initiation. 
These will be noted in the statistical report. 
 
Final analysis 
All patients enrolled in the study, will be accounted for. The number of patients who were not evaluable, who 
died or withdrew before treatment began will be recorded. The distribution of follow-up time will be described 
and the number of patients lost to follow-up will be given. Follow-up for progression-free and overall survival 
will be performed. 
 
Variables will be analysed to determine whether the criteria for the study conduct are met. This will include a 
description of patients who did not meet all the eligibility criteria, an assessment of protocol violations, study 
drug accountability and other data that impact on the general conduct of the study. 
 
Baseline characteristics will be summarised for all evaluable patients. Treatment related toxicity will be 
tabulated by type and grade of toxicity for cycle 1 alone and all cycles. All trial treatment and efficacy 
information will be summarised. 
 
Primary objectives:  
 
Dose Escalation 
The variables that define the DLTs and safety variables will be summarized by descriptive statistics with 
patients grouped according to dose level received. Number (with percentages) of patients with and without 
DLTs will also be presented according to dose level. 
 
Dose Expansion  
Safety and toxicity variables will be summarized by descriptive statistics within each genetically defined 
subgroup to investigate the safety and feasibility of expanded cohort patients at RPII dose.  
 
 
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Secondary Objectives: 
 
Analysis will be specified in the analysis plan. 
 
16 TRIAL COMMITTEES 
16.1 
Trial Management Group (TMG) 
The Chief Investigator will chair a TMG with responsibility for overseeing the successful conduct and 
publication of the trial in accordance with the protocol. The TMG will review safety and dose escalations with 
advice from the Independent Early Phase Trial Oversight Committee (IEPTOC) (see section 16.2). It will 
provide regular progress reports as required by the applicable steering committees and governance bodies.  
Members of the TMG will include: 
• 
Chief Investigator 
• 
Trial management staff from OCTO 
• 
Trial Statistician 
• 
Principal Investigators from participating sites. 
16.2 
Data and Safety Monitoring 
There is no Data and Safety Monitoring Committee. The IEPTOC will be in place to monitor the safety and 
progress of the trial. 
16.3 
Trial Steering Committee  
The role of the Trial Steering Committee will be fulfilled by the IEPTOC. 
17 DATA MANAGEMENT 
17.1 
Database considerations 
Data management will be performed via a web-based, bespoke trial database (OpenClinica). OpenClinica is 
a 
dedicated 
and 
validated 
clinical 
trials 
database 
designed 
for 
electronic 
data 
capture. 
See: http://www.openclinica.org 
 
The Chief Investigator will act as Data Custodian for the trial.  A guide explaining how to use OpenClinica will 
be provided to every site. Relevant OCTO staff will have overview of all entered data. 
17.2 
Case report forms (CRFs) 
The Investigator and study site staff will ensure that data collected on each subject is recorded in the CRFs 
within OpenClinica as accurately and completely as possible. The CRFs will not contain any source data. All 
appropriate laboratory data, summary reports and Investigator observations will be transcribed into the CRFs 
from the relevant medical record(s). Please ensure that: 
• 
the relevant CRFs are completed. 
• 
all CRF data are verifiable in the source documentation or the discrepancies must be explained.  
• 
CRF sections are completed in a timely fashion, i.e.  within 7-14 days of the study visit or reported 
event.. 
• 
Data queries are resolved and documented by authorised study staff, giving a reason for the change 
or correction where appropriate. 
 
The above considerations also apply to patients who are withdrawn early. If a patient withdraws from the 
study, the reason must be noted on the appropriate form and the patient must be followed-up as per 
protocol.  
17.3 
Accounting for missing, unused, or spurious data. 
Missing data found will be chased up and supplemented where possible after consultation with the 
investigator. The control of the correctness of the data is performed with ranking tests, validity tests and 
consistency checks. Unused data will be retained as for used data. 
 
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18 CLINICAL STUDY REPORT  
All clinical data will be presented at the end of the study as data listings. These will be checked to confirm 
the lists accurately represents the data collected during the course of the study.  The trial data will then be 
locked and a final data listing produced. The clinical study report will be based on the final data listings. The 
locked trial data may then be used for analysis and publication.  
19 STUDY SITE MANAGEMENT 
19.1 
Study site responsibilities 
The Principal Investigator (the PI or lead clinician for the study site) has overall responsibility for conduct of 
the study, but may delegate responsibility where appropriate to suitably experienced and trained members of 
the study site team (e.g. drug supplies will be monitored by the on-site pharmacist, trial forms completed by 
the Data Manager, etc.).  All members of the study site team must complete the delegation log or the Staff 
Contact Responsibility Sheet provided prior to undertaking any study duties.  The PI must counter sign and 
date each entry in a timely manner, authorising staff to take on the delegated responsibilities. The Principal 
Investigator must ensure that all staff involved in the study are adequately trained and their duties have been 
logged on the forms provided. All Principal Investigators and Co-Investigators must have valid and up to date 
GCP training. 
For further information on trial responsibilities, please refer to the ICH GCP guideline (E6).   
19.2 
Study site set up and activation 
A Principal Investigator should lead the study at each site, providing the local study office with all core 
documentation and attend ‘Site Training Call’ organized by the trial office or visit before the site becomes 
activated (usually carried out as a telephone conference call or personal visit).  The Trial Office will call to 
check that the site has all the required study information/documentation and is ready to recruit.  The site will 
then be notified once they are activated on the MErCuRIC database and able to recruit. 
19.3 
Arrangements for sites outside the UK 
Within each country (except the UK) the lead site will co-ordinate the applications to the necessary 
competent authority and other bodies (e.g. ethics) in line with national regulations.  Each participating centre 
will be responsible for obtaining any local approvals needed.  Any changes to the protocol or other 
supporting documents must be agreed with the Sponsor. Agreements will be put in place with each 
site/country which includes an appropriate delegation of responsibilities which will include producing 
translations into local language(s) of all patient documents. 
19.4 
Study documentation 
OCTO will provide an Investigator File and Pharmacy File (where applicable) to each investigational site 
including: contact details, study procedures and all other documents required for completion of the study.  
Further copies of documents are available from OCTO as appropriate. 
The trial office must review and approve any local changes made to any study documentation including 
patient information and consent forms prior to use. Additional documentation generated during the course of 
the trial, including relevant communications must be retained in the site files as necessary to reconstruct the 
conduct of the trial. 
A screening log must be kept of all patients considered for the study and subsequently excluded; the reason 
for exclusion must be recorded on this form. A copy of the screening log without patient identifiers should be 
sent through to OCTO on a monthly basis, or as requested by OCTO. The original must be retained on site. 
20 REGULATORY AND ETHICAL CONSIDERATIONS 
The Sponsor and Investigators will ensure that this protocol will be 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. 
3 GCP Directive 2005/28/EC. 
 
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20.1 
Ethical conduct of the trial and ethics approval 
The protocol, patient information sheet, consent form and any other information that will be presented to 
potential trial patients (e.g. advertisements or information that supports or supplements the informed 
consent) will be reviewed and approved by an appropriately constituted, independent Research Ethics 
Committee (REC) or equivalent for non-UK countries (IRB etc.). Principal Investigators will be approved by 
the relevant national and/or local body. 
20.2 
Regulatory Authority approval 
Approval to conduct the study will be obtained from the relevant Competent Authority in each participating 
country prior to initiating the study. In the UK the study will be conducted under a Medicines and Healthcare 
products Regulatory Agency (MHRA) Clinical Trial Authorisation (CTA).  
20.3 
Local Approvals 
Investigators are responsible for ensuring they obtain appropriate local approvals to conduct the trial in 
accordance with local arrangements and policies. 
20.4 
Protocol amendments 
Amendments are changes made to the research following initial approval. A ‘substantial amendment’ is an 
amendment to the terms of the Responsible Authority application (if applicable), the REC application, or to 
the protocol or any other supporting documentation, that is likely to affect to a significant degree: 
 
• 
the safety or physical or mental integrity of the subjects of the trial; 
• 
the scientific value of the trial; 
• 
the conduct or management of the trial; or 
• 
the quality or safety of the investigational medicinal product(s) used in the trial.  
 
Non-substantial amendments are those where the change(s) involve only minor logistical or administrative 
aspects of the study. 
 
All amendments will be generated and managed according to the trial office standard operating procedures 
to ensure compliance with applicable regulation and other requirements. Written confirmation of all 
applicable REC, regulatory and local approvals must be in place prior to implementation by Investigators. 
The only exceptions are for changes necessary to eliminate an immediate hazard to study patients (see 
below). 
 
It is the Investigator’s responsibility to update patients (or their authorised representatives, if applicable) 
whenever new information (in nature or severity) becomes available that might affect the patient’s willingness 
to continue in the trial.  The Investigator must ensure this is documented in the patient’s medical notes and 
the patient is re-consented if appropriate. 
 
20.5 
Urgent safety measures 
The sponsor or Investigator may take appropriate urgent safety measures to protect trial participants from 
any immediate hazard to their health or safety. Urgent safety measures may be taken without prior 
authorisation. The trial may continue with the urgent safety measures in place. The Investigator must 
inform the Oxford MErCuRIC team IMMEDIATELY if the study site initiates an urgent safety measure: 
 
Tel: +44 (0)1865 227194 
Email: octo-MERCURIC@oncology.ox.ac.uk 
 
The notification must include: 
• 
Date of the urgent safety measure; 
• 
Who took the decision; and 
• 
Why the action was taken. 
 
The Investigator will provide any other information that may be required to enable the trial office to report and 
manage the urgent safety measure in accordance with the current regulatory and ethical requirements for 
expedited reporting and close out. 
The Trials office will follow written procedures to implement the changes accordingly.    
 
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20.6 
Temporary halt 
The sponsor and Investigators reserve the right to place recruitment to this protocol on hold for short periods 
for administrative reasons or to declare a temporary halt. A temporary halt is defined as a formal decision to: 
• 
interrupt the treatment of subjects already in the trial for safety reasons; 
• 
stop recruitment on safety grounds; or 
• 
stop recruitment for any other reason(s) considered to meet the substantial amendment criteria, 
including possible impact on the feasibility of completing the trial in a timely manner. 
 
The trial office will report the temporary halt via an expedited substantial amendment procedure. The trial 
may not restart after a temporary halt until a further substantial amendment to re-open is in place.  If it is 
decided not to restart the trial this will be reported as an early termination. 
20.7 
Serious Breaches 
 The Medicines for Human Use (Clinical Trials) Regulations require the Sponsor to notify any "serious 
breaches" to the MHRA within 7 days of the sponsor becoming aware of the breach. A serious breach is 
defined as “A breach of GCP or the trial protocol which is likely to effect to a significant degree:  
• 
the safety or physical or mental integrity of the subjects of the trial; or 
• 
the scientific value of the trial” 
 
Investigators must notify the trials office at once if any serious breach of GCP is suspected.   
20.8 
Reports: Progress, Safety and End of Study Reports 
This protocol will comply with all current applicable Regulatory Authority, Research Ethics Committee and 
Sponsor requirements for the provision of periodic study safety and progress reports. Any additional reports 
will be provided on request. Reporting will be managed by the trials office according to internal SOPs. Sites 
will be urged to return as much data as possible before each database lock point. 
 
The trial office will determine which reports need to be circulated Principal Investigators and other interested 
parties according to internal SOPs. Study sites are responsible for forwarding trial reports they receive to 
their local Institutions as required. 
 
21 EXPENSES AND BENEFITS 
Each participating centre will follow local regulations and policy on reimbursement of travel expenses. 
 
22 QUALITY ASSURANCE 
22.1 
Risk assessment and monitoring 
The study will undergo a risk assessment prior to study start to determine the extent and nature of site 
monitoring. Risk assessments will be performed throughout the duration of the study on an ad hoc need 
basis and in line with any substantial amendments and any significant findings that might change the 
risk/benefit balance of the study.  Monitoring plans will be amended accordingly. Monitoring (on-site and 
central) will be performed according to the plan and trial office SOPs. 
 
On-Site Monitoring 
Data will be evaluated for compliance with the protocol and accuracy in relation to source documents. 
Monitoring visits reports will be sent to the site in a timely fashion. 
 
Central Monitoring 
Study sites will be monitored centrally by both programmed validation within the data collection database 
and   manual checking of incoming data for compliance with the protocol, data consistency, missing data and 
timing.  All changes to data that could influence the outcome will be queried with and approved by the study 
site in a timely manner. For all other data, where there is no doubt about the source of any errors, clear 
changes to data will be made internally by OCTO staff without referring back to the study site. Study staff will 
be in regular contact with site personnel to check on progress and deal with any queries that they may have 
including those arising from queries raised by OCTO.  
 
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22.2 Audit and Regulatory Inspection 
All aspects of the study conduct may be subject to internal or external quality assurance audit to ensure 
compliance with the protocol, GCP requirements and other applicable regulation or standards. It may also be 
subject to a regulatory inspection. Such audits or inspections may occur at any time during or after the 
completion of the study. Investigators and their host Institution(s) should understand that it is necessary to 
allow auditors/inspectors direct access to all relevant documents, study facilities and to allocate their time 
and the time of their staff to facilitate the audit or inspection visit. Anyone receiving notification of a 
Regulatory Inspection that will (or is likely to) involve this trial must inform the trial office without delay. 
 
23 RECORDS RETENTION & ARCHIVING 
During the clinical trial and after trial closure the Investigator must maintain adequate and accurate records 
to enable the conduct of a clinical trial and the quality of the research data to be evaluated and verified.  
These essential documents, detailed in the trial office SOP must be stored in such a way that ensures that 
they are readily available, upon request, to the sponsor or the Regulatory Agency, for the minimum period 
required by national legislation or for longer if needed.  The medical files of trial subjects shall be retained in 
accordance with national legislation and in accordance with the host institution policy. It is the University of 
Oxford’s policy to store research data for a minimum of 5 years. Retention and storage of laboratory records 
for clinical trial samples will follow national guidelines. 
 
Retention and storage of central laboratory records supporting PK or PD endpoints and the disposition of 
samples donated via the trial must also comply with applicable legislation and Sponsor requirements. 
 
It is the University of Oxford’s policy to store data for a minimum of 5 years. Investigators may not archive or 
destroy study essential documents or samples without written instruction from the trial office. 
 
24 PATIENT CONFIDENTIALITY 
Personal data recorded on all documents will be regarded as confidential, and to preserve each patient’s 
anonymity, only their patient study number, initials and date of birth (or other identified as appropriate to 
country regulations and agreed with the Sponsor) will be recorded on the CRFs.  
 
The Investigator site must maintain the patient’s anonymity in all communications and reports related to the 
research. The Investigator site team must keep a separate log of enrolled patients’ personal identification 
details as necessary to enable them to be tracked. These documents must be retained securely, in strict 
confidence. They form part of the Investigator Site File and are not to be released externally. 
 
25 STUDY FUNDING 
This trial is being organised by the Oncology Clinical Trials Office (OCTO) at the University of Oxford and is 
being funded by the European Commission. The trial is part of the NIHR portfolio, and any additional NHS 
clinical service support costs of patient care while on study should be met by the host study site. 
26 SPONSORSHIP AND INDEMNITY 
26.1 
Sponsorship 
The Sponsor will provide written confirmation of Sponsorship and authorise the trial commencement once 
satisfied that all arrangements and approvals for the proper conduct of the trial are in place. A separate study 
delegation agreement, setting out the responsibilities of the Chief Investigator and Sponsor will be put in 
place between the parties.  
26.2 
Insurance 
The University has a specialist insurance policy in place: - Newline Underwriting Management Ltd, at Lloyd’s 
of London - which would operate in the event of any participant suffering harm as a result of their 
involvement in the research. 
 
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26.3 
Contracts/Agreements 
This trial is subject to the Sponsor’s policy requiring that written contracts/agreements are agreed formally by 
the participating bodies as appropriate. A Clinical Trial Agreement (CTA) will be placed between the Sponsor 
and participating sites prior to site activation.  The Sponsor will also set up written agreements with any other 
external third parties involved in the conduct of the trial as appropriate.  
27 PUBLICATION POLICY 
Ownership and publication policy will be as per the MErCuRIC consortium agreement.  
Authors shall acknowledge that the study was sponsored by the University of Oxford and funded by the 
MErCuRIC EU 7th Framework Programme (Grant agreement number 602901-2). 
 
 
 
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APPENDIX 1: ECOG PERFORMANCE SCALE 
 
Activity Performance Description 
Score 
 
 
Fully active, able to carry out all on all pre-disease performance without restriction. 
0 
 
 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature, e.g. light housework, office work. 
1 
 
 
Ambulatory and capable of all self-care, but unable to carry out any work activities.  Up and 
about more than 50% of waking hours.  
2 
 
 
Capable of only limited self-care.  Confined to bed or chair more than 50% of waking hours.  
3 
 
 
Completely disabled. Cannot carry out any self-care. Totally confined to bed or chair. 
 
4 
 
 
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APPENDIX 2: COCKCROFT AND GAULT FORMULATION ESTIMATE GFR 
 
The estimated GFR is given by: 
 
Males:      1.25 x (140 – age) x weight (kg) 
                    serum creatinine (μmol/l) 
 
Females:  1.05 x (140 – age) x weight (kg) 
                    serum creatinine (μmol/l) 
 
• 
This formula usually under-estimates GFR by 10-30% compared with EDTA or measured 24-hour 
creatinine clearance, so is used in this trial as a screening test. 
• 
 
• 
A Cockcroft and Gault estimate of ≥50 ml/min is accepted as evidence of adequate renal function. 
• 
 
• 
Patients with a Cockcroft and Gault estimate of <50 ml/min prior to randomisation should have 
formal GFR measurement with EDTA or 24 urinary creatinine, which must be within the normal 
range. The corrected EDTA clearance should be ≥50ml/min. 
• 
 
• 
After the start of treatment, if the Cockcroft and Gault estimate falls by >25% from baseline or to 
below 50 ml/min, the EDTA measurement or 24 hour urinary creatinine should be re-checked. 
 
 
 
 
 
 
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APPENDIX 3: NCI-CTCAE V4.0 CRITERIA NEUROLOGIC DISORDERS 
 
Toxicity 
Grade 
1 
2 
3 
4 
Neurological 
Neuro-sensory 
mild paresthesias, 
loss of deep tendon 
reflexes 
mild or moderate 
objective sensory 
loss; moderate 
paresthesias 
severe objective 
sensory loss or 
paresthesias that 
interfere with 
function 
- 
Neuro-motor 
subjective 
weakness; 
no objective 
findings 
mild objective 
weakness without 
significant 
impairment of 
function 
objective weakness 
with impairment of 
function 
paralysis 
Neuro-cortical 
mild somnolence or 
agitation 
moderate 
somnolence or 
agitation 
severe 
somnolence, 
agitation, 
confusion, 
disorientation, or 
hallucinations 
coma, seizures, 
toxic 
psychosis 
Neuro-cerebellar 
slight 
incoordination, 
dysdiadochokinesia 
intention tremor, 
dysmetria, slurred 
speech, nystagmus 
locomotor ataxia 
cerebellar necrosis 
Neuro-mood 
mild anxiety or 
depression 
moderate anxiety 
or 
depression 
severe anxiety or 
depression 
suicidal ideation 
Neuro -- 
headache 
mild 
moderate or severe 
but transient 
unrelenting and 
severe 
- 
Neuro- 
constipation 
mild 
moderate 
severe 
ileus >96 hrs 
Neuro-hearing 
asymptomatic, 
hearing loss on 
audiometry only 
tinnitus 
hearing loss 
interfering with 
function but 
correctable with 
hearing aid 
deafness not 
correctable 
Neuro-vision 
- 
- 
symptomatic 
subtotal loss of 
vision 
blindness 
 
 
 
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APPENDIX 4: MEASUREMENT OF DISEASE - RECIST 1.1 CRITERIA 
RESPONSE EVALUATION CRITERIA IN SOLID TUMOURS 
Objective tumour response and time of progression will be measured according to the RECIST (Response 
Evaluation Criteria In Solid Tumours) criteria (version 1.1).  
Response criteria are essentially based on a set of measurable lesions identified at baseline as target 
lesions, and – together with other lesions that are denoted as non-target lesions – followed until disease 
progression. 
The following paragraphs are a quick reference to the RECIST criteria (version 1.1). The complete criteria 
are included in the published RECIST document: 
 
Eisenhauer, EA, Therasse, P, Bogaerts, J, et al. New response evaluation criteria in solid tumours: revised 
RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-247 
 
Up to date details are available at: http://www.eortc.be/RECIST 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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APPENDIX 5: MEDICATIONS TO BE AVOIDED OR USED WITH CAUTION WITH PF-
02341066 
 
NB. This list is not exhaustive and the absence of a drug from the list does not imply that its 
combination with PF-02341066 is safe.  Please contact the Trials office if further clarification is 
required. 
 
 
DRUGS AFFECTING CYTOCHROME P450 
 
Potent inhibitors of CYP3A4/5: may increase exposure to PF-02341066 by more than 3-fold 
The following drugs should not be combined with PF-02341066.  Recommended withdrawal periods for 
patients who have recently received treatment with these agents are indicated in the table.  For example, it is 
recommended that patients should not have received clarithromycin for at least 7 days before treatment with 
PF-02341066 is started. 
Contra-indicated 
Drug 
Inhibits 
Minimum washout period prior 
to PF-02341066 administration 
Ketoconazole, Ritonavir, Atazanavir, Saquinavir, 
Indinavir, Nefazodone, Nelfinavir 
CYP3A4/5 
2 days  
 
Itraconazole, Clarithromycin, Erythromycin*, 
Fluconazole>400 mg 
CYP3A4/5 
7 days  
Diltiazem 
CYP3A4/5 
2 Weeks  
* Topical use of erythromycin is permitted during treatment with PF-02341066 
 
Moderate Inhibitors of CYP3A4/5: may increase exposure to PF-02341066 
Caution should be exercised in combining the following drugs with PF-02341066. 
Warning of possible interaction 
Drug 
Inhibits 
 
Verapamil 
CYP3A4 
These drugs are permitted but caution should be 
exercised and patients monitored closely for possible drug 
interactions.  
Grapefruit juice 
CYP3A4 
Patients should abstain from eating large amounts of 
grapefruit and Seville oranges (and other products 
containing these fruits, e.g. grapefruit juice or marmalade) 
during the study.  Please do not have more than a small 
glass of grapefruit juice (120 mL) or half a grapefruit or 1-2 
teaspoons (15 g) of Seville orange marmalade daily. 
Seville oranges (and other 
products containing Seville 
oranges) 
CYP3A4 
 
Potent Inducers of CYP3A4/5: may reduce exposure to PF-02341066 by more than 3-fold 
The following drugs should not be combined with PF-02341066.  Recommended withdrawal periods for 
patients who have recently received treatment with these agents are indicated in the table.  For example; it is 
recommended that patients should not have received carbamazepine for at least 2 weeks before treatment 
with PF-02341066 is started 
 
 
 
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Contra-indicated 
Drug 
 
Minimum washout period prior to                     
PF-02341066 administration 
Barbiturates,Carbamazepine, Phenytoin, 
Rifampicin, Rifabutin, St John’s Wort 
 
2 Weeks 
 
Substrates of CYP3A4/5: PF-02341066 may increase exposure 
The following drugs should not be given with PF-02341066 
 
Contra-indicated 
Drug 
 
 
Dihydroergotamine, Ergotamine 
Pimozide, Astemizole, Cisapride 
Terfenadine 
 
CYP3A4/5 substrates with narrow therapeutic 
indices associated with life-threatening 
arrhythmias, and must be avoided during               
PF-02341066 administration 
 
The following drugs may be given with PF-02341066, but caution is advised 
 
Contra-indicated 
Drug 
 
 
Alfentanil, Cyclosporin,  
Fentanyl, Quinidine,  
Sirolimus, Tacrolimus 
 
CYP3A4/5 substrates with narrow therapeutic 
indices, caution must be exercised 
 
The following bradycardic agents (e.g. beta-blockers, non-dihydropyridine calcium channel blockers) should 
not be given with PF-02314066 
 
 
Contra-indicated 
Drug 
 
 
Verapamil, Diltiazem 
Clonidine, 
Digoxin 
 
Increased risk of symptomatic bradycardia 
 
 
DRUGS THAT MAY PROLONG QT INTERVAL 
 
The drugs listed in this section are taken from information provided by The Arizona Center for Education and 
Research on Therapeutics and The Critical Path Institute, Tucson, Arizona and Rockville, Maryland. 
http://www.arizonacert.org/medical-pros/drug-lists/drug-lists.htm 
The following drugs are known to prolong QT interval or induce Torsades de Pointes and should not be 
combined with PF-02341066.  Recommended withdrawal periods for patients who have recently received 
treatment with these agents are indicated in the following table.  
 
 
 
 
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Contraindicated drug 
Withdrawal period  
Droperidol, Procainamide 
2 days 
Cisapride Clarithromycin, Disopyramide, Dofetilide, Domperidone, Erythromycin**, 
Ibutilide, Quinidine, Sotalol, Sparfloxacin, Thioridazine 
7 days 
Bepridil, Chlorpromazine, Halofantrine, Haloperidol, Mesoridazine 
14 days 
Levomethadyl, Methadone, Pimozide 
4 weeks 
Arsenic trioxide 
6 weeks* 
Pentamidine 
8 weeks 
Amiodarone, Chloroquine 
1 year 
* 
Estimated value as pharmacokinetics of arsenic trioxide has not been studied 
** 
Topical use of erythromycin is permitted during treatment with PF-02341066 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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APPENDIX 6: RECOMMENDED DOSE MODIFICATIONS FOR BINIMETINIB (MEK 162) 
Guidelines – Binimetinib (MEK162) 
 
Recommended Dose Modifications 
Version 2    11 November 2015 
 
Binimetinib (MEK162) Dose Modifications 
Patients will be monitored for adverse events at each visit with the NCI CTCAE version 4.03 used 
for all grading. Doses of MEK162 should be adjusted for AEs throughout the study. In general, 
doses should not be reduced or interrupted for Grade 1 AEs unless the AE is a specific treatment-
related ocular AE. Treatment to control symptoms should be provided as appropriate. All dose 
modifications should be based on the worst preceding toxicity (CTCAE version 4.03). 
An individual patient may have their dose of MEK162 reduced to the dose levels specified in Table 
6. When the AE that resulted in a dose reduction improves to and remains stable at the patient’s 
Baseline for a minimum of 14 days, the dose can be re-escalated to the next dose level at the 
discretion of the Investigator, provided there are no other concomitant MEK162-related toxicities 
that would prevent drug re-escalation. There is no limit to the number of times the patient can have 
their dose reduced or re escalated (in 15 mg increments); however, no dose re escalation is allowed 
after a dose reduction due to LVEF dysfunction or prolonged QTcF ≥ 501 msec. 
A dose reduction below 30 mg BID is not allowed (Table 6). Patients requiring additional 
reductions must be discontinued from study treatment.  Dose interruptions of more than 21 days are 
not allowed. 
 
Eye disorders should be graded according to CTCAE version 4.03 as described below in Table 1. 
Table 1 CTCAE grading for eye disorders 
Grade 
Description 
1 
Asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not 
indicated 
2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age appropriate 
instrumental ADL 
3 
Severe or medically significant but not immediately sight threatening; 
Hospitalization or prolongation of existing hospitalization indicated; disabling; limiting self-
care ADL 
4 
Sight-threatening consequences; urgent intervention indicated; blindness (20/200 or worse) 
in the affected eye 
ADL= activities of daily living 
Retinal detachment should be graded according to the CTCAE version 4.03 as described below in Table 2. 
Table 2 
CTCAE grading for retinal detachment 
Grade 
Description 
1 
Asymptomatic 
2 
Exudative and visual acuity 20/40* or better 
3 
Rhegmatogenous or exudative detachment; operative intervention indicated; decline in 
vision 
(worse than 20/40*but better than 20/200*) 
4 
Blindness (20/200* or worse) in the affected eye 
* Please refer to Appendix 7 for Snellen Equivalence (Visual Acuity Conversion Chart). 
 
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Uveitis should be graded according to the CTCAE version 4.03 as described below in Table 3.  
Table 3 CTCAE grading for uveitis 
Grade 
Description 
1 
Asymptomatic; clinical or diagnostic observations only 
2 
Anterior uveitis; medical intervention indicated 
3 
Posterior or pan-uveitis 
4 
Blindness (20/200* or worse) in the affected eye 
* Please refer to Snellen Equivalence (Visual Acuity Conversion Chart). 
 
Hand Foot Skin Reaction should be graded according to CTCAE version 4.03 as described below in Table 4. 
Table 4 
CTCAE grading of Hand foot skin reaction (HFSR)a 
Grade 
Descriptionb 
1 
Minimal skin changes or dermatitis (e.g., erythema, edema, numbness, dysesthesia, 
paresthesia, tingling or hyperkeratosis) without pain 
2 
Skin changes (e.g.,peeling, blisters, bleeding, edema, or hyperkeratosis) with pain; limiting 
instrumental ADL 
3 
Severe skin changes (e.g., peeling, ulceration, blisters, bleeding, edema, or 
hyperkeratosis) with pain; limiting self-care ADL 
ADL=activities of daily living 
aHFSR or palmar-plantar erythrodysaesthesia syndrome, a disorder characterized by redness, marked 
discomfort, swelling, and tingling in the palms of the hands or the soles of the feet; 
bMore specifics examples to grade 1 and grade 3 are added to facilitate proper grading [from the sorafenib 
package insert (West Haven, CT: Bayer Pharmaceuticals Corporation; 2007); Porta et al 2007]. 
Diarrhea should be graded according to CTCAE version 4.03 as described below in Table 5. 
Table 5 CTCAE grading of diarrhea 
Grade 
Description 
1 
Increase of < 4 stools per day over baseline; mild increase in ostomy output compared to 
baseline 
2 
Increase of 4-6 stools per day over baseline; moderate increase in ostomy output 
compared to baseline 
1-2 
Complicated  
Definition as above with the following complicating signs/symptoms: 
• Moderate to severe cramping 
• Grade ≥ 2 nausea/vomiting 
• Decreased performance status 
• Fever 
• Sepsis 
• Neutropenia 
• Frank bleeding 
• Dehydration 
• 
Unresolved diarrhea after 48 hours of treatment with loperamide (including high dose 
administration) and initiation of second-line treatment 
3 
Increase of ≥ 7 stools per day over baseline; hospitalization indicated; severe increase in 
ostomy output compared to baseline; limiting self-care ADL 
4 
Life threatening consequences; urgent intervention indicated 
ADL=activities of daily living 
 
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Dose modification and dose delay for MEK162 
Table 6 
Dose reduction for MEK162  
Missed/skipped doses will not be made up (i.e. the patient should not double their dose if the previous dose 
was missed). When the toxicity that resulted in a dose reduction improves to and remains stable at Grade 1 
or less for a minimum of 21 days, the dose can be re-escalated at the investigator’s discretion provided there 
are no other concomitant toxicities.  
No dose re-escalation is allowed after dose reduction due to left ventricular dysfunction or prolonged 
QTcF > 500 msec. 
Dose reduction/interruption/discontinuation decisions should be based on the CTCAE grade of the toxicity 
and the guidelines provided below. All AEs should be followed weekly or as clinically appropriate until 
stabilization or resolution. 
Please refer to the tables below for dose adjustment recommendations for MEK162 induced toxicities.  
Dose reduction* 
 
Binimetinib 
(MEK162) 
Dose (level - 0) 
Dose level - 1** 
45 mg BID 
30 mg BID 
*Dose reduction should be based on the highest AE grade 
**Dose reduction below 30 mg bid is not allowed 
 
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MEK162 – Recommended dose modifications associated with treatment-related adverse events  
Worst Toxicity 
CTCAE v4.03 
Grade 
(unless 
otherwise 
specified) 
                                  Dose Modification for Binimetinib 
Eye Disorder – Serous Detachment of the Retina Eventsb,c 
Grade 1 
 
• Maintain dose level of binimetinib and increase frequency of 
ophthalmic monitoring to at least every 14 days until stabilization or 
resolution 
Grade2 
 
• Maintain dose level of binimetinib and refer the patient to 
ophthalmologist within 1 week: 
o 
If resolved to Grade ≤ 1 in ≤ 21 days, maintain dose of 
binimetinib 
o 
If not resolved to Grade ≤ 1 in ≤ 21 days, reduce 1 dose leveld 
of binimetinib or maintain dose of binimetinib based upon the 
Investigator’s discretion after consultation with the 
ophthalmologist 
Grade 3 
 
• Interrupt binimetinib and refer the patient to ophthalmologist within 
1 week: 
o 
If resolved to Grade ≤ 1 in ≤ 21 days, reduce 1 dose leveld of 
binimetinib 
o 
If not resolved to Grade ≤ 1 in ≤ 21 days, permanently 
discontinue binimetinib and close follow-up with ophthalmic 
monitoring until stabilization or resolution 
Grade 4 
• Permanently discontinue binimetinib and immediate follow-up with 
ophthalmic monitoring until stabilization or resolution 
Eye Disorder – RVOc 
RVO of any grade 
• Permanently discontinue binimetinib and immediate follow-up with 
ophthalmic monitoring until stabilization or resolution 
Other Eye Disorders (i.e., Non-retinal Events)c 
Grade 1-2 
 
• Maintain dose level of binimetinib and increase frequency of 
ophthalmic monitoring to at least every 14 days until stabilization or 
resolution 
Grade 3 
• Interrupt binimetinib and refer patient to ophthalmologist within 
1 week: 
o If resolved to Grade ≤ 1 in ≤ 21 days, reduce 1 dose leveld of 
binimetinib 
o If not resolved to Grade ≤ 1 in ≤ 21 days, permanently 
discontinue binimetinib and close follow-up with ophthalmic 
monitoring until stabilization or resolution 
Grade 4 
• Permanently discontinue binimetinib and immediate follow-up with 
ophthalmic monitoring until stabilization or resolution 
 
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Worst Toxicity 
CTCAE v4.03 Grade 
(unless otherwise specifieda) 
Dose Modification for Binimetinib 
Liver-related Adverse Events 
Grade 1 
ALT or AST > ULN to 3 × ULN 
• Maintain dose level of binimetinib 
 
Grade 2 
For patients with Baseline 
ALT/AST values ≤ ULN: 
ALT or AST > 3.0 to 5.0 × ULN 
and blood bilirubinf ≤ 2.0 × ULN 
• Interrupt binimetinib until resolved to Grade ≤ 1, then: 
o 
If resolved in ≤ 14 days, maintain dose level of binimetinib 
o 
If not resolved in ≤ 14 days, reduce 1 dose leveld of 
binimetinib 
For patients with liver metastases 
or ALT/AST Baseline 
values >ULN: 
ALT or AST 3 × Baseline value to 
5.0 × ULN and blood bilirubinf 
≤ 2.0 × ULN 
• Interrupt binimetinib until resolved to Grade ≤ 2, then: 
o 
If resolved in ≤ 14 days, maintain dose level of binimetinib 
o 
If not resolved in ≤ 14 days, reduce 1 dose leveld of 
binimetinib  
For all patients: 
ALT or AST > 3.0 to 5.0 × ULN 
and blood bilirubinf > 2.0 × ULN  
 
• Interrupt binimetinib until resolved to Grade ≤ 1, then: 
o 
If resolved in ≤ 7 days, reduce 1 dose leveld of binimetinib 
o 
If not resolved in ≤ 7 days, permanently discontinue 
binimetinib  
Grade 3 
ALT or AST > 5.0 to 8.0 × ULN  
and blood bilirubinf ≤ 2.0 × ULN 
 
 
ALT or AST > 8.0 ×ULN  
and blood bilirubinf ≤ 2.0 × ULN 
 
ALT or AST > 5.0 × ULN  
and blood bilirubinf > 2.0 × ULN 
• Interrupt binimetinib until resolved to Grade ≤ 1 (or Grade ≤ 2 in 
case of liver metastasis), then: 
o 
If resolved in ≤ 14 days, maintain dose level of binimetinib 
o 
If not resolved in ≤ 14 days, reduce 1 dose leveld of 
binimetinib 
 
• Permanently discontinue binimetinib 
 
• 
Permanently discontinue binimetinib 
 
Grade 4  
ALT or AST > 20.0 × ULN 
• Permanently discontinue binimetinib 
QTc Prolongation 
Grade 3 
mean triplicate QTcF ≥ 501 msec 
(confirmed by a separate mean 
triplicate ECG) 
First Occurrence: 
• Interrupt binimetinib. Electrolyte abnormalities (if applicable) 
should be corrected and any concomitant medication that could 
potentially prolong QT should be discontinued 
• Monitor patient until resolution of the AE. Include a consultation 
with a cardiologist, if indicated 
• Once resolved to Grade ≤ 1, resume binimetinib at 1 reduced dose 
leveld 
Second Occurrence: 
• If second occurrence is attributed to binimetinib, permanently 
discontinue binimetinib 
 
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Worst Toxicity 
CTCAE v4.03 Grade 
(unless otherwise specifieda) 
Dose Modification for Binimetinib 
Cardiac Disorders - Left Ventricular Systolic Dysfunctiona 
Asymptomatic absolute decrease 
of > 10% in LVEF compared to 
Baseline and the LVEF is below 
the institution’s LLN (e.g., a 
decrease of 60% to 48% is an 
absolute decrease of 12%) 
• Interrupt binimetinib and repeat evaluation of LVEF within 2 weeks: 
o If the LVEF recovers (defined as LVEF ≥ 50% or ≥ LLN and 
absolute decrease ≤ 10% compared to Baseline) in ≤ 21 days, 
reduce 1 dose leveld after approval of the Medical Monitor. 
Monitor LVEF 2 weeks after resuming binimetinib, every 
4 weeks for 12 weeks and subsequently as per protocol 
o If the LVEF does not recover in ≤ 21 days, permanently 
discontinue binimetinib. Closely monitor LVEF until resolution 
or for up to 16 weeks 
Grade 3-4 
• Permanently discontinue binimetinib. Closely monitor LVEF until 
resolution or for up to 16 weeks 
Note: Copies of ECHO and/or MUGA scans may be requested to be 
available to the Sponsor for patients with absolute decrease of > 10% 
in LVEF compared to Baseline and LVEF < LLN 
CK Elevations 
Grade 1-2 
• Maintain dose level of binimetinib 
o If total CK ≥ 3 × ULN, measure CK, CK isoenzymes and 
myoglobin in blood or urine weekly for 3 weeks and if total CK 
remains ≤ Grade 2, continue to assess CK, CK isoenzymes 
and myoglobin along with regularly scheduled clinical chemistry 
assessments 
Grade 3  
> 5.0 to 10.0 × ULN 
• If asymptomatic, maintain dose of binimetinib and monitor closely 
o Measure CK, CK isoenzymes and myoglobin in blood or urine 
weekly for 3 weeks and if total CK remains ≤ Grade 3, continue 
to assess CK, CK isoenzymes and myoglobin along with 
regularly scheduled clinical chemistry assessments 
• If symptomatic (muscle pain/spasms), interrupt binimetinib until 
resolved to Grade ≤ 1 and monitor closely, then: 
o 
If resolved in ≤ 21 days, reduce 1 dose leveld of binimetinib 
o 
If not resolved in ≤ 21 days, permanently discontinue 
binimetinib  
Grade 4 
• If asymptomatic, interrupt binimetinib until resolved to Grade ≤ 1 
and monitor closely, then: 
o 
If resolved in ≤ 21 days, reduce 1 dose leveld of binimetinib 
o 
If not resolved in ≤ 21 days, permanently discontinue 
binimetinib 
• If symptomatic, permanently discontinue binimetinib 
 
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Worst Toxicity 
CTCAE v4.03 Grade 
(unless otherwise specifieda) 
Dose Modification for Binimetinib 
Rash 
Grade 1 
• Maintain dose level of binimetinib 
• Initiate Initial Rash Treatment Regimen if it was not already started 
and rash should be closely monitored 
Grade 2  
 
First Occurrence: 
• Maintain dose level of binimetinib and rash should be closely 
monitored 
• Initiate Initial Rash Treatment if it was not already started 
• Reassess within ≤ 14 days. If rash worsens or does not improve, 
interrupt binimetinib until resolved to Grade ≤ 1. Resume 
binimetinib at current dose level 
Second Occurrence: 
• Reassess within ≤ 14 days. If rash worsens or does not improve, 
interrupt binimetinib until resolved to Grade ≤ 1. Resume 
binimetinib at 1 reduced dose leveld 
Grade 3 
 
First Occurrence: 
• Interrupt binimetinib until resolved to Grade ≤ 1. Reassess weekly. 
Resume binimetinib at current dose level 
• Consider referral to dermatologist and manage rash per 
dermatologist’s recommendation 
Second Occurrence: 
• Interrupt binimetinib until resolved to Grade ≤ 1. Reassess weekly. 
Resume binimetinib at 1 reduced dose leveld 
• Consider referral to dermatologist and manage rash per 
dermatologist’s recommendation 
Grade 4 
• Permanently discontinue binimetinib 
Diarrhea 
Uncomplicated Grade 1-2 
• Consider temporary interruption of binimetinib until resolved to 
Grade ≤ 1. Resume binimetinib at current dose level 
Complicated Grade 1-2 
• Temporarily interrupt binimetinib until resolved to Grade ≤ 1. 
Resume binimetinib at 1 reduced dose leveld 
Grade 3 
• Temporarily interrupt binimetinib until resolved to Grade ≤ 1. 
Resume binimetinib at 1 reduced dose leveld 
Grade 4 
• Temporarily interrupt binimetinib until resolved to Grade ≤ 1. 
Resume binimetinib at 1 reduced dose leveld 
 
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Worst Toxicity 
CTCAE v4.03 Grade 
(unless otherwise specifieda) 
Dose Modification for Binimetinib 
All Other Binimetinib Treatment-related Adverse Events 
Grade 1-2 
 
• If the event is Grade 1 or non-persistent Grade 2, maintain dose 
level of binimetinib and monitor until stabilization or resolution 
• If the event is a persistent Grade 2 AE not responsive to a specific 
therapy, consider binimetinib dose interruption or reductiond 
Grade 3 
 
• Interrupt binimetinib until resolved to Grade ≤1 or to 
pretreatment/Baseline level. If the event resolves ≤ 21 days, then 
binimetinib may be resumed at 1 reduced dose leveld based upon 
the Investigator’s discretion 
Grade 4 
• Permanently discontinue binimetinib e 
Abbreviations: AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
BID = twice daily; CK = creatine kinase; CTCAE = Common Terminology Criteria for Adverse Events; 
ECHO = echocardiogram; LLN = lower limit of normal; LVEF = left ventricular ejection fraction; mg = 
milligram(s); MUGA = multi-gated acquisition; OCT = optical coherence tomography; RVO = retinal vein 
occlusion; ULN = upper limit of normal 
a 
Not according to CTCAE. 
b 
Further evaluation with specialized retinal imaging (e.g., OCT [spectral domain OCT recommended] of 
the macula for non-vascular abnormalities; and color fundus photography of the central 30 degrees 
and/or fluorescein angiography for vascular abnormalities) is recommended. 
c 
Images/results of the ophthalmic examinations (at a minimum, OCT, color fundus photography and/or 
fluorescein angiography) must be made available upon Sponsor request. 
d 
The lowest recommended dose level of MEK162 is 15 mg BID. When the AE that resulted in a dose 
reduction improves to and remains stable at ≤ Grade 1 for a minimum of 14 days, the dose can be re-
escalated to the next dose level at the discretion of the Investigator, provided there are no other 
concomitant toxicities. There is no limit to the number of times the patient can have their dose reduced 
or re-escalated (in 15 mg increments); however, no dose re escalation is allowed after a dose reduction 
due to LVEF dysfunction or prolonged QTcF > 500 msec. 
e 
A patient with a Grade 4 AE may resume treatment at the lower dose level if the AE recovers to Grade 
≤ 1 within 21 days of interrupting drug and, if in the opinion of the Investigator and Medical Monitor, the 
event is not life-threatening, and the patient can be managed and monitored for recurrence of AE. Dose 
interruptions of more than 21 days are not allowed unless approved by the Investigator, and the Array 
BioPharma Medical Monitor or designee. 
f 
Refers to total bilirubin. 
 
 
 
 
 
 
 
 
 
 
 
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APPENDIX 6A: UPDATED RECOMMENDED DOSE MODIFICATIONS FOR 
BINIMETINIB (MEK 162) 
Guidelines – Binimetinib (MEK162) 
 
Recommended Dose Modifications 
Version 2    11 November 2015 – updated to guidelines Mar 2017 
 
Binimetinib (MEK162) Dose Modifications 
Patients will be monitored for adverse events at each visit with the NCI CTCAE version 4.03 used 
for all grading. Doses of MEK162 should be adjusted for AEs throughout the study. In general, 
doses should not be reduced or interrupted for Grade 1 AEs unless the AE is a specific treatment-
related ocular AE. Treatment to control symptoms should be provided as appropriate. All dose 
modifications should be based on the worst preceding toxicity (CTCAE version 4.03). 
An individual patient may have their dose of MEK162 reduced to the dose levels specified in Table 
6. When the AE that resulted in a dose reduction improves to and remains stable at the patient’s 
Baseline for a minimum of 14 days, the dose can be re-escalated to the next dose level at the 
discretion of the Investigator, provided there are no other concomitant MEK162-related toxicities 
that would prevent drug re-escalation. There is no limit to the number of times the patient can have 
their dose reduced or re escalated (in 15 mg increments); however, no dose re escalation is allowed 
after a dose reduction due to LVEF dysfunction or prolonged QTcF ≥ 501 msec. 
A dose reduction below 30 mg BID is not allowed (Table 6). Patients requiring additional 
reductions must be discontinued from study treatment.  Dose interruptions of more than 21 days are 
not allowed. 
 
Eye disorders should be graded according to CTCAE version 4.03 as described below in Table 1. 
Table 1 
CTCAE grading for eye disorders 
Grade 
Description 
1 
Asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not 
indicated 
2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age appropriate 
instrumental ADL 
3 
Severe or medically significant but not immediately sight threatening; 
Hospitalization or prolongation of existing hospitalization indicated; disabling; limiting self-
care ADL 
4 
Sight-threatening consequences; urgent intervention indicated; blindness (20/200 or worse) 
in the affected eye 
ADL= activities of daily living 
Retinal detachment should be graded according to the CTCAE version 4.03 as described below in Table 2. 
Table 2 
CTCAE grading for retinal detachment 
Grade 
Description 
1 
Asymptomatic 
2 
Exudative and visual acuity 20/40* or better 
3 
Rhegmatogenous or exudative detachment; operative intervention indicated; decline in 
vision 
(worse than 20/40*but better than 20/200*) 
 
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Grade 
Description 
4 
Blindness (20/200* or worse) in the affected eye 
* Please refer to Appendix 7 for Snellen Equivalence (Visual Acuity Conversion Chart). 
Uveitis should be graded according to the CTCAE version 4.03 as described below in Table 3.  
Table 3 CTCAE grading for uveitis 
Grade 
Description 
5 
Asymptomatic; clinical or diagnostic observations only 
6 
Anterior uveitis; medical intervention indicated 
7 
Posterior or pan-uveitis 
8 
Blindness (20/200* or worse) in the affected eye 
* Please refer to Snellen Equivalence (Visual Acuity Conversion Chart). 
 
Hand Foot Skin Reaction should be graded according to CTCAE version 4.03 as described below in Table 4. 
Table 4 
CTCAE grading of Hand foot skin reaction (HFSR)a 
Grade 
Descriptionb 
1 
Minimal skin changes or dermatitis (e.g., erythema, edema, numbness, dysesthesia, 
paresthesia, tingling or hyperkeratosis) without pain 
2 
Skin changes (e.g.,peeling, blisters, bleeding, edema, or hyperkeratosis) with pain; limiting 
instrumental ADL 
3 
Severe skin changes (e.g., peeling, ulceration, blisters, bleeding, edema, or 
hyperkeratosis) with pain; limiting self-care ADL 
ADL=activities of daily living 
aHFSR or palmar-plantar erythrodysaesthesia syndrome, a disorder characterized by redness, marked 
discomfort, swelling, and tingling in the palms of the hands or the soles of the feet; 
bMore specifics examples to grade 1 and grade 3 are added to facilitate proper grading [from the sorafenib 
package insert (West Haven, CT: Bayer Pharmaceuticals Corporation; 2007); Porta et al 2007]. 
Diarrhea should be graded according to CTCAE version 4.03 as described below in Table 5. 
Table 5    
CTCAE grading of diarrhea 
Grade 
Description 
1 
Increase of < 4 stools per day over baseline; mild increase in ostomy output compared to 
baseline 
2 
Increase of 4-6 stools per day over baseline; moderate increase in ostomy output 
compared to baseline 
1-2 
Complicated  
Definition as above with the following complicating signs/symptoms: 
• Moderate to severe cramping 
• Grade ≥ 2 nausea/vomiting 
• Decreased performance status 
• Fever 
• Sepsis 
• Neutropenia 
• Frank bleeding 
• Dehydration 
• 
Unresolved diarrhea after 48 hours of treatment with loperamide (including high dose 
administration) and initiation of second-line treatment 
 
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Grade 
Description 
3 
Increase of ≥ 7 stools per day over baseline; hospitalization indicated; severe increase in 
ostomy output compared to baseline; limiting self-care ADL 
4 
Life threatening consequences; urgent intervention indicated 
ADL=activities of daily living 
Dose modification and dose delay for MEK162 
Table 6 
Dose reduction for MEK162  
Missed/skipped doses will not be made up (i.e. the patient should not double their dose if the previous dose 
was missed). When the toxicity that resulted in a dose reduction improves to and remains stable at Grade 1 
or less for a minimum of 21 days, the dose can be re-escalated at the investigator’s discretion provided there 
are no other concomitant toxicities.  
No dose re-escalation is allowed after dose reduction due to left ventricular dysfunction or prolonged 
QTcF > 500 msec. 
Dose reduction/interruption/discontinuation decisions should be based on the CTCAE grade of the toxicity 
and the guidelines provided below. All AEs should be followed weekly or as clinically appropriate until 
stabilization or resolution. 
Please refer to the tables below for dose adjustment recommendations for MEK162 induced toxicities.  
 
 
Dose reduction* 
 
Binimetinib 
(MEK162) 
Dose (level - 0) 
Dose level - 1** 
45 mg BID 
30 mg BID 
*Dose reduction should be based on the highest AE grade 
**Dose reduction below 30 mg bid is not allowed 
 
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MEK162 – Recommended dose modifications associated with treatment-related adverse events  
Worst Toxicity 
CTCAE v4.03 
Grade 
(unless 
otherwise 
specified) 
                                  Dose Modification for Binimetinib 
Eye Disorder – Serous Detachment of the Retina Eventsb,c 
Grade 1 
 
• Maintain dose level of binimetinib and increase frequency of 
ophthalmic monitoring to at least every 14 days until stabilization or 
resolution 
Grade2 
 
• Maintain dose level of binimetinib and refer the patient to 
ophthalmologist within 1 week: 
o 
If resolved to Grade ≤ 1 in ≤ 21 days, maintain dose of 
binimetinib 
o 
If not resolved to Grade ≤ 1 in ≤ 21 days, reduce 1 dose leveld 
of binimetinib or maintain dose of binimetinib based upon the 
Investigator’s discretion after consultation with the 
ophthalmologist 
Grade 3 
 
• Interrupt binimetinib and refer the patient to ophthalmologist within 
1 week: 
o 
If resolved to Grade ≤ 1 in ≤ 21 days, reduce 1 dose leveld of 
binimetinib 
o 
If not resolved to Grade ≤ 1 in ≤ 21 days, permanently 
discontinue binimetinib and close follow-up with ophthalmic 
monitoring until stabilization or resolution 
Grade 4 
• Permanently discontinue binimetinib and immediate follow-up with 
ophthalmic monitoring until stabilization or resolution 
Eye Disorder – RVOc 
RVO of any grade 
• Permanently discontinue binimetinib and immediate follow-up with 
ophthalmic monitoring until stabilization or resolution 
Other Eye Disorders (i.e., Non-retinal Events)c 
Grade 1-2 
 
• Maintain dose level of binimetinib and increase frequency of 
ophthalmic monitoring to at least every 14 days until stabilization or 
resolution 
Grade 3 
• Interrupt binimetinib and refer patient to ophthalmologist within 
1 week: 
o If resolved to Grade ≤ 1 in ≤ 21 days, reduce 1 dose leveld of 
binimetinib 
o If not resolved to Grade ≤ 1 in ≤ 21 days, permanently 
discontinue binimetinib and close follow-up with ophthalmic 
monitoring until stabilization or resolution 
Grade 4 
• Permanently discontinue binimetinib and immediate follow-up with 
ophthalmic monitoring until stabilization or resolution 
 
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Worst Toxicity 
CTCAE v4.03 Grade 
(unless otherwise specifieda) 
Dose Modification for Binimetinib 
Liver-related Adverse Events 
Grade 1 
ALT or AST > ULN to 3 × ULN 
• Maintain dose level of binimetinib 
 
Grade 2 
For patients with Baseline 
ALT/AST values ≤ ULN: 
ALT or AST > 3.0 to 5.0 × ULN 
and blood bilirubinf ≤ 2.0 × ULN 
• Interrupt binimetinib until resolved to Grade ≤ 1, then: 
o 
If resolved in ≤ 14 days, maintain dose level of binimetinib 
o 
If not resolved in ≤ 14 days, reduce 1 dose leveld of 
binimetinib 
For patients with liver metastases 
or ALT/AST Baseline 
values >ULN: 
ALT or AST 3 × Baseline value to 
5.0 × ULN and blood bilirubinf 
≤ 2.0 × ULN 
• Interrupt binimetinib until resolved to Grade ≤ 2, then: 
o 
If resolved in ≤ 14 days, maintain dose level of binimetinib 
o 
If not resolved in ≤ 14 days, reduce 1 dose leveld of 
binimetinib  
For all patients: 
ALT or AST > 3.0 to 5.0 × ULN 
and blood bilirubinf > 2.0 × ULN  
 
• Interrupt binimetinib until resolved to Grade ≤ 1, then: 
o 
If resolved in ≤ 7 days, reduce 1 dose leveld of binimetinib 
o 
If not resolved in ≤ 7 days, permanently discontinue 
binimetinib  
Grade 3 
ALT or AST > 5.0 to 8.0 × ULN  
and blood bilirubinf ≤ 2.0 × ULN 
 
 
ALT or AST > 8.0 ×ULN  
and blood bilirubinf ≤ 2.0 × ULN 
 
ALT or AST > 5.0 × ULN  
and blood bilirubinf > 2.0 × ULN 
• Interrupt binimetinib until resolved to Grade ≤ 1 (or Grade ≤ 2 in 
case of liver metastasis), then: 
o 
If resolved in ≤ 14 days, maintain dose level of binimetinib 
o 
If not resolved in ≤ 14 days, reduce 1 dose leveld of 
binimetinib 
 
• Permanently discontinue binimetinib 
 
• 
Permanently discontinue binimetinib 
 
Grade 4  
ALT or AST > 20.0 × ULN 
• Permanently discontinue binimetinib 
QTc Prolongation 
Grade 3 
mean triplicate QTcF ≥ 501 msec 
(confirmed by a separate mean 
triplicate ECG) 
First Occurrence: 
• Interrupt binimetinib. Electrolyte abnormalities (if applicable) 
should be corrected and any concomitant medication that could 
potentially prolong QT should be discontinued 
• Monitor patient until resolution of the AE. Include a consultation 
with a cardiologist, if indicated 
• Once resolved to Grade ≤ 1, resume binimetinib at 1 reduced dose 
leveld 
Second Occurrence: 
• If second occurrence is attributed to binimetinib, permanently 
discontinue binimetinib 
 
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Worst Toxicity 
CTCAE v4.03 Grade 
(unless otherwise specifieda) 
Dose Modification for Binimetinib 
Cardiac Disorders - Left Ventricular Systolic Dysfunctiona 
Asymptomatic absolute decrease 
of > 10% in LVEF compared to 
Baseline and the LVEF is below 
the institution’s LLN (e.g., a 
decrease of 60% to 48% is an 
absolute decrease of 12%) 
• Interrupt binimetinib and repeat evaluation of LVEF within 2 weeks: 
o If the LVEF recovers (defined as LVEF ≥ 50% or ≥ LLN and 
absolute decrease ≤ 10% compared to Baseline) in ≤ 21 days, 
reduce 1 dose leveld after approval of the Medical Monitor. 
Monitor LVEF 2 weeks after resuming binimetinib, every 
4 weeks for 12 weeks and subsequently as per protocol 
o If the LVEF does not recover in ≤ 21 days, permanently 
discontinue binimetinib. Closely monitor LVEF until resolution 
or for up to 16 weeks 
Grade 3-4 
• Permanently discontinue binimetinib. Closely monitor LVEF until 
resolution or for up to 16 weeks 
Note: Copies of ECHO and/or MUGA scans may be requested to be 
available to the Sponsor for patients with absolute decrease of > 10% 
in LVEF compared to Baseline and LVEF < LLN 
CK Elevations 
Grade 1-2 
• Maintain dose level of binimetinib 
o If total CK ≥ 3 × ULN, measure CK, CK isoenzymes and 
myoglobin in blood or urine weekly for 3 weeks and if total CK 
remains ≥ Grade 2, continue to assess CK, CK isoenzymes 
and myoglobin along with regularly scheduled clinical chemistry 
assessments 
Grade 3  
> 5.0 to 10.0 × ULN 
• If asymptomatic, maintain dose of binimetinib and monitor closely 
o Measure CK, CK isoenzymes and myoglobin in blood or urine 
weekly for 3 weeks and if total CK remains ≥ Grade 3, continue 
to assess CK, CK isoenzymes and myoglobin along with 
regularly scheduled clinical chemistry assessments 
• If symptomatic (muscle pain/spasms),  or asymptomatic with an 
increase in creatinine ≥ 1,5 x the patient’s Baseline screening 
creatinine, interrupt binimetinib until resolved to Grade ≤ 1 and 
monitor closely, then: 
o 
If resolved in ≤ 21 days, reduce 1 dose leveld of binimetinib 
o 
If not resolved in ≤ 21 days, permanently discontinue 
binimetinib  
Grade 4 
• If asymptomatic, interrupt binimetinib until resolved to Grade ≤ 1 
and monitor closely, then: 
o 
If resolved in ≤ 21 days, reduce 1 dose leveld of binimetinib 
o 
If not resolved in ≤ 21 days, permanently discontinue 
binimetinib 
• If symptomatic, or asymptomatic with an increase in creatinine ≥ 
1,5 x the patient’s Baseline screening creatinine , permanently 
discontinue binimetinib 
 
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Worst Toxicity 
CTCAE v4.03 Grade 
(unless otherwise specifieda) 
Dose Modification for Binimetinib 
Rash 
Grade 1 
• Maintain dose level of binimetinib 
• Initiate Initial Rash Treatment Regimen if it was not already started 
and rash should be closely monitored 
Grade 2  
 
First Occurrence: 
• Maintain dose level of binimetinib and rash should be closely 
monitored 
• Initiate Initial Rash Treatment if it was not already started 
• Reassess within ≤ 14 days. If rash worsens or does not improve, 
interrupt binimetinib until resolved to Grade ≤ 1. Resume 
binimetinib at current dose level 
Second Occurrence: 
• Reassess within ≤ 14 days. If rash worsens or does not improve, 
interrupt binimetinib until resolved to Grade ≤ 1. Resume 
binimetinib at 1 reduced dose leveld 
Grade 3 
 
First Occurrence: 
• Interrupt binimetinib until resolved to Grade ≤ 1. Reassess weekly. 
Resume binimetinib at current dose level 
• Consider referral to dermatologist and manage rash per 
dermatologist’s recommendation 
Second Occurrence: 
• Interrupt binimetinib until resolved to Grade ≤ 1. Reassess weekly. 
Resume binimetinib at 1 reduced dose leveld 
• Consider referral to dermatologist and manage rash per 
dermatologist’s recommendation 
Grade 4 
• Permanently discontinue binimetinib 
Diarrhea 
Uncomplicated Grade 1-2 
• Consider temporary interruption of binimetinib until resolved to 
Grade ≤ 1. Resume binimetinib at current dose level 
Complicated Grade 1-2 
• Temporarily interrupt binimetinib until resolved to Grade ≤ 1. 
Resume binimetinib at 1 reduced dose leveld 
Grade 3 
• Temporarily interrupt binimetinib until resolved to Grade ≤ 1. 
Resume binimetinib at 1 reduced dose leveld 
Grade 4 
• Temporarily interrupt binimetinib until resolved to Grade ≤ 1. 
Resume binimetinib at 1 reduced dose leveld 
 
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Worst Toxicity 
CTCAE v4.03 Grade 
(unless otherwise specifieda) 
Dose Modification for Binimetinib 
All Other Binimetinib Treatment-related Adverse Events 
Grade 1-2 
 
• If the event is Grade 1 or non-persistent Grade 2, maintain dose 
level of binimetinib and monitor until stabilization or resolution 
• If the event is a persistent Grade 2 AE not responsive to a specific 
therapy, consider binimetinib dose interruption or reductiond 
Grade 3 
 
• Interrupt binimetinib until resolved to Grade ≤1 or to 
pretreatment/Baseline level. If the event resolves ≤ 21 days, then 
binimetinib may be resumed at 1 reduced dose leveld based upon 
the Investigator’s discretion 
Grade 4 
• Permanently discontinue binimetinib e 
Abbreviations: AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
BID = twice daily; CK = creatine kinase; CTCAE = Common Terminology Criteria for Adverse Events; 
ECHO = echocardiogram; LLN = lower limit of normal; LVEF = left ventricular ejection fraction; mg = 
milligram(s); MUGA = multi-gated acquisition; OCT = optical coherence tomography; RVO = retinal vein 
occlusion; ULN = upper limit of normal 
a 
Not according to CTCAE. 
b 
Further evaluation with specialized retinal imaging (e.g., OCT [spectral domain OCT recommended] of 
the macula for non-vascular abnormalities; and color fundus photography of the central 30 degrees 
and/or fluorescein angiography for vascular abnormalities) is recommended. 
c 
Images/results of the ophthalmic examinations (at a minimum, OCT, color fundus photography and/or 
fluorescein angiography) must be made available upon Sponsor request. 
d 
The lowest recommended dose level of MEK162 is 15 mg BID. When the AE that resulted in a dose 
reduction improves to and remains stable at ≤ Grade 1 for a minimum of 14 days, the dose can be re-
escalated to the next dose level at the discretion of the Investigator, provided there are no other 
concomitant toxicities. There is no limit to the number of times the patient can have their dose reduced 
or re-escalated (in 15 mg increments); however, no dose re escalation is allowed after a dose reduction 
due to LVEF dysfunction or prolonged QTcF > 500 msec. 
e 
A patient with a Grade 4 AE may resume treatment at the lower dose level if the AE recovers to Grade 
≤ 1 within 21 days of interrupting drug and, if in the opinion of the Investigator and Medical Monitor, the 
event is not life-threatening, and the patient can be managed and monitored for recurrence of AE. Dose 
interruptions of more than 21 days are not allowed unless approved by the Investigator, and the Array 
BioPharma Medical Monitor or designee. 
f 
Refers to total bilirubin. 
 
 
 
 
 
 
 
 
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APPENDIX 7:  INCLUSION AND EXCLUSION CRITERIA FOR DOSE ESCALATION 
PHASE USING PF-02341066 WITH PD-0325901 
INCLUSION CRITERIA 
• 
Age ≥ 16 years 
• 
ECOG performance status 0-1 (Appendix 1) 
• 
Adequate respiratory and cardiac function (left ventricular function WNL on echocardiography) 
• 
Able to give informed consent and be capable of co-operating with the protocol 
• 
Haematological and biochemical indices within the ranges shown below: 
− 
Haemoglobin (Hb) ≥9g/dl (transfusion to achieve this allowed),  
− 
Neutrophils≥ 1,500/µl,  
− 
Platelet count ≥ 100,000/µl,  
− 
AST or ALT ≤ 3 x ULN, alkaline phosphatase ≤ 2 x ULN, 
− 
Serum Bilirubin ≤ 1.5 x ULN,  
− 
Creatinine Clearance ≥ 30ml/min (Calculated by Cockcroft Gault equation, or by EDTA) 
(Appendix 2) 
• 
Able to swallow oral medication 
• 
Only well-controlled CNS metastatic disease ie stable for at least 12 weeks after therapy (surgery,   
radiotherapy) for brain metastases. 
• 
Life expectancy of at least 3 months. 
• 
Patients with any advanced solid tumours  
• 
Patients for whom the combination of PF-02341066 with PD‐0325901 is a reasonable option. 
 
 
EXCLUSION CRITERIA 
All patients 
• 
Unstable ischemic heart disease, cardiac dysrhythmias, coronary/peripheral artery bypass 
graft or cerebrovascular accident within 6 months prior to starting treatment.  
• 
Ongoing congestive heart failure or cardiac dysrhythmias of NCI CTCAE Grade ≥2 or 
uncontrolled atrial fibrillation.  
• 
History of extensive disseminated/bilateral or known presence of Grade 3 or 4 interstitial 
fibrosis or interstitial lung disease, including a history of pneumonitis, hypersensitivity 
pneumonitis, interstitial pneumonia, interstitial lung disease (ILD), obliterative bronchiolitis, 
and pulmonary fibrosis. A history of prior radiation pneumonitis is allowed.  
• 
Spinal cord compression unless treated with the patient attaining good pain control and 
stable or recovered neurologic function.  
• 
Carcinomatous meningitis or leptomeningeal disease.  
• 
History of hypoalbuminaemia, with peritoneael disease or pleural disease, where patient has 
requirement for ascites or pleural taps. 
• 
History of retinal vein occlusion, intraocular pressure > 21 mmHg or patient considered at 
risk of retinal vein thrombosis. 
• 
Active infections (including chronic hepatitis type B or C and HIV infection if status known), 
severe immunologic defect, compromised bone marrow function 
• 
Other severe acute or chronic medical (including severe gastro-intestinal disorders e.g. 
partial bowel obstruction, malabsorption, active inflammatory bowel disease) or psychiatric 
conditions or laboratory abnormalities that the investigator considers would make the patient 
a poor trial candidate, would impart excess risk associated with study participation or drug 
administration or could interfere with protocol compliance or the interpretation of trial 
results. 
• 
Use of drugs or foods that are known potent CYP3A4 inhibitors or inhibitors or are CYP3A4 
substrates with narrow therapeutic indices (see Appendix 5)  
• 
Radiotherapy (except for palliative reasons), endocrine therapy, immunotherapy or 
chemotherapy during the previous four weeks (six weeks for nitrosoureas, Mitomycin-C) and 
four weeks for investigational medicinal products before treatment. Patients with prostate 
cancer may continue to receive endocrine therapy to maintain castrate levels of androgens. 
• 
Resting ECG with QTc >480msec at 2 or more time points within a 24h period. 
• 
Requirement for medication known to prolong QT interval (see appendix 5). 
• 
History of other malignancy less than 5 years before the diagnosis of current cancer, 
EXCLUDING the following: Non-melanoma skin cancer, in situ carcinoma of the cervix treated 
 
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surgically with curative intent, other malignant tumours that have been treated curatively and 
patient is deemed disease-free  
• 
Women with the ability to become pregnant (or already pregnant or lactating).  However, 
those female patients who have a negative serum or urine pregnancy test before enrolment 
and agree to use two highly effective forms of contraception (oral, injected or implanted 
hormonal contraception and condom plus spermicide, have an intra-uterine device and 
condom plus spermicide, diaphragm with spermicidal gel and condom with spermicide) for 
four weeks before entering the trial, during the trial and for six months afterwards are 
considered eligible.  
• 
Male patients with partners of child-bearing potential (unless they agree to take measures not 
to father children by using two forms of highly effective contraception including oral, injected 
or implanted hormonal contraception and condom plus spermicide during the trial and for six 
months afterwards).  Men with pregnant or lactating partners should be advised to use 
barrier method contraception (condom plus spermicidal gel) to prevent exposure to the 
foetus or neonate. 
• 
Prior exposure to a HGF or cMET inhibitor and/or a MEK inhibitor. 
 
 
 
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APPENDIX 8:   STUDY EVALUATIONS FOR DOSE ESCALATION PHASE USING PF-
02341066 WITH PD-0325901 
1. Main screening: pre-dosing evaluations 
The following must be performed/obtained within the 28 days before the patient receives the first 
administration of study drug.  
 
• 
Written informed consent 
• 
Demographic details 
• 
Medical history (including prior diagnosis, prior treatment, concomitant diseases, concomitant 
medications, therapies received by patient within 28 days prior to cycle 1, day minus 7, known 
ophthalmologic medical history). 
• 
ECOG Performance Status (PS) 
• 
Full physical examination 
• 
Clinical and radiological (CT chest/abdomen/pelvis or CT chest with MRI abdomen/pelvis) 
disease assessment  
• 
Vital signs (systolic/diastolic blood pressure, pulse, body temperature), height and weight. 
• 
Ophthalmic assessment, including visual acuity, pressure, perimetry, slit lamp examination, 
fundoscopy with digital photography, optical coherence tomography and fluorescin angiography.  
• 
Safety blood laboratory examination [Haematology: haemoglobin, white blood cells (WBC) with 
differential count and platelets; Clinical chemistry: sodium, potassium, calcium, phosphate, urea, 
creatinine, total protein, albumin, bilirubin, alkaline phosphatase (alk phos), AST and/or ALT and 
LDH; Coagulation screen: APTT, PT) 
• 
Serum or urine Human Chorionic Gonadotropin (HCG) pregnancy test for women of childbearing 
potential. 
• 
12-lead electrocardiogram 
• 
Echocardiography  
• 
Review of inclusion and exclusion criteria 
• 
Obtain archived tumour tissue for biomarker analysis  
• 
Draw blood sample for germline DNA  
• 
Obtain fresh skin biopsy for PD assessment 
• 
Obtain fresh tumour biopsy for PD assessment, where additional consent has been given. 
 
2. Evaluations during dosing 
Cycle 1 day minus 7 
ECOG PS 
Record of concomitant medications 
Full physical examination  
Vital signs (systolic/diastolic blood pressure, pulse, body temperature) and weight. 
ECG (12-lead) 
Blood for assessment of haematology, clinical chemistry, and coagulation status 
Blood for assessment of Carcinoembryonic Antigen (CEA) 
PD assessment of ERK phosphorylation according to timings in section 7.4. 
PD assessment of soluble c-MET and HGF according to timings in section 7.4 
Assessment of adverse events  
Dosing with PD‐0325901. 
 
Cycle 1 day minus 6 
Blood for PD assessment (24 hour sample)  
Dosing with PD‐0325901. 
 
Cycle 1 day minus 1 
Blood for PK assessment: blood draws as per section 7.3. 
Dosing with PD-0325901. 
 
Cycle 1 day 1 
ECOG PS 
 
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Record of concomitant medications 
Full physical examination  
Vital signs (systolic/diastolic blood pressure, pulse, body temperature) and weight. 
ECG (12-lead) 
Blood for assessment of haematology, clinical chemistry, and coagulation status 
Blood for assessment of Carcinoembryonic Antigen (CEA) 
PK sampling (24 hour sample) 
PD assessments according to timings in section 7.4. 
Plasma samples for biomarkers; blood draws as per section 7.4. 
Assessment of adverse events  
Start PF-02341066 and PD‐0325901. 
        Obtain blood sample for ctDNA as per section 7.5. 
 
Cycle 1 day 2 
Blood for PD assessment (24 hour sample) as per section 7.4.  
Dosing with PD‐0325901 and PF-02341066. 
 
Cycle 1 day 8 
ECOG PS 
Record of concomitant medications 
Full physical examination  
Vital signs (systolic/diastolic blood pressure, pulse, body temperature) and weight. 
Assessment of adverse events  
Dosing with PD‐0325901 and PF-02341066. 
 
Cycle 1 day 15  
ECOG PS 
Record of concomitant medications 
Full physical examination  
Vital signs (systolic/diastolic blood pressure, pulse, body temperature) and weight. 
ECG (12-lead) 
Blood for assessment of haematology, clinical chemistry, and coagulation status 
Blood for assessment of Carcinoembryonic Antigen (CEA) 
PD assessments according to timings in section 7.4. 
Plasma samples for biomarkers; blood draws as per section 7.4. 
Assessment of adverse events  
Dosing with PD‐0325901 and PF-02341066 
4-6 hours post-dose fresh skin biopsy for PD assessment  
4-6 hours post-dose fresh tumour biopsy for PD assessment (for patients in the dose expansion 
phase and those patients who have consented to the biopsy in the escalation phase). 
 
Cycle 1 day 16 
Blood for PD assessment (24 hour sample) 
Dosing with PD‐0325901 and PF-02341066. 
 
Cycle 1 day 21 
ECOG PS 
Record of concomitant medications 
Full physical examination  
Vital signs (systolic/diastolic blood pressure, pulse, body temperature) and weight. 
PK sampling: blood draws as per section 7.3. 
Ophthalmic assessment, including visual acuity, pressure, perimetry, slit lamp examination, 
fundoscopy with digital photography, optical coherence tomography and fluorescin 
angiography. 
Assessment of adverse events  
Dosing with PD-0325901 and PF-02341066 
 
 
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Cycle 1 day 22 
PK sampling (24 hour sample) 
Dosing with PF-02341066 only 
 
Cycle 1 day 28 
ECOG PS 
Record of concomitant medications 
Full physical examination  
Vital signs (systolic/diastolic blood pressure, pulse, body temperature) and weight. 
PK sampling: blood draws as per section 7.3  
ECG (12-lead) 
Blood for assessment of haematology, clinical chemistry, and coagulation status 
Blood for assessment of Carcinoembryonic Antigen (CEA) 
Assessment of adverse events  
Dosing with PF-02341066 only 
 
Cycle 2 day 1 (Day 29) 
PK sampling (24 hour sample) 
Plasma samples for biomarkers; blood draws as per section 7.4. 
Blood sample for ctDNA (dose expansion phase only) 
 
Dosing with PF-02341066 and restart PD-0325901 
 
Cycle 2 onwards, day 8 
ECOG PS 
Record of concomitant medications 
Full physical examination  
Vital signs (systolic/diastolic blood pressure, pulse, body temperature). 
Assessment of adverse events  
Dosing with PD‐0325901 and PF-02341066 
  
Cycle 2 onwards, day 15 
ECOG PS 
Record of concomitant medications 
Full physical examination  
Vital signs (systolic/diastolic blood pressure, pulse, body temperature). 
Assessment of adverse events  
Dosing with PD‐0325901 and PF-02341066  
Plasma samples for biomarkers; blood draws as per section 7.4 (cycle 2 only). 
 
Cycle 2 onwards, day 21 
ECOG PS 
Record of concomitant medications 
Full physical examination  
Vital signs (systolic/diastolic blood pressure, pulse, body temperature). 
PK sampling: blood draws as per section 7.3 (trough level and 2h after dosing, cycles 2, 4, 6, 8, 
10 and 12). 
Assessment of adverse events  
Dosing with PD-0325901 and PF-02341066 
 
 
Cycle 3 onwards day 1 
ECOG PS 
Record of concomitant medications 
Full physical examination  
Clinical and radiological (CT chest/abdomen/pelvis or CT chest with MRI abdomen/pelvis) 
disease assessment  
 
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Vital signs (systolic/diastolic blood pressure, pulse, body temperature) and weight. 
ECG (12-lead) 
Blood for assessment of haematology, clinical chemistry, and coagulation status 
Blood for assessment of Carcinoembryonic Antigen (CEA) 
Plasma samples for biomarkers; blood draws as per section 7.4. 
Blood sample for ctDNA (dose expansion phase only) 
Assessment of adverse events  
Dosing with PF-02341066 and re-start PD-0325901 
 
3.  End of treatment evaluations 
ECOG PS 
Record of concomitant medications 
Full physical examination  
Vital signs (systolic/diastolic blood pressure, pulse, body temperature) and weight. 
Blood for assessment of haematology, clinical chemistry, and coagulation status 
Blood for assessment of Carcinoembryonic Antigen (CEA) 
Blood for ctDNA (dose expansion phase only) 
Ophthalmic assessment, including visual acuity, pressure, perimetry, slit lamp examination, 
fundoscopy with digital photography, optical coherence tomography and fluorescin 
angiography. 
Assessment of adverse events  
ECG (12-lead) 
Tumour assessment: CT scan chest/abdomen/pelvis (or CT chest with MRI abdomen/pelvis) 
using RECIST v1.1. 
Biopsy of representative metastases for molecular profiling (dose expansion phase only: 
optional) 
 
 
4. Post treatment follow-up - evaluations 
• 
Assessment of adverse events  
• 
Patients will be followed up every 3 months for survival status until death or study closure, 
whichever happens first. 
 
5. Evaluations on early withdrawal 
If the patient is withdrawn from treatment, for any of the reasons indicated in section 6, a final off-study visit 
assessment should be performed 28 - 30 days after the last administration of PF-02341066 and PD‐
0325901. The following assessments will be done: 
• 
ECOG PS 
• 
Record of concomitant medications 
• 
Full physical examination  
• 
Vital signs (systolic/diastolic blood pressure, pulse, body temperature) and weight. 
• 
Blood for assessment of haematology, clinical chemistry, and coagulation status 
• 
Assessment of adverse events  
• 
ECG (12-lead) 
 
 
If the patient is withdrawn from the trial and declines attendance for a final off-study visit, then a withdrawal 
assessment should be performed, if possible on the day the decision is made to take the patient off-study or 
as soon as possible. Telephone review is permitted in these circumstances. These patients will be followed 
up for progression and overall survival.  
 
 
 
 
 
 
 
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APPENDIX 9: SCHEDULE OF EVENTS FOR DOSE ESCALATION PHASE USING PF-02341066 WITH PD-0325901 
 
 
Visit Description 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
onwards 
End of  
Treatment o 
Post end of 
treatment 
follow-up 
Visit No 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
Repeat 
cycle 3 
and 4  
 
 
Day 
-28 to 
-1 
-7 
-6 
-1 
1 
2 
8 
15 
16 
21 
22 
28 
29±3 
36 
43 
49 
57±3 
64 
71 
78 
85±3 
92 
99 
105 
D 28-30 
after last 
dose 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics & History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medication 
X 
X 
 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG 
X 
X 
 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination a 
X 
X 
 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Tumour Assessment b 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Vital signs 
X 
X 
 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height & Weight c 
X 
X 
 
 
X 
 
X 
X 
 
X 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Ophthalmic Exam  d 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Haem &  
Clin Chem Bloods e 
X 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Pregnancy test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12 lead ECG 
X 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Echocardiography f 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CEA g 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
PK 24 hours profile h 
 
 
 
X 
X 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
PK trough i 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
PD PBMC/plasma j 
 
X 
X 
 
X 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE review 
 
X 
 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PD-0325901 administration k 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PF-02341066 administration 
 
 
 
Continuous administration 
Survival data (PFS and OS) 
 
 
 
 
X 
Biomarker studies 
 
 
 
 
Archival tumour sample 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sample germline DNA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD skin biopsy l  
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD tumour biopsy m  
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma soluble  
biomarkers n 
 
X 
 
 
X 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
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a To include vital signs (pulse and systolic/diastolic blood pressure, body temperature) and neurological examination. 
b CT includes chest, abdomen and pelvis. Measurements using modified RECIST 1.1. At screening and after 2nd, 4th, 6th cycle, and every 2 cycles thereafter until intolerable toxicity or progressive disease. 
c Height to measured only at screening. 
d Ophthalmic exam on Cycle 1 Day 21 time window of +/- 2 days  
e To include FBC with differential and platelets, Na, K, Ca, phosphate, urea, creatinine, total protein, albumin, bilirubin, alk phos, AST and /or ALT, LDH, coagulation screen,  APTT, PT (validity period of 
bloods is 3 days). 
f ECHO will only be repeated as clinically indicated. 
g At same time as CT scan (optional at every cycle) plus Cycle 1 Day 28. 
h Serum PK measurements will be taken as specified in the protocol (section 7.3). 
i PK trough sample pre-dose (morning) and 2 hours post dose  day 21 of cycles 2, 4, 6, 8, 10 and 12. 
j PD PBMC/Plasma samples  will be taken as specified in the protocol (section 7.4) 
k Run-in day -7 to day -1 then days 1-21 of each 28 day cycle. 
l Day 15 +/- 7 days. 
m At  Screening and Day 15 +/- 7 days. Optional biopsy if separate consent obtained. 
 n  At each sampling point 4ml of plasma obtained. 
o Disease progression, intolerance or withdrawal. 
 
 
 
 
 
 
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APPENDIX 10:  AMENDMENT HISTORY 
Amendment 
No. 
Protocol 
Version 
No. 
Date issued 
Author(s) of 
changes 
Details of Changes made 
001 substantial 
2.0 
29Jul2014 
Mark Middleton (CI) 
Sharon Love (Stats) 
OCTO 
Pfizer 
 
In response to MHRA NFGNA: clarification 
re MTD and dose modification; Protocol and 
PIS inclusion of MHRA contraception 
guidelines; IMP information correction to 
CTA. 
004 substantial 
3.0 
27Jan2015 
Mark Middleton (CI) 
Sharon Love (Stats) 
OCTO 
Pfizer 
 
Amend IRAS Dataset updated with changes.  
Protocol; Dose Escalation and Dose 
Expansion PIS/CFs; Patient Diary Card; 
Patient Study Card 
Belfast site PI - notice of change of status. 
007 substantial 
4.0 
14Jul2015 
Mark Middleton (CI) 
Sharon Love (Stats) 
OCTO 
Pfizer 
 
Inclusion of interim dose level. Additional 
exclusion criteria. 
Removal of Ondansetron as recommended 
treatment for Vomiting. 
Correction to ECG event Cycle 1 Day 15 
008 substantial 
5.0 
13Apr2016 
Mark Middleton (CI) 
Sharon Love (Stats) 
OCTO 
Pfizer 
Array Biopharma 
Include new study drug, MEK inhibitor 
Binimetinib as replacement for the MEK 
inhibitor PD-0325901. 
Inclusion of an extra short dose escalation 
phase using the new combination study drug 
Binimetinib with PF-02341066. 
 
Change to the study design of the dose 
expansion phase to incorporate specific 
cohorts of RAS wild type colorectal patients. 
 
Additional Investigator Brochure for 
Binimetinib 
 
Notification of change of investigator at an 
existing site, European St Georges 
Pompidou Hospital, Paris. 
011 substantial 
6.0 
14Mar2017 
Mark Middleton (CI) 
OCTO 
Clarification to CPK DLT criteria and dose 
modification guidelines in Protocol secs 8.5 
and 8.5.1 
012 substantial 
7.0 
11May2017 
Mark Middleton (CI) 
Sharon Love (Stats) 
OCTO 
Pfizer 
Array Biopharma 
Amendment to protocol, doe expansion 
phase patient information and screening 
consent form and GP letter.. 
Update to patient numbers required for 
escalation phase as well as total patient 
numbers. 
Update of dose escalation phase site 
numbers from 4to 5. 
Update to dose expansion phase site 
numbers from 8 to 8-10 sites.  
To capture early phase Ib dose expansion 
objective responses to study treatment in a) 
RASMT CRC and b) RASWT/c-
METmut/amplified CRC and c) RASWT/c-
MET over-expressed CRC. This also 
requires an increase in patient number 
target. 
 Update to eligibility and exclusion criteria. 
Update to contraception guidelines. 
Correction to the sec 3.0 dose expansion 
phase secondary endpoints where CT 
scanning was listed in addition to the primary 
 
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endpoint. 
 
Revision of dose expansion phase sample 
collection to exclude pERK sample collection 
in PBMCs and reduction in skin biopsy 
samples to include a limited cohort of 10 
patients. 
 
Change of lab information for processing of 
skin biopsies.   
 
Dose Expansion Schedule changes for: i) 
clarification of post end of treatment and 
follow up and (ii) removal of C1 day 2 and C1 
day 16 as no longer required for PD pERK 
samples. 
Update to dose modification guidelines for 
AEs (pneumonitis and LVEF) 
Change to PI at the Vall d’Hebron, Barcelona 
site. 
013 substantial 
8.0 
11Sep2017 
Mark Middleton (CI) 
OCTO 
Sandra Van 
Schaeybroeck 
(Project coordinator) 
Amendment to sec 7.2 to include PDUM 
facility for evaluation of amplification and c-
MET expression 
Clarifications to sec 15.1 and correction to 
sample size typographical error 
Typographical corrections and clarifications 
to ensure consistency throughout the 
protocol. 
Screening PIS – clarification to reporting 
timeline for RAS genotype  
014 
8.0 
29Aug2018 
Mark Middleton (CI) 
OCTO 
 
Update to IBs -  binimetinib (v Mar2018 and 
crizotinib (v Oct2017) 
015 
9.0 
29Oct2018 
Mark Middleton (CI) 
OCTO 
 
Change of trial statistician details. 
Change in protocol design to include early 
patient recruitment closure – protocol 
synopsis and sec 2.1 and sec 2.3. 
Clarification of CPK dose modification 
guidelines in sec 8.5.1 and Appendix 6A. 
Removal of ctDNA sample collection time-
point in Summary Schedule of Events at 
screening – dose expansion phase and alsp 
sec 5.4 as not required.  
 
 
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