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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.  
| 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/oncologyclinical-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                                      | Professor Richard Wilson                                                                                                                                                                                                                          |
| and Scientific Project Lead                       | 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                               |                                                                                                                                                                                                                                                   |  
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  
| TABLE OF CONTENTS                                                                                                         |                                                                                                                            |                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------|
| GENERAL CONTACT INFORMATION                                                                                               |                                                                                                                            |                                                                                                                 |
| TABLE OF CONTENTS                                                                                                         |                                                                                                                            |                                                                                                                 |
| PROTOCOL SYNOPSIS                                                                                                         |                                                                                                                            |                                                                                                                 |
| SUMMARY SCHEDULE OF EVENTS                                                                                                |                                                                                                                            |                                                                                                                 |
| DOSE E SCALATION P HASE - S CHEDULE OF E VENTS FOR PF-02341066 WITH B INIMETINIB ..................................... 17 |                                                                                                                            |                                                                                                                 |
| DOSE E XPANSION P HASE - S CHEDULE OF E VENTS FOR PF-02341066 WITH B INIMETINIB ................................... 189   |                                                                                                                            |                                                                                                                 |
| ABBREVIATIONS                                                                                                             |                                                                                                                            |                                                                                                                 |
| 1                                                                                                                         | INTRODUCTION .                                                                                                             |                                                                                                                 |
| B BACKGROUND .                                                                                                            |                                                                                                                            |                                                                                                                 |
| 1.1                                                                                                                       |                                                                                                                            |                                                                                                                 |
| 1.2                                                                                                                       | INVESTIGATIONAL MEDICINAL PRODUCTS USED IN THE STUDY .                                                                     |                                                                                                                 |
| 1.3                                                                                                                       | OTHER RESEARCH INTERVENTIONS                                                                                               |                                                                                                                 |
| 1.4                                                                                                                       | RATIONALE FOR THE STUDY                                                                                                    |                                                                                                                 |
| 1.5                                                                                                                       | PRIMARY HYPOTHESIS OF THE TRIAL                                                                                            |                                                                                                                 |
| TRIAL DESIGN .                                                                                                            |                                                                                                                            |                                                                                                                 |
| 2                                                                                                                         | 2.1                                                                                                                        | O OUTLINE                                                                                                       |
| 2.2                                                                                                                       | T T REATMENT S CHEDULE AND DURATION                                                                                        |                                                                                                                 |
| 2.3                                                                                                                       | P P ROJECTED N UMBER OF S UBJECTS                                                                                          |                                                                                                                 |
| 2.4                                                                                                                       | REPLACEMENT OF S UBJECTS .                                                                                                 |                                                                                                                 |
| 2.5                                                                                                                       | P P OST - TRIAL CARE AND F OLLOW -                                                                                         |                                                                                                                 |
| 3                                                                                                                         | OBJECTIVES AND ENDPOINTS .                                                                                                 |                                                                                                                 |
| PATIENT SELECTION                                                                                                         |                                                                                                                            |                                                                                                                 |
| 4                                                                                                                         | INCLUSION CRITERIA                                                                                                         |                                                                                                                 |
| 4.1                                                                                                                       |                                                                                                                            |                                                                                                                 |
| 4.2                                                                                                                       | E EXCLUSION CRITERIA .                                                                                                     |                                                                                                                 |
| 4.3                                                                                                                       | PROTOCOL DEVIATIONS AND WAIVERS TO ENTRY CRITERIA                                                                          |                                                                                                                 |
| 4.4                                                                                                                       | RE-SCREENING IF PATIENT DOES NOT MEET INCLUSION/EXCLUSION CRITERIA FIRST TIME ROUND ......... 40                           |                                                                                                                 |
| 4.5                                                                                                                       | PATIENT REGISTRATION PROCEDURE .                                                                                           |                                                                                                                 |
| TRIAL ASSESSMENTS AND PROCEDURES .                                                                                        |                                                                                                                            |                                                                                                                 |
| 5                                                                                                                         | 5.1                                                                                                                        | P P RE-TRIAL SCREENING CONSENT AND PROCEDURE (DOSE-EXPANSION PHASE ONLY) ................................... 41 |
| INFORMED CONSENT FOR MAIN STUDY                                                                                           |                                                                                                                            |                                                                                                                 |
| 5.2                                                                                                                       | INFORMED CONSENT FOR TRANSLATIONAL SUB-STUDIES                                                                             |                                                                                                                 |
| 5.3                                                                                                                       | M MAIN SCREENING: PRE-DOSING EVALUATIONS .                                                                                 |                                                                                                                 |
| 5.4                                                                                                                       |                                                                                                                            |                                                                                                                 |
| 5.5                                                                                                                       | EVALUATIONS DURING DOSING                                                                                                  |                                                                                                                 |
| 5.6                                                                                                                       | END OF TREATMENT EVALUATIONS                                                                                               |                                                                                                                 |
| 5.7                                                                                                                       | POST TREATMENT FOLLOW-UP - EVALUATIONS .                                                                                   |                                                                                                                 |
| 5.8                                                                                                                       | EVALUATIONS ON EARLY WITHDRAWAL                                                                                            |                                                                                                                 |
| 6.                                                                                                                        | EARLY PATIENT WITHDRAWAL .                                                                                                 |                                                                                                                 |
| 6.1                                                                                                                       | T T REATMENT W ITHDRAWAL .                                                                                                 |                                                                                                                 |
| 6.2                                                                                                                       | W WITHDRAWAL OF C ONSENT .                                                                                                 |                                                                                                                 |
| 6.3                                                                                                                       | P P TIENT EVALUABILITY AND REPLACEMENT .                                                                                   |                                                                                                                 |
| SAMPLES FOR LABORATORY ANALYSIS                                                                                           |                                                                                                                            |                                                                                                                 |
| 7.                                                                                                                        | 7.1                                                                                                                        | S SAMPLES TO BE ANALYSED IN LOCAL LABORATORIES .                                                                |
| 7.2                                                                                                                       | S S AMPLES TO BE SENT TO AND ANALYSED IN A C ENTRAL L ABORATORY                                                            |                                                                                                                 |
| 7.3                                                                                                                       | PHARMACOKINETIC ASSAYS                                                                                                     |                                                                                                                 |
| 7.4                                                                                                                       | PHARMACODYNAMIC ASSAYS                                                                                                     |                                                                                                                 |
| 7.5                                                                                                                       | S SAMPLES FOR MOLECULAR ANALYSIS AND PATIENT DERIVED XENOGRAFTS ....................................................... 49 |                                                                                                                 |
| 7.6                                                                                                                       | SUMMARY OF SAMPLES/ASSAYS TO BE TAKEN DURING THE STUDY .                                                                   |                                                                                                                 |
| 7.7                                                                                                                       | S S AMPLES FOR B IOBANKING .                                                                                               |                                                                                                                 |
| 7.8                                                                                                                       | L L ABELLING AND CONFIDENTIALITY OF SAMPLES SENT .                                                                         |                                                                                                                 |
| 7.9                                                                                                                       | CLINICAL REPORTING OF EXPLORATORY RESEARCH ASSAY RESULTS .                                                                 |                                                                                                                 |
| 7.10                                                                                                                      | T TRIAL SAMPLE RETENTION AT END OF STUDY .                                                                                 |                                                                                                                 |
| 7.11                                                                                                                      | WITHDRAWAL OF CONSENT FOR SAMPLE COLLECTION AND/OR RETENTION                                                               |                                                                                                                 |
| MErCuRIC1_Protocol_V9.0_29Oct2018                                                                                         | Protocol Template V3.0_18Feb2013                                                                                           |                                                                                                                 |
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| MErCuRIC1                                                                                                                | Confidential                                                                              |
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| INVESTIGATIONAL MEDICINAL PRODUCTS (IMPS)                                                                                |                                                                                           |
| 8.1                                                                                                                      | NAME OF IMPS                                                                              |
| 8.2                                                                                                                      | T T REATMENT DOSE                                                                         |
| 8.3                                                                                                                      | D DURATION OF TREATMENT                                                                   |
| MNAGEMENT OF DRUG ADMINISTRATION .                                                                                       |                                                                                           |
| 8.4                                                                                                                      |                                                                                           |
| 8.5                                                                                                                      | D DOSE MODIFICATION                                                                       |
| 8.6                                                                                                                      | COMPLIANCE                                                                                |
| 8.7                                                                                                                      | MNAGEMENT OF OVERDOSE                                                                     |
| OTHER TREATMENTS (NON-IMPS)                                                                                              |                                                                                           |
| 9.1                                                                                                                      | S S UPPORTIVE MEDICATION .                                                                |
| 9.2                                                                                                                      | CONCOMITANT MEDICATION AND NON-DRUG THERAPIES                                             |
| P P ROHIBITED THERAPIES                                                                                                  |                                                                                           |
| 9.3                                                                                                                      |                                                                                           |
| 9.4                                                                                                                      | (P OTENTIAL ) D RUG I NTERACTIONS                                                         |
| DRUG MANAGEMENT                                                                                                          |                                                                                           |
| 10.1                                                                                                                     | D DRUG SUPPLIES                                                                           |
| 10.2                                                                                                                     | D DRUG ORDERING                                                                           |
| 10.3                                                                                                                     | IMP R ECEIPT .                                                                            |
| 10.4                                                                                                                     | H HANDLING AND STORAGE .                                                                  |
| 10.5                                                                                                                     | L L ABELLING .                                                                            |
| 10.6                                                                                                                     | D DOSING DISPENSING                                                                       |
| 10.7                                                                                                                     | D DRUG ACCOUNTABILITY                                                                     |
| 10.8                                                                                                                     | DRUG RETURNS FROM PATIENTS                                                                |
| 10.9                                                                                                                     | D DRUG DESTRUCTION                                                                        |
| 10.10                                                                                                                    | OCCUPATIONAL SAFETY                                                                       |
| EVALUATION OF RESPONSE .                                                                                                 |                                                                                           |
| MENT OF DISEASE FOR SOLID TUMOUR .                                                                                       |                                                                                           |
| 11.1                                                                                                                     |                                                                                           |
| 11.2                                                                                                                     | T TUMOUR ASSESSMENT                                                                       |
| 1.3                                                                                                                      | T T UMOUR RESPONSE                                                                        |
| 1.4                                                                                                                      | OTHER DEFINITIONS OF OUTCOME:                                                             |
| ASSESSMENT OF SAFETY .                                                                                                   |                                                                                           |
| 12.1                                                                                                                     | A A DVERSE E VENT D EFINITIONS .                                                          |
| 12.2                                                                                                                     | CLINICAL LABORATORY ABNORMALITIES AND OTHER ABNORMAL ASSESSMENTS AS AES AND SAES ..... 68 |
| 12.3                                                                                                                     | DETERMINING ADVERSE EVENT CAUSALITY                                                       |
| 12.4                                                                                                                     | E E XPECTED ADVERSE EVENTS                                                                |
| S SUSPECTED UNEXPECTED S ERIOUS A DVERSE D RUG R EACTIONS (SUSARS) .................................................. 69 |                                                                                           |
| 12.5                                                                                                                     |                                                                                           |
| 12.6                                                                                                                     | EXPEDITED REPORTING OF SAES                                                               |
| 12.7                                                                                                                     | FOLLOW-UP OF SERIOUS ADVERSE EVENTS                                                       |
| 12.8                                                                                                                     | REPORTING A DVERSE E VENTS ON THE CRF                                                     |
| 12.9                                                                                                                     | E EVENTS EXEMPT FROM BEING REPORTED AS AE/ SAEs  .                                        |
| 12.10                                                                                                                    | D DEVELOPMENT S AFETY U DATE R EPORTS                                                     |
| 12.11                                                                                                                    | INFORMING INVESTIGATORS OF NEW SAFETY INFORMATION                                         |
| PREGNANCY AND BREAST FEEDING .                                                                                           |                                                                                           |
| DEFINING THE END OF TRIAL                                                                                                |                                                                                           |
| STATISTICAL CONSIDERATIONS                                                                                               |                                                                                           |
| 15.1                                                                                                                     | S SAMPLE SIZE                                                                             |
| 15.2                                                                                                                     | STATISTICAL ANALYSIS PLAN                                                                 |
| TRIAL COMMITTEES .                                                                                                       |                                                                                           |
| 16.1                                                                                                                     | T TRIAL MANAGEMENT G ROUP (TMG)                                                           |
| 16.2                                                                                                                     | D DATA AND S AFETY M ONITORING                                                            |
| 16.3                                                                                                                     | T TRIAL STEERING C OMMITTEE                                                               |  
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| MErCuRIC1                                                                                                                                                           | Confidential                                                                                                                              |                                                    |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------|
| DATA MANAGEMENT.                                                                                                                                                    |                                                                                                                                           |                                                    |
| 17                                                                                                                                                                  | DATABASE CONSIDERATIONS                                                                                                                   |                                                    |
| 17.1                                                                                                                                                                |                                                                                                                                           |                                                    |
| 17.2                                                                                                                                                                | CASE REPORT FORMS (CRFs) .                                                                                                                |                                                    |
| 17.3                                                                                                                                                                | A A CCOUNTING FOR MISSING , UNUSED , OR SPURIOUS DATA                                                                                     |                                                    |
| 18                                                                                                                                                                  | CLINICAL STUDY REPORT.                                                                                                                    |                                                    |
| 19                                                                                                                                                                  | STUDY SITE MANAGEMENT                                                                                                                     |                                                    |
| STUDY SITE RESPONSIBILITIES                                                                                                                                         |                                                                                                                                           |                                                    |
| 19.1                                                                                                                                                                |                                                                                                                                           |                                                    |
| 19.2                                                                                                                                                                | STUDY SITE SET UP AND ACTIVATION                                                                                                          |                                                    |
| 19.3                                                                                                                                                                | ARRANGEMENTS FOR SITES OUTSIDE THE UK                                                                                                     |                                                    |
| 19.4                                                                                                                                                                | STUDY DOCUMENTATION                                                                                                                       |                                                    |
| REGULATORY AND ETHICAL CONSIDERATIONS                                                                                                                               |                                                                                                                                           |                                                    |
| 20                                                                                                                                                                  | 20.1                                                                                                                                      | ETHICAL CONDUCT OF THE TRIAL AND ETHICS APPROVAL . |
| R R EGULATORY A UTHORITY APPROVAL                                                                                                                                   |                                                                                                                                           |                                                    |
| 20.2                                                                                                                                                                |                                                                                                                                           |                                                    |
| 20.3                                                                                                                                                                | L L OCAL A P P R O V A L S .                                                                                                              |                                                    |
| PROTOCOL AMENDMENTS                                                                                                                                                 |                                                                                                                                           |                                                    |
| 20.4                                                                                                                                                                |                                                                                                                                           |                                                    |
| 20.5                                                                                                                                                                | URGENT SAFETY MEASURES                                                                                                                    |                                                    |
| 20.6                                                                                                                                                                | T T EMPORARY HALT                                                                                                                         |                                                    |
| 20.7                                                                                                                                                                | S S ERIOUS B REACHES .                                                                                                                    |                                                    |
| 20.8                                                                                                                                                                | REPORTS: Progress, Safety and End of Study Reports ................................................................................... 76 |                                                    |
| 21                                                                                                                                                                  | EXPENSES AND BENEFITS                                                                                                                     |                                                    |
| QUALITY ASSURANCE                                                                                                                                                   |                                                                                                                                           |                                                    |
| 2                                                                                                                                                                   | R R ISK ASSESSMENT AND MONITORING                                                                                                         |                                                    |
| 2.1                                                                                                                                                                 |                                                                                                                                           |                                                    |
| 22.2                                                                                                                                                                | A A UDIT AND R EGULATORY I NSPECTION                                                                                                      |                                                    |
| 23                                                                                                                                                                  | RECORDS RETENTION & ARCHIVING                                                                                                             |                                                    |
| 24                                                                                                                                                                  | PATIENT CONFIDENTIALITY                                                                                                                   |                                                    |
| STUDY FUNDING                                                                                                                                                       |                                                                                                                                           |                                                    |
| 25                                                                                                                                                                  | SPONSORSHIP AND INDEMNITY                                                                                                                 |                                                    |
| 26                                                                                                                                                                  | 26.1                                                                                                                                      | SPONSORSHIP                                        |
| 26.2                                                                                                                                                                | INSURANCE                                                                                                                                 |                                                    |
| 26.3                                                                                                                                                                | CONTRACTS/AGREEMENTS .                                                                                                                    |                                                    |
| 27                                                                                                                                                                  | PUBLICATION POLICY .                                                                                                                      |                                                    |
| 28                                                                                                                                                                  | REFERENCES .                                                                                                                              |                                                    |
| APPENDIX 1: ECOG PERFORMANCE SCALE .                                                                                                                                |                                                                                                                                           |                                                    |
| APPENDIX 2: COCKCROFT AND GAULT FORMULATION ESTIMATE GFR                                                                                                            |                                                                                                                                           |                                                    |
| APPENDIX 3: NCI-CTCAE V4.0 CRITERIA NEUROLOGIC DISORDERS .                                                                                                          |                                                                                                                                           |                                                    |
| APPENDIX 4: MEASUREMENT OF DISEASE - RECIST 1.1 CRITERIA                                                                                                            |                                                                                                                                           |                                                    |
| APPENDIX 5: MEDICATIONS TO BE AVOIDED OR USED WITH CAUTION WITH PF-02341066 ...................................86                                                   |                                                                                                                                           |                                                    |
| APPENDIX 6: RECOMMENDED DOSE MODIFICATIONS FOR BINIMETINIB (MEK162)                                                                                                 |                                                                                                                                           |                                                    |
| APPENDIX 6A: RECOMMENDED DOSE MODIFICATIONS FOR BINIMETINIB (MEK162)...UPDATED                                                                                      |                                                                                                                                           |                                                    |
| APPENDIX 7: INCLUSION AND EXCLUSION CRITERIA FOR DOSE ESCALATION PHASE USING PF-02341066                                                                            |                                                                                                                                           |                                                    |
| WW                                                                                                                                                                  |                                                                                                                                           |                                                    |
| APPENDIX 8: STUDY EVALUATIONS FOR DOSE ESCALATION PHASE USING PF-02341066 WITH PD-                                                                                  |                                                                                                                                           |                                                    |
| 0325901.                                                                                                                                                            |                                                                                                                                           |                                                    |
| APPENDIX 9: SCHEDULE OF EVENTS FOR DOSE ESCALATION PHASE USING PF-02341066 WITH PD-                                                                                 |                                                                                                                                           |                                                    |
| 0325901.                                                                                                                                                            |                                                                                                                                           |                                                    |
| APPENDIX 10: AMENDMENT HISTORY..................................................................................................................................104 |                                                                                                                                           |                                                    |  
| 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 PF02341066 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 PF02341066 when administrated in combination. - To investigate pharmacodynamic (PD) biomarkers of Binimetinib and PF02341066 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.                                                                                                                                                                                                                       |
| MErCuRIC1_Protocol_V9.0_29Oct2018        | Protocol Template V3.0_18Feb2013                                                                                                                                                                                      |  
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| MErCuRIC1                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | Confidential                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |
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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 wildtype 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 PF02341066: - 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                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |
| MErCuRIC1_Protocol_V9.0_29Oct2018                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | Protocol Template V3.0_18Feb2013                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |  
| 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                                                                                                                                                                               | Dose escalation phase using PD-0325901 in combination with PF-02341066:                                                                                                                                                                                                     |                                                                                                                    |         |      |               |        |               |
| Endpoints:                                                                                                                                                                              | -                                                                                                                                                                                                                                                                           | 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 PF02341066 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 PF02341066: - 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 PF02341066 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                                                                                                                                                                                         |                                                                                                                                                                                                                                                                             |                                                                                                                    |         |      |               |        |               |
| MErCuRIC1_Protocol_V9.0_29Oct2018                                                                                                                                                       | Protocol Template V3.0_18Feb2013                                                                                                                                                                                                                                            |                                                                                                                    |         |      |               |        |               |
| Page 9 of 121                                                                                                                                                                           |                                                                                                                                                                                                                                                                             |                                                                                                                    |         |      |               |        |               |  
| MErCuRIC1                                  | Confidential                                                                                                                                           |                                                                     |
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| METY1234/1235 in skin and tumour biopsies. |                                                                                                                                                        |                                                                     |
| Exploratory and                            | -                                                                                                                                                      | Whole exome sequencing and miRNA profiling on tumour biopsies taken |
| Tertiary Endpoints:                        | 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 PD0325901. 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/cMETmut/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 PF02341066 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 PF02341066 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                                                                                                                                                        |                                                                     |
| MErCuRIC1_Protocol_V9.0_29Oct2018          | Protocol Template V3.0_18Feb2013                                                                                                                       |                                                                     |  
| MErCuRIC1                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | Confidential                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |    |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----|
| patients only for stage 1) with RASMT CRC, up to 29 patients with RASWT/cMETmut/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/cMETmut/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                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | INCLUSION CRITERIA                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |    |
| exclusion 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, |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |    |
| MErCuRIC1_Protocol_V9.0_29Oct2018                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | Protocol Template V3.0_18Feb2013                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |    |  
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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 overexpressed.  
− 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 PF02341066/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.  
| −                                                                                                                                                                                                                                                                                                    | 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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| MErCuRIC1       | Confidential                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |         |
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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  | Dose escalation phase: PF-02341066 in combination with PD-0325901                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |         |
| administration: | 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. PF02341066 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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| MErCuRIC1                         | Confidential                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |
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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                  | Dose escalation phase using PD-0325901 in combination with PF-02341066                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |
| and frequency:                    | 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 posttrial:                                   | Patients may receive further standard treatment, treatment within another clinical  trial or palliative and supportive care as appropriate and all will have long-term                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |
| MErCuRIC1_Protocol_V9.0_29Oct2018 | Protocol Template V3.0_18Feb2013                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |
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| MErCuRIC1                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | Confidential                                                                   |       |    |                           |
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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                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | For Dose Escalation phase using PF-02341066 with PD-0325901:                   |       |    |                           |
| assays:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | 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 HPLCMS/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                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | We will investigate the impact of the MEK and MET inhibitors on established    |       |    |                           |
| assays:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | 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 |                                                                                |       |    |                           |
| MErCuRIC1_Protocol_V9.0_29Oct2018                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Protocol Template V3.0_18Feb2013                                               |       |    |                           |  
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| MErCuRIC1            | Confidential                                                                                                                                                                                                                                                                                                                                                                                                                 |
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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 PF02341066 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 to the trial closed on 23Oct2018 with 82 patients recruited following                                                                                                                                                                                                                                                                                                                                            |
| recruitment          | 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.                                                                                                                                                                                                                                     |