untitled h1
summary schedule of events

Note: The Schedule of Events table for the Dose Escalation phase using PF-02341066 with PD-0325901 is located in Appendix 9  
| Dose Escalation Phase - Schedule of Events for PF-02341066 and Binimetinib Visit Description Screenin g Cycle 1 Cycle 2 Cycle 3   | Cycle 4                                              | Cycle 5   | Treatment p   | Post end of   |     |     |     |     |    |    |     |     |    |    |     |     |    |    |     |     |                          |
|-----------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------|-----------|---------------|---------------|-----|-----|-----|-----|----|----|-----|-----|----|----|-----|-----|----|----|-----|-----|--------------------------|
| End of                                                                                                                            | treatment                                            | Follow    |               |               |     |     |     |     |    |    |     |     |    |    |     |     |    |    |     |     |                          |
| onwards                                                                                                                           | Up                                                   |           |               |               |     |     |     |     |    |    |     |     |    |    |     |     |    |    |     |     |                          |
| Visit No                                                                                                                          | 1                                                    | 2         | 3             | 4             | 5   | 6   | 7   | 8   | 9  | 10 | 11  | 12  | 13 | 14 | 15  | 16  | 17 | 17 | 19  | 20  |                          |
| Day                                                                                                                               | -28 to 1                                             | D1        | D2            | D8            | D15 | D16 | D21 | D22 | D1 | D8 | D15 | D21 | D1 | D8 | D15 | D21 | D1 | D8 | D15 | D21 | D 28-30 after  last dose |
| Informed Consent                                                                                                                  | X                                                    |           |               |               |     |     |     |     |    |    |     |     |    |    |     |     |    |    |     |     |                          |
| Demographics & History                                                                                                            | X                                                    |           |               |               |     |     |     |     |    |    |     |     |    |    |     |     |    |    |     |     |                          |
| Concomitant medication                                                                                                            | X                                                    | X         | X             | X             | X   | X   | X   | X   | X  | X  | X   | X   | X  | X  | X   | X   | X  | X  | X   |     |                          |
| ECOG                                                                                                                              | X                                                    | X         | X             | X             | X   | X   | X   | X   | X  | X  | X   | X   | X  | X  | X   | X   | X  | X  | X   |     |                          |
| Physical examination a                                                                                                            | X                                                    | X         | X             | X             | X   | X   | X   | X   | X  | X  | X   | X   | X  | X  | X   | X   | X  | X  | X   |     |                          |
| Tumour Assessment b                                                                                                               | X                                                    | X         | X             |               |     |     |     |     |    |    |     |     |    |    |     |     |    |    |     |     |                          |
| Vital signs c                                                                                                                     | X                                                    | X         | X             | X             | X   | X   | X   | X   | X  | X  | X   | X   | X  | X  | X   | X   | X  | X  | X   |     |                          |
| Height & Weight d                                                                                                                 | X                                                    | X         | X             | X             | X   | X   | X   | X   | X  | X  |     |     |    |    |     |     |    |    |     |     |                          |
| Repeat  cycle 3  and 4                                                                                                            |                                                      |           |               |               |     |     |     |     |    |    |     |     |    |    |     |     |    |    |     |     |                          |
| Ophthalmic Exam e                                                                                                                 | X                                                    | X         | X             | X             |     |     |     |     |    |    |     |     |    |    |     |     |    |    |     |     |                          |
| Haem & Clin Chem Bloods f                                                                                                         | X                                                    | X         | X             | X             | X   | X   | X   | X   |    |    |     |     |    |    |     |     |    |    |     |     |                          |
| Urinalysis                                                                                                                        | X                                                    | X         | X             | X             | X   | X   | X   | X   |    |    |     |     |    |    |     |     |    |    |     |     |                          |
| Pregnancy test g                                                                                                                  | X                                                    | X         | X             | X             | X   | X   |     |     |    |    |     |     |    |    |     |     |    |    |     |     |                          |
| 12 lead ECG                                                                                                                       | X                                                    | X         | X             | X             | X   | X   | X   | X   |    |    |     |     |    |    |     |     |    |    |     |     |                          |
| Echocardiography/MUGA -h                                                                                                          | X                                                    | X         | X             |               |     |     |     |     |    |    |     |     |    |    |     |     |    |    |     |     |                          |
| Inclusion/exclusion criteria                                                                                                      | X                                                    |           |               |               |     |     |     |     |    |    |     |     |    |    |     |     |    |    |     |     |                          |
| Tumour marker i                                                                                                                   | X                                                    | X         | X             |               |     |     |     |     |    |    |     |     |    |    |     |     |    |    |     |     |                          |
| PK 24 hours profile j                                                                                                             | X                                                    | X         |               |               |     |     |     |     |    |    |     |     |    |    |     |     |    |    |     |     |                          |
| PK trough k                                                                                                                       | X                                                    | X         |               |               |     |     |     |     |    |    |     |     |    |    |     |     |    |    |     |     |                          |
| PD PBMC/plasma l                                                                                                                  | X                                                    | X         | X             | X             |     |     |     |     |    |    |     |     |    |    |     |     |    |    |     |     |                          |
| AE review                                                                                                                         | X                                                    | X         | X             | X             | X   | X   | X   | X   | X  | X  | X   | X   | X  | X  | X   | X   | X  | X  | X   | X   |                          |
| Binimetinib administration                                                                                                        | Continuous administration or Days 1-21 every 28 days |           |               |               |     |     |     |     |    |    |     |     |    |    |     |     |    |    |     |     |                          |
| PF-02341066 administration                                                                                                        | Continuous administration                            |           |               |               |     |     |     |     |    |    |     |     |    |    |     |     |    |    |     |     |                          |
| Survival data (PFS and OS)                                                                                                        | X                                                    | X         |               |               |     |     |     |     |    |    |     |     |    |    |     |     |    |    |     |     |                          |
| Biomarker studies Archival tumour sample                                                                                          | X                                                    |           |               |               |     |     |     |     |    |    |     |     |    |    |     |     |    |    |     |     |                          |
| Blood sample germline DNA                                                                                                         | X                                                    |           |               |               |     |     |     |     |    |    |     |     |    |    |     |     |    |    |     |     |                          |
| PD skin biopsy m                                                                                                                  | X                                                    | X         |               |               |     |     |     |     |    |    |     |     |    |    |     |     |    |    |     |     |                          |
| PD tumour biopsy n                                                                                                                | X                                                    | X         |               |               |     |     |     |     |    |    |     |     |    |    |     |     |    |    |     |     |                          |
| Plasma soluble biomarkers o                                                                                                       | X                                                    | X         | X             | X             | X   | X   |     |     |    |    |     |     |    |    |     |     |    |    |     |     |                          |
| a To include neurological examination.                                                                                            |                                                      |           |               |               |     |     |     |     |    |    |     |     |    |    |     |     |    |    |     |     |                          |  
b CT includes chest, abdomen and pelvis. Measurements using modified RECIST 1.1. At screening and after 2nd, 4th, 6th cycle, and every 2 cycles thereafter until intolerable toxicity or progressive disease. c To include pulse and systolic/diastolic blood pressure, body temperature. Blood pressure is to be measured after resting for 5 minutes in a sitting position. d Height measured only at screening.  
e Ophthalmic exam at baseline, and Day 21of cycles 2, 4, 6 and 9 and every third cycle (12 weekly) after this and also as clinically indicated. Time window for examination allowable +/- 2 days fTo include FBC with differential and platelets, Na, K, Ca, phosphate, urea, creatinine, total protein, albumin, bilirubin, alk phos, AST and /or ALT, LDH, coagulation screen, APTT, PT, CK, Troponin,
(validity period of blood samples is 3 days). g Serum pregnancy test to be performed at screening and urine pregnancy test required every 3-4 weeks for women of child-bearing potential Echo or MUGA at baseline and at Day 21 of cycles 1, 3, 5, 8 and every third cycle (12 weeks) afterwards and also repeated as clinically indicated. For non-UK territories: if ECHO cannot be performed, a MUGA scan may be performed in compliance with local policy, applicable national legislation and relevant approvals. Cardiac ejection fraction must be determined as measured by echocardiogram (ECHO)
in the UK.  
iFor patients with relevant tumour types, tumour marker (CEA, CA-125, PSA or CA19-9 as relevant) will be checked during screening and after 2nd, 4th, 6th cycle, and every 2 cycles thereafter jSerum PK measurements will be taken as specified in the protocol (section 7.3). k PK trough sample pre-dose (morning) and 2 hours post dose Day 21 of cycles 2, 4, 6, 8, 10 and 12. lPD PBMC/Plasma samples will be taken as specified in the protocol (section 7.4)
m At screening and Day 15 +/- 7 days. n At screening and Day 15 +/- 7 days. Optional biopsy if separate consent obtained. oAt each sampling point 4ml of plasma is obtained. p Disease progression, intolerance or withdrawal.  
Dose Expansion Phase - Schedule of Events for PF-02341066 and Binimetinib  
| Follow                                   |             |                                                      |                        |         |         |         |         |        |          |    |    |     |     |    |    |     |     |                   |    |
|------------------------------------------|-------------|------------------------------------------------------|------------------------|---------|---------|---------|---------|--------|----------|----|----|-----|-----|----|----|-----|-----|-------------------|----|
| Visit Description                        | PreScreen             | Screening                                            | Cycle 1                | Cycle 2 | Cycle 3 | Cycle 4 | Cycle 5 | End of | Post end | up |    |     |     |    |    |     |     |                   |    |
| of                                       |             |                                                      |                        |         |         |         |         |        |          |    |    |     |     |    |    |     |     |                   |    |
| onwards                                  | Treatment r | treatment                                            |                        |         |         |         |         |        |          |    |    |     |     |    |    |     |     |                   |    |
| Visit No                                 | 0           | 1                                                    | 2                      | 3       | 4       | 5       | 6       | 7      | 8        | 9  | 10 | 11  | 12  | 13 | 14 | 15  | 16  | 17                | 18 |
| Day                                      | -28 to -1   | D1                                                   | D8                     | D15     | D21     | D22     | D1      | D8     | D15 D21  | D1 | D8 | D15 | D21 | D1 | D8 | D15 | D21 | D 28-30 post dose |    |
| Informed Consent                         | X a         | X                                                    |                        |         |         |         |         |        |          |    |    |     |     |    |    |     |     |                   |    |
| Demographics & History                   | X           | X                                                    |                        |         |         |         |         |        |          |    |    |     |     |    |    |     |     |                   |    |
| Concomitant medication                   | X           | X                                                    | X                      | X       | X       | X       | X       | X      | X        | X  | X  | X   | X   | X  | X  | X   | X   | X                 | X  |
| ECOG                                     | X           | X                                                    | X                      | X       | X       | X       | X       | X      | X        | X  | X  | X   | X   | X  | X  | X   | X   | X                 | X  |
| Physical examination b                   | X           | X                                                    | X                      | X       | X       | X       | X       | X      | X        | X  | X  | X   | X   | X  | X  | X   | X   | X                 | X  |
| Tumour Assessment c                      | X           | X                                                    | X                      |         |         |         |         |        |          |    |    |     |     |    |    |     |     |                   |    |
| Vital signs d                            | X           | X                                                    | X                      | X       | X       | X       | X       | X      | X        | X  | X  | X   | X   | X  | X  | X   | X   | X                 | X  |
| Height & Weight e                        | X           | X                                                    | X                      | X       | X       | X       | X       | X      | X        | X  |    |     |     |    |    |     |     |                   |    |
| Ophthalmic Exam f                        | X           | X                                                    | X                      | X       |         |         |         |        |          |    |    |     |     |    |    |     |     |                   |    |
| Haem & Clin Chem Bloods g                | X           | X                                                    | X                      | X       | X       | X       | X       | X      |          |    |    |     |     |    |    |     |     |                   |    |
| Urinalysis                               | X           | X                                                    | X                      | X       | X       | X       | X       | X      |          |    |    |     |     |    |    |     |     |                   |    |
| Pregnancy test h                         | X           | X                                                    | X                      | X       | X       | X       |         |        |          |    |    |     |     |    |    |     |     |                   |    |
| 12 lead ECG                              | X           | X                                                    | X                      | X       | X       | X       | X       | X      |          |    |    |     |     |    |    |     |     |                   |    |
| Echocardiography/MUGA i                  | X           | X                                                    | X                      |         |         |         |         |        |          |    |    |     |     |    |    |     |     |                   |    |
| Inclusion/exclusion criteria             | X           |                                                      |                        |         |         |         |         |        |          |    |    |     |     |    |    |     |     |                   |    |
| Tumour marker j                          | X           | X                                                    | X                      |         |         |         |         |        |          |    |    |     |     |    |    |     |     |                   |    |
| PK 24 hours profile k                    | X           | X                                                    |                        |         |         |         |         |        |          |    |    |     |     |    |    |     |     |                   |    |
| PK trough l                              | X           | X                                                    | Repeat  cycle 3  and 4 |         |         |         |         |        |          |    |    |     |     |    |    |     |     |                   |    |
| AE review                                | X           | X                                                    | X                      | X       | X       | X       | X       | X      | X        | X  | X  | X   | X   | X  | X  | X   | X   | X                 | X  |
| Binimetinib administration               | X           | Continuous administration or Days 1-21 every 28 days |                        |         |         |         |         |        |          |    |    |     |     |    |    |     |     |                   |    |
| PF-02341066 administration               | X           | Continuous administration                            |                        |         |         |         |         |        |          |    |    |     |     |    |    |     |     |                   |    |
| Survival data (PFS and OS)               | X m         |                                                      |                        |         |         |         |         |        |          |    |    |     |     |    |    |     |     |                   |    |
| Biomarker studies Archival tumour sample | X a         | X                                                    |                        |         |         |         |         |        |          |    |    |     |     |    |    |     |     |                   |    |
| Tumour (CRC Mets)sample                  | X a         |                                                      |                        |         |         |         |         |        |          |    |    |     |     |    |    |     |     |                   |    |
| Blood sample germline DNA                | X           |                                                      |                        |         |         |         |         |        |          |    |    |     |     |    |    |     |     |                   |    |
| PD skin biopsy n                         | X           | X                                                    |                        |         |         |         |         |        |          |    |    |     |     |    |    |     |     |                   |    |
| PD tumour biopsy o                       | X           | X                                                    | X s                    |         |         |         |         |        |          |    |    |     |     |    |    |     |     |                   |    |
| Plasma soluble biomarkers p              | X           | X                                                    | X                      | X       | X       |         |         |        |          |    |    |     |     |    |    |     |     |                   |    |
| Plasma sample for ctDNA q                | X           | X                                                    | X                      | X       | X       |         |         |        |          |    |    |     |     |    |    |     |     |                   |    |  
a Pre-trial screening for c-MET and RAS status b To include neurological examination. cCT includes chest, abdomen and pelvis. Measurements using modified RECIST 1.1. At screening and after 2nd, 4th, 6th cycle, and every 2 cycles thereafter until intolerable toxicity or progressive disease d to include pulse and systolic/diastolic blood pressure and body temperature (Blood pressure to be measured after resting for 5 minutes in a sitting position.) e Height to measured only at screening.  
fOphthalmic exam at baseline, and at Day 21 cycles 2, 4, 6 and 9 and every third cycle (12 weekly) after this and also as clinically indicated. This has an allowed time window of +/- 2 days g To include FBC with differential and platelets, Na, K, Ca, phosphate, urea, creatinine, total protein, albumin, bilirubin, alk phos, AST and /or ALT, LDH, coagulation screen, APTT, PT, CK, Troponin (validity period of bloods is 3 days).  
h Serum pregnancy test at screening and serum or urine pregnancy testing required every 3-4 weeks for women of child-bearing potential. iEcho/MUGA at baseline and at Day 21of cycles, 1, 3, 5, 8 and every third cycle (12 weeks) afterwards and also repeated as clinically indicated. For non-UK territories: if ECHO cannot be performed, a MUGA scan may be performed in compliance with local policy, applicable national legislation and relevant approvals. Cardiac ejection fraction must be determined as measured by echocardiogram (ECHO) in the UK.  
jTumour markers (CEA, CA-125, PSA or CA19-9 as relevant) will be checked during screening and after 2nd, 4th, 6th cycle, and every 2 cycles thereafter kSerum PK measurements will be taken as specified in the protocol (section 7.3) lPK trough sample pre-dose (morning) and 2 hours post dose day 21 of cycles 2, 4, 6, 8, 10 and 12 m Survival status to be updated every 3 months post end of trial until death notification n At screening and Day 15 +/- 7 days for initial cohort of 10 patients only o At screening and Day 15 +/- 7 days. Also optional biopsy of metastases at disease progression p At each sampling point 4ml of plasma obtained.  
q Blood samples for the detection of ctDNA will be obtained every 4 weeks until disease progression.  
rDisease progression, intolerance or withdrawal.  
sOptional. Within 28 days following radiological confirmation of disease progression  
| ABBREVIATIONS AE Adverse Event ADL Activities of Daily Living ADR Adverse Drug Reaction ALT Alanine Transaminase ANC Absolute Neutrophil Count AST Aspartate Transaminase AUC Area Under the Curve BAL Bronchoalveolar Lavage BD Bi Daily BHSCT Belfast Health and Social Care Trust BNP B-type Natriuretic Peptide BRAT Mnemonic for bananas, rice, apple and toast CCRCB Centre for Cancer Research and Cell Biology CEA Carcinoembryonic Antigen CHF Congestive Heart Failure CI Chief Investigator CK Creatinine Kinase CML Chronic Myeloid Leukaemia CNS Central Nervous System CR Complete Response CRC Colorectal cancer CRF Case Report Form CSR Central Serous Retinopathy CT Computerized Tomography ctDNA Circulating tumour DNA CTA Clinical Trials Authorisation CTA Clinical Trial Agreement CTCAE Common Toxicity Criteria Adverse Events CTIMP Clinical Trial of an Investigational Medicinal Product DLT Dose Limiting Toxicity DNA Deoxyribonucleic Acid DSMC Data & Safety Monitoring Committee DSUR Development Safety Update Report ECG Electrocardiogram eCRF Electronic Case Report Form ELISA Enzyme-Linked ImmunoSorbant Assay EMA European Medicines Agency EGFR Epidermal growth factor receptor EP Early Progression ERK Extracellular-Signal-Regulated Kinases EU European Union FBC Full Blood Count FDA Federal Drug Administration FDG-PET Fluorodeoxyglucose Positron Emission Tomography FFPE Formulin-fixed Paraffin Embedded GAPs GTPase Activating Proteins GCP Good Clinical Practice GEPs Guanine Nucleotide Releasing Factors GI Gastro-Intestinal GMP Good Manufacturing Practices Hb Haemoglobin HCG Human Chorionic Gonadotrophin HDPE High-density PolyEthylene HGF Hepatocyte growth factor HGFR Hepatocyte growth factor receptor HIV Human Immunodeficiency Virus HTA Human Tissue Act IB Investigator Brochure IC50 50% Inhibitory Concentration MErCuRIC1_Protocol_V9.0_29Oct2018   | Protocol Template V3.0_18Feb2013   |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------|
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| MErCuRIC1                         | Confidential                                        |
|-----------------------------------|-----------------------------------------------------|
| IEPTOC                            | Independent Early Phase Trial Oversight Committee   |
| IHC                               | Immunohistochemistry                                |
| ILD                               | Interstitial Lung Disease                           |
| IMP                               | Investigational Medicinal Product                   |
| IMPD                              | Investigational Medicinal Product Dossier           |
| iV                                | Intravenous                                         |
| RAS                               | Rat Sarcoma                                         |
| KPS                               | Karnofsky Performance Score                         |
| LVEF                              | Left-Ventricular-Ejection-Fraction                  |
| LDH                               | Lactate Dehydrogenase                               |
| LPLV                              | Last Patient Last Visit                             |
| mCRC                              | Metastatic Colorectal Cancer                        |
| MEK                               | Mitogen Activated Protein Kinase                    |
| MHRA                              | Medicines and Healthcare products Regulatory Agency |
| MoABs                             | Monoclonal Antibodies                               |
| MRI                               | Magnetic Resonance Imaging                          |
| MTD                               | Maximum Tolerated Dose                              |
| MU                                | Mazaryk University                                  |
| MUGA                              | Multigated Acquisition                              |
| NCI                               | National Cancer Institute                           |
| NE                                | Not Evaluable                                       |
| NGS                               | Next Generation Sequencing                          |
| NHS                               | National Health Service                             |
| NIMP                              | Non-Investigational Medicinal Product               |
| NSCLC                             | Non-Small cell Lung Cancer                          |
| OCTO                              | Oncology Clinical Trials Office                     |
| OCTRU                             | Oxford Clinical Trials Research Unit                |
| OD                                | Once Daily                                          |
| ORB                               | Oxford Radcliffe Biobank                            |
| OS                                | Overall survival                                    |
| PD                                | Pharmacodynamic or Progressive Disease              |
| PDUM                              | Paris Descartes Universite Medecine                 |
| PFS                               | Progression Free Survival                           |
| PI                                | Principal Investigator                              |
| PK                                | Pharmacokinetic                                     |
| PBMC                              | Peripheral blood mononuclear cells                  |
| PO                                | Per Os                                              |
| PR                                | Partial Response                                    |
| QP                                | Qualified Person                                    |
| QT                                | QT interval                                         |
| QTc                               | Corrected QT interval                               |
| QUB                               | Queen's University Belfast                          |
| REC                               | Research Ethics Committee                           |
| RECIST                            | Response Evaluation Criteria In Solid Tumours       |
| RPII                              | Recommended phase II dose                           |
| RR                                | Response Rate                                       |
| RVO                               | Retinal Vein Occlusion                              |
| SAE                               | Serious Adverse Event                               |
| SD                                | Stable Disease                                      |
| SOP                               | Standard Operating Procedure                        |
| SmPC                              | Summary of Product Characteristics                  |
| SUSAR                             | Suspected Unexpected Serious Adverse Reaction       |
| Tdp                               | Torsades De Pointes                                 |
| TPN                               | Total Parenteral Nutrition                          |
| TSC                               | Trial Steering Committee                            |
| ULN                               | Upper Limit of Normal                               |
| UNITO                             | Italian Università degli Studi di Torino            |
| USS                               | Ultrasound Scan                                     |
| UZA                               | Universitair Ziekenhuis Antwerpen                   |
| VHIO                              | Vall Hebron Institute of Oncology                   |
| WBC                               | White Blood Count                                   |
| MErCuRIC1_Protocol_V9.0_29Oct2018 | Protocol Template V3.0_18Feb2013                    |  
Page 23
untitled h1
1 introduction 1.1 background disease

Colorectal cancer (CRC) is a significant health issue for men and women worldwide, with > 1 million cases and over 680,700 deaths each year (Malvezzi et al., 2011). In the European Union (2008), 334,092 new patients (151,478 women / 182,614 men) were diagnosed with CRC and 149,159 patients (68,999 women/80,160 men) died of the disease http://globocan.iarc.fr) (Jemal et al., 2010). Approximately 450,000 new cases of CRC will be diagnosed within Europe and 143,460 in the US in 2012 (Siegel et al., 2013). In addition, with an estimated 232,000 deaths in 2012 (Europe) and approximately 51,690 deaths (US), CRC remains the second most common cause of cancer death within the Western world (Siegel et al., 2013). The incidence increases significantly with age, with >80% of cases occurring in the 60 years or older population.  
Given the ageing population in Europe, CRC's already considerable health and societal burden is expected to increase significantly. Metastatic colorectal cancer (mCRC) is a malignancy with a dismal overall survival (OS) rate. Due to its asymptomatic nature, CRC is frequently diagnosed only after cancer has spread to the lymph nodes (stage III) and/or distant organs (stage IV), eg liver, lung, peritoneum.
untitled h1
treatment background

Standard chemotherapy for advanced CRC include combination of 5-Fluorouracil (5-FU) with Irinotecan
(FOLFIRI) or Oxaliplatin (FOLFOX). Resistance to chemotherapy, either intrinsic or acquired, ultimately results in treatment failure for the majority of CRC patients. Approximately 50% of CRC patients eventually develop metastases (stage IV disease, mCRC) and receive systemic chemotherapy, with 5-year OS rates lower than 5%. For chemotherapy-naive mCRC patients, response rates (RR) are ∼40%-50% (FOLFOX, FOLFIRI) while median OS are ∼16-19 months (de Gramont et al., 2000; Douillard et al., 2000). When FOLFIRI/FOLFOX is given as 2nd line treatment, RR is 10-15%, progression-free survival (PFS) is 4 months and OS is 10-11 months respectively (Guglielmi and Sobrero, 2007). Recently, the treatment paradigm for mCRC has evolved to include targeted therapeutics. The Epidermal growth factor receptor (EGFR) signalling pathway is of key importance for the survival of CRC and other cancer cells (Laurent-Puig et al., 2012; Peeters et al., 2010; Van Schaeybroeck et al., 2005). These findings have led to the development of therapeutic monoclonal antibodies (MoAbs) (eg. chimeric MoAb cetuximab and fully human MoAb panitumumab), that inhibit ligand binding to the EGFR and subsequently EGFR activation and downstream signalling. Cetuximab and panitumumab have significantly improved PFS and OS
when combined with FOLFIRI in patients with chemo-naive metastatic stage IV CRC patients (Berlin et al., 2007; Van Cutsem et al., 2011). Historically, "one-size-fits-all" approaches have been standard practice in CRC treatment, but with the increased understanding of the molecular/genetic heterogeneity of CRC, it is clear that novel treatments must be developed and tested in selected subgroups to maximize the benefit of these new developments.
untitled h1
ras as a predictive biomarker

The RAS guanosine triphosphate (GTP)-ases act as critical "on-off" switches in cellular growth and survival
(Ramjaun and Downward, 2007). RAS is activated by several receptor tyrosine kinases (RTKs), and is regulated by guanine nucleotide releasing factors (GEFs) and GTPase-activating proteins (GAPs). Active GTP-bound RAS interacts with a range of effectors to activate multiple downstream pathways, most notably the RAF/MEK/ERK and PI-3 kinase pathways. The RAS sub-family consists of three proto-oncogenes: *cHarvey (H)-*ras*, c-Kirsten (K)-*ras, and *c-Neuroblastoma (N)-*ras (Reuther and Der, 2000). RAS functions downstream of EGFR and is a critical mediator of EGFR induced signalling. RAS genes become oncogenic by single point mutations, which alter the guanine nucleotide binding region, rendering RAS unresponsive to GAPs and resulting in constitutive RAS activation, aberrant downstream signalling, increased proliferation and survival.  
The presence of activating *RAS/NRAS* mutations abolishes the ability of anti-EGFR drugs to inhibit cell survival signalling in cancer cells. RAS is mutated in 40%-45% of CRC (*RASMT)*, and RAS mutations are associated with poorer survival in CRC (Richman et al., 2009). Several phase III studies, led by members of MErCuRIC, have shown that patients harbouring activating RAS and *NRAS* mutations (found in 4%-5% of CRC) do not benefit from anti-EGFR therapies (Maughan et al., 2011; Peeters et al., 2012; Peeters et al., 2010). These therapies represent a personalized medicine approach in CRC, as patients are stratified according to their RAS mutational status. The European Medicines Agency (EMA), the US Food and Drug Administration (FDA) and the American Society for Clinical Oncology (ASCO) now recommend that all mCRC patients who are candidates for anti-EGFR therapy should be tested for RAS mutations and, if a mutation is detected, they should not receive anti-EGFR therapies (Allegra et al., 2009).
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the need for new therapeutic

Studies have also suggested that activating mutations in *BRAF, NRAS* and *PIK3CA,* loss of *PTEN* and expression of EGFR ligands epiregulin and amphiregulin, likewise correlated with resistance to anti-EGFR targeted therapies (Khambata-Ford et al., 2007; Perrone et al., 2009). Since its approval, cetuximab has become a €855 million p.a. drug, and > 50% of CRC patients are currently treated with anti-EGFR MoAb therapies (http://www. Firstwordpharma.com/node/1017862). Nevertheless, between 50%-60% of RAS Wild Type (RASWT) or indeed quadruple WT patients (i.e. KRAS, NRAS, *BRAF, PI3KCA* WT with high levels of epiregulin and amphiregulin and no loss of *PTEN*) will not benefit from the addition of an EGFR MoAb to standard chemotherapy (De Roock et al., 2010). Hence, novel treatment strategies are urgently needed for RASMT patients and >50% of RASWT CRC patients, especially in second line where responses to standard chemotherapy are relatively low. RASMT mCRC patients have few therapeutic options post-chemotherapy failure. Inhibitors of farnesyl protein transferase (resulting in impaired RAS membrane localization and activity) as single agents failed to show significant activity in unselected patient groups in CRC and NSCLC (Adjei et al., 2003; Rao et al., 2004). Chemical library screens using isogenic RASWT and MT cell lines have identified compounds exhibiting greater lethality in tumour cells harbouring mutations in RAS *(Guo et al., 2008; Ji et al., 2009).* Translation of these studies into the clinical setting has been impeded by the difficulty in identifying the protein target for these compounds, a prerequisite for further drug development. More recently, genome wide shRNA screens have unravelled novel biology associated with oncogenic *RAS,* but these studies have yet to be translated into the clinic (Barbie et al., 2009; Luo et al., 2009).  
MErCuRIC is a pan-European collaboration to use a personalised medicine clinical trial strategy to target two key proteins, MEK and MET, which are deregulated in both RAS WT and RAS MT mCRC. The trial hypothesis is that inhibition of both MEK and MET in combination (MEKi)/METi), will improve PFS and ultimately OS in the stratified mCRC cohort. The comprehensive scientific dissection of disease biology will not only provide new insights on efficacy, but will also underpin development of new diagnostic and predictive tools to combat mCRC. The clinical trial has unique characteristics of (i) employing a novel treatment strategy targeting the biology of the disease; (ii) using next generation sequencing (NGS), miRNA and companion diagnostics strategies to identify/stage CRC patient subgroups who will maximally benefit from this novel treatment strategy and (iii) deploying (a) non-invasive detection tools (b) relevant preclinical models to underpin novel stratified solutions for patients with acquired drug-resistance.
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1.2 investigational medicinal products used

The Investigational Medicinal Products (IMPs) in this trial are PF-02341066, PD-0325901 and Binimetinib.  
PF-02341066 (Crizotinib); Pfizer) has a Marketing Authorisation in the EU for the indication of previously treated ALK+ NSCLC (http://www.medicines.org.uk/EMC/medicine/27168/SPC/Xalkori+200mg+and+250mg+hard+capsule/) but is not authorised for use in colorectal cancer. PD-0325901 is a new chemical agent developed by Pfizer and is provided in capsule form. Binimetinib is a new chemical agent developed by Array Biopharma and is provided in tablet form.
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pf-02341066 (crizotinib)

PF-02341066 (Crizotinib) is a selective ATP-competitive small-molecule oral inhibitor of the anaplastic lymphoma kinase (ALK), c-Met/hepatocyte growth factor receptor (HGFR), Recepteur d'Origine Nantais (RON), and ROS receptor tyrosine kinases (RTKs) and their oncogenic variants (e.g., c-Met/HGFR
mutations and ALK or ROS fusion proteins). PF-02341066 demonstrated a mean Ki value of 0.5 nM for inhibition of recombinant human ALK and a mean Ki value of 0.62 nM for inhibition of recombinant human cMet/HGFR. PF-02341066 also demonstrated a mean Ki value of 9.1 nM for inhibition of the RON RTK which was approximately 20-fold higher than the Ki for inhibition of ALK.  
PF-02341066 inhibited cell proliferation (EC50 = 54 nM) and induced apoptosis (EC50 = 110 nM) at concentrations comparable to those required to inhibit EML4- ALK phosphorylation (EC50 = 63 nM) in NCIH3122 lung adenocarcinoma cells expressing EML4-ALK variant 1. PF-02341066 also inhibited proliferation of Karpas 299 or SU-DHL-1 ALCL cells that express an NPM-ALK fusion protein due to a t(2;5)
chromosomal translocation. Growth inhibition by PF-02341066 in these NPM-ALK positive lymphoma cells was associated with G0/G1 cell cycle arrest and induction of apoptosis. PF-02341066 has also been found to inhibit potently HGF (ligand for cMET)-stimulated human NCI-H441 lung carcinoma cell migration and invasion through a matrigel matrix (IC50 values of 11 nM and 6.1 nM, respectively), and HGF-stimulated MDCK cell motility/scattering (IC50 = 16 nM). PF-02341066 inhibited cell proliferation (EC50 = 59 nM) at concentrations comparable to those required to inhibit ROS phosphorylation (EC50 = 44 nM) in HCC78 lung adenocarcinoma cells expressing the SLC34A-ROS fusion variant. *In vivo* PF-02341066 inhibited xenograft growth in a variety of models while inhibiting ALK or cMET activity.  
PF-02341066 has a long t1/2 (42 hrs), takes 15 days to reach steady-state and has stable exposure unaffected by body weight, gender, age, and race. PF-02341066 is excreted by the faecal route and is both a CYP3A substrate and inhibitor. The extent and duration of inhibition of c-MET is directly linked to its antitumor efficacy - near complete inhibition (>90%) of c-MET activity during the entire treatment period is necessary to achieve robust antitumor effects. PK/PD analyses established the target efficacious free plasma concentration range of 8.1 to 12.8 nM (40 - 62 ng/mL in human plasma) for c-MET (and approximately 2-fold greater for ALK inhibition). Vision disorders are seen in >50% (98% mild) of patients, so there is a need for baseline ophthalmic assessment which is repeated if patients become symptomatic.  
Expected toxicities (usually mild) include nausea, vomiting, diarrhoea, constipation, peripheral oedema, fatigue and rashes and oesophageal-related disorders, and significant myelosuppression is rare. Responses have been seen in c-MET aberrant tumours.  
In a phase I study in patients with ALK-positive non-small-cell lung cancer, dose-limiting fatigue in the cohort receiving 300mg BD led to the establishment of a regimen of 250mg BD as the MTD (Camidge et al., 2012; Kwak et al., 2010). As a single agent for ALK+ve NSCLC, PF-02341066 is licensed for use at 250mg BD. If this is not tolerated, the suggested dose reductions are 200mg BD, then 250mg once daily (OD), then to permanently discontinue. Available capsule sizes are 200mg and 250mg, with no current availability for the previous 150mg formulation. Doses of 200 mg or more once daily resulted in a mean plasma trough concentration of more than 60 ng per milliliter, the pre-clinically predicted effective concentration to inhibit cMET (J Clin Oncol 27:15s, 2009 (suppl; abstr 3509). Hence, 250mg OD will be the lowest concentration tested in combination with PD-0325901. Inhibition of c-MET activity is critical, so the dose of PF-02341066 will be increased initially in cohort 2. Doses that will be explored for PF-02341066 to be used in combination with PD-0325901 are 250mg OD and 200mg BD. The highest dose to be evaluated is 200mg BD in combination with PD-0325901 8mg BD. If this is the Maximum Tolerated Dose we have put the provision to check the lower PF-02341066 dose (250mg OD) with the higher dose of PD-0325901 (8mg BD see below). We will not explore a higher dose of PF-02341066 (eg. 250mg BD) in combination with MEK inhibitor PD-0325901 for the following reasons (1) the PF-02341066 target trough dose needed to inhibit our target (c-MET) is approximately 50% of that needed to inhibit ALK, (2) a consistent increase in toxicity is seen, albeit at acceptable frequency and severity, with escalation of the monotherapy PF-02341066 dose level from 200mg BD to 250mg BD, and (3) our experience and that of others over the last few years has been that combining oral targeted agents in oncology clinical trials has been rarely achievable with both compounds at full monotherapy doses, with lower dosing needed of one or both and/or a change to alternative schedules with less frequent dosing. Within the restrictions of available capsule size and known single dose tolerability, our current design explores the full range of possible doses. PF-02341066 in combination with PD-0325901 will be administrated in this phase I dose escalation and dose expansion until disease progression, intolerance or withdrawal.  
PF-02341066 is approved in the United States for the treatment of patients with locally advanced or metastatic NSCLC that is ALK-positive as detected by an FDA-approved test. PF-02341066 is also approved in the Republic of Korea for the treatment of patients with ALK-positive locally advanced or metastatic NSCLC. PF-02341066 has been authorised in the European Union under an EMA 'conditional approval' scheme, which means that further evidence on this medicinal product is awaited, and is indicated for the treatment of adults with previously treated ALK-positive NSCLC.  
Randomized phase 3 studies of single-agent PF-02341066 vs. standard chemotherapy are ongoing in the first- and second-line ALK-positive advanced NSCLC treatment settings. Other indications under study with single-agent PF-02341066 treatment include but are not limited to MET-amplified NSCLC, ROS-positive NSCLC, ALK-positive anaplastic large cell lymphoma, ALK-positive inflammatory myofibroblastic tumor, and ALK-positive neuroblastoma. Clinical trials of PF-02341066 in combination with EGFR TKI in advanced NSCLC patients are ongoing. PF-02341066 is also under investigation in advanced cancer patients with various degrees of hepatic impairment, subjects with severe renal impairment, and pediatric cancer patients.
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pd-0325901

PD-0325901 is a highly specific non-ATP-competitive inhibitor of MEK1 and MEK2. The Kiapp of PD-0325901 for an activated form of MEK1, MEK1-S218D/S222D, was 1.1±0.2 nM, while the Kiapp of PD-0325901 for an activated form of MEK2, MEK2-S222D/S226D was 0.79±0.2 nM. Specificity of PD-0325901 was also evaluated against a panel of 27 kinases. This panel, which was comprised of tyrosine kinases as well as a multitude of serine/threonine kinases, was completely refractory to inhibition by PD-0325901 at a concentration of 10 µM. Therefore, PD-0325901 appears to be exquisitely specific for MEK1/2. In vitro studies have shown that PD-0325901 inhibits phosphorylation of ERK of colon 26 (murine), HCT-116 colon (human), and MDCK (dog) cells with IC50 values of 0.34, 0.28, and 0.31 nM, respectively. In vivo, PD0325901 has been found to inhibit potently phosphorylation of ERK in 2 human tumour xenograft models
(HT-29 colon, and MiaPaCa2 pancreatic). Oral administration of 25 mg/kg PD-0325901 resulted in 79% and 93% inhibition of pERK expression 24 hours after dosing, as measured in excised HT-29 and MiaPaCa2 tumours, respectively.  
Four studies evaluating the safety, efficacy, and/or PK of PD-0325901 have been undertaken. Study A4581001 was a phase 1/2 study in cancer patients, with 79 patients dosed (66 in Phase 1 (LoRusso et al., 2010) and 13 in Phase 2). The phase I component evaluated the toleration of alternate treatment regimens [eg, intermittent (3 wk on treatment/1 wk off), continuous (daily (OD), and continuous with breaks (5 d on/2 d off treatment). 5 days on/2 days off dosing). Doses ≥2 mg BD, the dose level at which the plasma concentration of PD-0325901 exceeded the target inhibition based on xenograft mouse models (16.5-53.5 ng/mL), consistently caused >60% suppression of pERK in melanoma samples from patients. The most frequently reported treatment-related AEs on all treatment schedules were rash, diarrhoea, fatigue, nausea, and visual disturbances/eye disorders, a toxicity profile consistent with those observed for other MEK
inhibitors. The maximum tolerated dose (MTD), based on first cycle dose-limiting toxicities, was 15 mg BD continuously. However, 10 and 15 mg BD continuous dosing and 10 mg BD 5 days on/2 days off schedules were associated with delayed development of RVO; thus, further enrolment to this trial was stopped. Intermittent dose scheduling between 2 and 10 mg BD should be explored to identify a recommended dose with long-term PD-0325901 use.  
Study A4581002 was a phase 2 study in patients having advanced non small cell lung cancer (NSCLC) (N =
34) (Haura et al., 2010). PD-0325901 was initially administrated orally 15mg BD on an intermittent schedule (3 wk on/1 wk off; schedule A). This schedule was not well tolerated. Consequently the same dose 15mg BD
was administrated with additional weekends "off treatment" (i.e. 5 d on/2d off for 3 wk, followed by 1 wk off, schedule B). The introduction of treatment breaks was thought more likely to improve patient safety.  
Treatment related toxicities included diarrhoea, fatigue, rash, vomiting and nausea. There was a substantial decrease in the incidence of visual disturbances with schedule B, neurologic events were similar between the 2 schedules. Visual disturbances include blurred vision, halo vision, photopsia and diplopia. There were no objective responses. Conclusion was that further studies should focus on PD-0325901, rational combination strategies and enrichment of patient selection based on the mode of action.  
Study B1271002, is an ongoing phase 1, open label, triple-arm, multi-centre, dose escalation study of two dual PI3K/mTOR inhibitors, PF-04691502 and PF-05212384, each in combination with irinotecan or PD0325901 in patients with advanced cancer. In this study PD-0325901 has been explored in combination with PF-04691502 in RAS or RAF mutated tumours (N = 7). In addition, a formal food effect study (A4581004) in healthy subjects (N = 23) evaluated the effect of food on plasma pharmacokinetics of PD-0325901. Doses have been administered on an intermittent (i.e., 3 weeks on/1 week off) or continuous daily dosing schedule.  
Study B1271002 is a Phase 1b study that explores two PI3K/mTOR inhibitors (PF-04691502 and PF05212384) in combination with either PD-0325901 or irinotecan in patients with advanced cancer. This is the first clinical trial exploring PD-0325901 in combination, in this case with the oral PI3K/mTOR inhibitor, PF04691502. However because PF-05212384 when combined with irinotecan showed a better safety profile and higher antitumor activity than the combination of PF-04691502 and irinotecan, the arm assessing the combination of PD-0325901 with PF-04691502 will be closed and a new arm combining PD-0325901 with PF-05212384 will be explored. Once identified the recommended phase 2 dose (RP2D) of the combination an expansion cohort will be conducted in up to 20 patients with advanced, RAS mutated, colorectal cancer.  
As of 20 June 2012, six patients were diagnosed with significant findings on eye examinations. These included 3 cases of retinal vein occlusion, 2 cases of optic neuropathy, 1 case of optic atrophy and 1 case of iridocyclitis and retinal detachment. The case of retinal detachment was reported in study B1271002. In humans, the plasma pharmacokinetics of PD-0325901 was characterized by rapid absorption, with peak concentrations occurring within 1 to 2 hours of dosing, generally dose proportional changes in exposures, and an average elimination half-life of 8.6 hours (range 5 to 18 hours across dosing cohorts). Food appeared to reduce PD-0325901 peak plasma concentrations, but the effect on AUC was variable. The plasma half-life of the carboxylic acid metabolite PD-0315209 was longer than that for the parent.  
Dose of PD‐0325901 at 4mg inhibits pERK1/2 for >12 hours in xenograft mouse models. We will start with the suggested dose from the xenograft model of 4mg BD and then define a cohort taking 8mg BD. Dose levels of 8mg BD or lower (continuous and intermittent) are safe and did not result in any CNS toxicity or retinal vein occlusion/thrombosis. We therefore have no desire to exceed 8mg BD on safety grounds and as this is a dose that will inhibit the target of MEK1 and MEK2.  
Based on in vitro studies, PD-0325901 and its circulating metabolite, PD-0315209, have a low potential to inhibit CYP2D6, CYP3A4, CYP1A2, and CYP2C19. However, the metabolite (PD-0315209) has the potential to inhibit CYP2C8 and CYP2C9. Caution should be exercised when co-administering PD-0325901 with drugs that are substrates for CYP2C8 or CYP2C9. Patients taking concomitant phenytoin and/or warfarin should be monitored on a regular basis. During the dose escalation phase of this trial studying the combination of PF-02341066 and PD-0325901, a decision was made by Pfizer that they would not pursue clinical development of PD-0325901 whilst continuing to be fully supportive of the underlying rationale for this trial. Pfizer retained their commitment to use of PF-02341066 as a cMET inhibitor in all components of the clinical trial. It was agreed that we would proceed to completion of the dose escalation phase of the trial using the combination of PF-02341066 and PD-0325901, but that the investigators should explore the use of an alternate MEK inhibitor in combination with PF-02341066.An abbreviated dose escalation combination trial was considered suitable for the PF02341066 and Binimetinib combination as Binimetinib is further on its research development than the MEKi PD-0325901, thus providing good evidence for the choice of dosage level to be studied in this trial. The new combination of PF-02341066 and Binimetinib will then be used for the dose expansion phase of this trial. The MEK inhibitor Binimetinib has proceeded through phase I-III clinical trials as both monotherapy (in phase III trials in low-grade serous ovarian cancer, BRAF-mutant melanoma and NRAS-mutant melanoma, with the latter indication likely to proceed to registration filing in 2016) and in combination with various cytotoxics and other novel agents in phase I and II trials and was agreed as the preferred combinatorial partner with PF02341066for this trial. Array BioPharma have agreed to provide Binimetinib for use in the MErCuRIC trial in combination with PF-02341066.
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binimetinib

Binimetinib (also known as MEK162 or ARRY-438162) is an orally bioavailable, selective and potent mitogen-activated protein (MAP) kinase kinase (MEK) 1 and MEK 2 inhibitor. Binimetinib is currently being investigated as a single agent and in combination with a variety of additional compounds including paclitaxel, and inhibitors of PI3K, RAF, EGFR, PKC, CDK4/6 and IGF-1R in patients with selected advanced or metastatic solid tumors, including, among other tumors, melanoma, biliary, colorectal, and ovarian cancers. The clinical development program of binimetinib encompasses patients with selected advanced or metastatic solid tumors, including NRAS- and BRAF-mutant melanoma, BRAF- and KRAS- mutant NSCLC, high-grade platinum-resistant ovarian cancer, low-grade serous ovarian cancer, biliary, colorectal, and pancreatic cancers.  
Binimetinib is an ATP-uncompetitive inhibitor of MEK1/2. In cell-free systems, binimetinib inhibits MEK1/2 with an IC50 of 12 nM. *In vitro*, binimetinib potently inhibits MEK- dependent phosphorylation of ERK in human BRAF-mutant melanoma cell lines as well as NRAS-mutant melanoma lines. *In vivo*, Binimetinib treatment results in dose- and time-dependent inhibition of phosphorylation of ERK in the HT-29 human colorectal carcinoma xenograft. Similarly, levels of both pERK and DUSP6 mRNA (a target gene of phosphorylated ERK) are reduced in the A375 melanoma xenograft. Lastly, in ex vivo experiments, Binimetinib reduces pERK levels in human whole blood cells. *In vitro*, Binimetinib potently inhibits the proliferation of human cancer cell lines. Binimetinib is particularly active in cells harboring activating mutations in the BRAF, NRAS and KRAS genes, although activity is also observed in cell lines that lack such mutations. Synergistic interactions with the RAF inhibitor encorafenib and PI3K inhibitors BEZ235 (pan-PI3K/mTOR), buparlisib and BYL719 (PI3Kα) have been observed in subsets of melanoma, colorectal, pancreatic and lung-derived cancer cell lines. *In vivo*, single-agent Binimetinib inhibits the growth of tumours in numerous xenograft models, including those derived from colorectal, non-small cell lung, pancreatic and melanoma cancers. Binimetinib is also active in primary human explant models derived from several cancer types including colorectal. Combining Binimetinib with a variety of standard chemotherapy agents such as cisplatin, gemcitabine, taxanes or 5-FU/oxaliplatin resulted in enhanced anti-tumour activity in numerous *in vivo* tumour models. Similarly, combinations of Binimetinib with a variety of targeted agents have shown activity in vivo in multiple tumour models. In subsets of xenograft models of CRC, NSCLC and pancreatic cancer, anti-tumour effects have been observed when Binimetinib was combined with a variety of PI3K inhibitors. As of 07-January-2015, a total of 2430 healthy subjects and patients have been enrolled in Binimetinib studies and 1945 of whom received at least one dose of Binimetinib, and have been evaluated for safety, including 204 healthy subjects, 6 liver dysfunction patients, 164 patients with rheumatoid arthritis and 1571 patients with advanced cancer. As of the data-cut off Binimetinib experience as a single agent in 705 cancer patients includes 6 studies: - [ARRAY-162-111]: phase I, dose-escalation study in patients with advanced solid tumours followed by expansion cohorts in patients with advanced or metastatic biliary cancer or KRAS- or BRAF-mutant metastatic colorectal cancer (CCR). - [CMEK162X2201]: phase II study in patients with locally advanced and unresectable or metastatic malignant cutaneous melanoma, harbouring BRAFV600 or NRAS mutations. - [CMEK162X1101]: phase I, dose escalation study in Japanese patients with advanced solid tumours with the expansion part in patients whose tumours harbour RAS or BRAF mutations.  
- [CMEK162A2301]: phase III, two-arm, randomized study in patients with advanced unresectable or metastatic NRAS Q61 mutation-positive melanoma.  
- [ARRAY-162-311]: phase III, two-arm, randomized study in patients with recurrent or persistent lowgrade serous carcinomas of the ovary, fallopian tube or primary peritoneum.  
- [CMEK162AUS11]: phase II study in patients with RAS/RAF/MEK activated tumours.  
The study [ARRAY-162-111] was a phase I, open-label, dose-escalation of oral Binimetinib in patients with advanced solid tumours followed by expansion cohorts in patients with advanced or metastatic biliary cancer or KRAS- or BRAF-mutant metastatic CRC. A total of 93 patients received at least 1 dose of Binimetinib.  
Four dose levels were evaluated: 30 mg BID, 45 mg BID, 60 mg BID and 80 mg BID. Two of 4 patients receiving 80 mg BID experienced dose- limiting toxicities (DLTs), thus the 80 mg BID dose was declared non-tolerable. Seven patients were enrolled at 60 mg BID and no DLTs were observed, therefore, 60 mg BID was declared the MTD. Following completion of the Dose-Escalation Phase, a total of 74 patients were enrolled in the Expansion Phase. The dose of 45 mg BID was determined as the recommended phase II dose (RP2D) mainly due to the frequency of ocular AEs in patients at the 60 mg dose level.  
The study [CMEK162X1101] is an ongoing, phase I, open label, dose escalation study of Binimetinib in Japanese patients with advanced solid tumors with an expansion part in patients whose tumours harbour RAS or BRAF mutations. A total of 21 patients received at least 1 dose of Bnimetinib: 6 patients received 30 mg BID and 15 patients received 45 mg BID. Eighteen patients (as of 10-February-2014) were discontinued from the study and 3 patients were still ongoing. Two patients in the 45 mg BID dose level cohort (dose escalation part) reported 2 DLTs, both were recurrent Grade 2 detachment of retinal pigment epithelium. Therefore, 45 mg BID was declared the MTD in Japanese patients. No DLT was reported in patients enrolled in the expansion part.  
The most frequently reported AEs suspected to be related to Binimetinib, regardless of grade and Binimetinib dose were dermatological events (rash, dermatitis acneiform), gastrointestinal (GI) events (nausea, vomiting, diarrhea), edema peripheral, fatigue and CPK increased. The majority of these AEs were Grade 1 or 2 with less than 5% of cases Grade 3 or 4, with the exception of elevation of blood CPK, reported as 24% (44/183 patients) Grade 3 or 4 in [CMEK162X2201] and 17.2% (10/58 patients) in dose escalation and 16.6% (11/66 patients) in dose expansion [CMEK162X1101] studies. Binimetinib experience in combination with others agents include 866 patients in 13 studies:
Five studies with RAF inhibitors Encorafenib or RAF265:
- [CMEK162X2102]: phase II study of sequential, single-agent Encorafenib followed by a rational combination with targeted agents (including Binimetinib) after progression, to overcome resistance in adult patients with locally advanced or metastatic BRAFV600 melanoma.  
- [CMEK162X2110]: phase Ib dose finding, dose escalation study of Binimetinib in combination with encorafenib, in selected advanced solid tumors.  
- [CLGX818X2102]: phase II study of Binimetinib in combination with Encorafenib in patients with locally advanced or metastatic BRAFV600 mutant melanoma. - [CMEK162B2301]: phase III, randomized, 2-part study in patients with BRAFV600- mutant locally advanced unresectable or metastatic melanoma. - [CLGX818X2109]: phase II, open-label study of Encorafenib and Binimetinib, followed by a rational combination with targeted agents after progression on Encorafenib and Binimetinib, to overcome resistance in adult patients with locally advanced or metastatic BRAF V600 melanoma. Three studies with PI3KC/AKT pathway inhibitors BEZ235 (pan-PI3K/mTOR) Buparlisib (pan-PI3K) or BYL719 (PI3Kα):
- [CMEK162X2103], [CMEK162X2101] and [CMEK162X2109]: all three are phase Ib, dose escalation and expansion studies in selected advanced solid tumours. One study with PKC-selective inhibitor sotrastaurin
- [CMEK162X2203]: phase Ib/II study in patients with metastatic uveal melanoma.  
One study with CDK4/6 inhibitor LEE011 - [CMEK162X2114]: phase Ib/II study, in patients with NRAS mutant melanoma.  
One study with IGF-1R monoclonal inhibitor Ganitumab
- [CMEK162X2111]: phase Ib/II dose-escalation and expansion study in patients with selected advanced solid tumours. One study with EGFR inhibitor Panitumumab
- [CMEK162X2116]: phase Ib/II, dose-escalation study in patients with mutant RAS or wild-type RAS
metastatic CRC. One study with standard chemotherapy agent paclitaxel - [ARRAY-162-112] phase Ib, dose-escalation and expansion study in women with platinum-resistant or refractory epithelial ovarian, fallopian tube or primary peritoneal cancer.  
The target RP2D of Binimetinib for combination studies with targeted agents is 45 mg BID. Overall, the frequently reported AEs suspected to be related to Binimetinib in combination studies were found to be similar to those found in single-agent studies, which include GI events (diarrhea, nausea, vomiting),
dermatological events (dermatitis acneiform, rash) CPK elevation and retinal events. The percentage of patients that discontinued study drug due to AEs regardless of relationship to Binimetinib ranged from 2.6% [CMEK162X2203] to 36% [CMEK162X2101]. A total of 52 DLTs were observed in the dose-escalation part of combination studies, as following: 10 DLTs in [CMEK162X2102], 6 DLTs in [CMEK162X2110], 7 DLTs in [CMEK162X2111], 6 DLTs in [CMEK162X2103], 13DLTs in [CMEK162X2101] and 10 DLTs in
[CMEK162X2201] study. Of these 52 DLTs, 13 were reported in the [CMEK162X2101] study combining Binimetinib with the PI3K inhibitor Buparlisib. The most frequents DLTs reported were gastrointestinal events, followed by ocular and dermatological events. A total of 128 deaths were reported during the study or within 30 days of last dose of study drug in cancer patients, either in single-agent or combination studies
(45 and 46 respectively). The most frequent cause of treatment discontinuation was disease progression and other events not related to study drug. Based on the experience from the 13 completed phase I studies (9 in healthy subjects , 3 in cancer patients, 1 in rheumatoid arthritis patients) and 1 completed phase II study (in rheumatoid arthritis patients), Binimetinib has demonstrated an acceptable and manageable safety profile with the majority of AEs Grades 1 or 2 of intensity and reversible.  
Currently one phase III study of Binimetinib at 45mg BID is being conducted in patients with unresectable or metastatic BRAFV600-mutant melanoma in combination with encorafenib [CMEK162B2301]. The exposure of Binimetinib when combined with Bncorafenib described by Cmax and AUC has the same ranges of values founded in the single agent studies. Binimetinib has demonstrated an acceptable safety profile in non-clinical toxicology and clinical studies. As with any new investigational drug, unexpected AEs may occur. Regarding reproductive toxicity
(teratogenicity), there are no clinical data. However, Binimetinib must not be used in pregnant women or nursing women and the use of highly-effective contraception is recommended for male and female subjects participating in clinical trials. Patients with a history or current evidence of retinal vein occlusion (RVO) or risk factors for RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndrome) should be excluded from studies with binimetinib. Patients with a medical history of deficient liver glucuronidation (Gilbert syndrome) should be excluded from the clinical studies. Strict attention should be given to cardiovascular comorbidities, specifically, coronary artery disease and hypertension. Before Binimetinib administration patients should have a baseline left ventricular ejection fraction (LVEF) evaluation. Investigators should follow specific recommendations for dose adjustments due to specific toxicities like dermatologic events, diarrhoea, hepatic abnormalities, decrease of LVEF,
increase in blood pressure (systolic and diastolic), retinal events and CPK elevation in blood. Supportive therapy for the management of binimetinib associated toxicities should be based on Investigator experience; guidance is provided in the protocols. Patients reporting de-novo or worsening of visual symptoms should be referred to an ophthalmologist. Ocular coherence tomography should be used for diagnosis and monitoring of retinal events. Early intervention is recommended for skin toxicities (including prophylactic measures, topical and/or systemic treatment and referral to a specialist as necessary), and management of diarrhoea.
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1.3 other research interventions

Fundamental to our approach is the evaluation of the effects of drug administration on tumour biology. This requires access to tumour and surrogate tissues for detailed molecular analyses. To identify molecular signatures of sensitivity to MEKi/METi treatment in the RASMT and RASWT/cMET+ subgroups, 2 core biopsies from representative metastases (one for fixation and one for fresh frozen material) will be obtained prior to treatment. In addition, a whole blood sample for germline DNA and ctDNA analyses will be obtained prior to treatment. Patients who demonstrate a response to MEKi/METi (as determined by RECIST 1.1), but then develop secondary resistance, will undergo a second biopsy (2 cores fresh frozen and 1 for fixation)
from a metastasis. At the time of trial enrolment, 20 mL of whole blood will be collected from each patient for extraction of cell free circulating DNA.
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1.4 rationale for the study

Scientific Rationale:  
We have employed a systems biology approach, comprising gene expression profiling, metacore pathway analysis and siRNA screening, to identify novel targets/pathways critical for the survival of *KRAS*MT
tumours, both basally and following MEK inhibitor treatment. We found that JAK1/2-STAT3 and the upstream receptor tyrosine kinase c-MET are important pro-survival signals in *KRAS*MT CRC (Van Schaeybroeck et al, Cancer Cell, in revision). Further studies indicated that c-MET is acutely activated following MEK1/2 inhibition in *KRAS*MT 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 *KRAS*MT CRC cells. Importantly, combining PF-02341066 with the MEKi AZD6244 resulted in synergistic reduction in tumour growth in *KRAS*MT xenograft models. These preclinical *in vitro* and *in vivo* data support the further clinical evaluation of combined MEKi/METi treatment to combat metastases in RASMT CRC patients (Figure 1).  
Figure 1(as above). Preclinical *in vitro* and *in vivo* data of combined treatment with MEK inhibitor AZD6244 and c-MET inhibitor crizotinib in *KRAS***MT CRC models. (A)** *KRAS*MT CRC cell lines, LS174T and GP5D (mutations in codon 12), were co-treatment with AZD6244 and crizotinib for 24 hours and apoptosis (cell death) was determined by Western blotting for PARP and caspase 3 cleavage. These data show a synergistic increase in cell death with combined AZD6244/crizotinib treatment in both models. (B) Growth rate of RASMT HCT116 (upper panel) and SW620 (lower panel) xenografts in BALB/c SCID mice.  
Mice were treated with vehicle, AZD6244, crizotinib or combined AZD6244/crizotinib treatment. Differences in growth were determined using Student's t test and by calculating subsequent P values. ***, P < 0.001.  
These data show a synergistic reduction in tumour growth in mice treated with combination of AZD6244 and crizotinib.
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clinical rationale evidence underpinning the

Functional dysregulation of c-MET in cancer Under normal conditions, c-MET activation is tightly regulated by ligand activation on the cell surface, ligandactivated receptor internalization/degradation and paracrine ligand delivery. Despite these controls, pathway deregulation occurs in multiple cancers. Binding of the physiological ligand HGF induces c-MET
autophosphorylation on the tyrosine residues Y1234 and Y1235 at the tyrosine kinase domain c-MET, which leads to autophosphorylation of the carboxy-terminal bidentate substrate-binding site (Tyr 1349 and Tyr 1356) of MET (Ponzetto et al., 1994; Weidner et al., 1996). Various cytoplasmic effector proteins, including GAB1, GRB2, phospholipase C and SRC are directly recruited to this site and become phosphorylated on tyrosine residues, resulting in a diversity of cellular responses such as cell survival, cell proliferation, migration, invasion and epithelial-to-mesenchymal transition (Birchmeier et al., 2003; Zeng et al., 2008). A number of reports have shown the role of c-MET in metastatic progression (Moshitch-Moshkovitz et al.,
2006).  
MEK as a potential therapeutic target in mCRC
Inhibition of MEK1/2, a downstream effectors of RAS, is an attractive treatment strategy for RASMT CRC (Van Schaeybroeck et al., 2011). A number of preclinical *in vivo* models have shown that the MEKi
(AS703026 and AZD6244) could inhibit RASMT CRC tumour growth (Little et al., 2011; Yoon et al.,
2011). 37 A phase II study of the MEKi AZD6244 in highly pre-treated unselected mCRC patients showed similar efficacy compared to oral 5-FU (capecitabine). However, acute activation of pro-survival pathways and other resistance mechanisms such as driver oncogene amplification can cause resistance, limiting its success as a single agent in the clinic (Little et al., 2011).
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c-met mediates resistance to anti

c-MET is overexpressed in ∼50%-60%, amplified in ∼10% and mutated in ∼5% of CRC (Di Renzo et al.,
1995; Fumagalli et al., 2010). A number of studies have shown that activation of c-MET is an important resistance mechanism following treatment with EGFR inhibitors in NSCLC and head and neck cancers (Wheeler et al., 2008; Yano et al., 2008). Ectopic overexpression of the MET receptor or paracrine activation of *c-MET* using its ligand HGF in quadruple WT CRC cells, conferred resistance to cetuximab or panitumumab to a degree equivalent to that triggered by mutant RAS. Notably, the ability of WT *c-MET* to drive resistance to EGFR was abolished by concomitant treatment with the anti-cMET inhibitor, JNJ38877605 (Bardelli et al, Cancer Discovery, submitted). These studies highlight the role of c-MET in mediating primary and secondary resistance to anti-EGFR targeted therapies in CRC. A recent retrospective study in 73 mCRC patients, suggested that c-MET overexpression may have a role in resistance to antiEGFR targeted therapies in RASWT CRC (Inno et al., 2011). All these studies indicate that patients with RASWT tumours with aberrant c-MET (RASWT/c-MET+) expression do not respond to EGFR targeted therapies and may benefit from anti-c-MET targeted therapies.  
Figure 2. **The HGF-c-MET axis signalling network and targeted therapies strategies.**
The pathway which transduces invasive growth signals from mesenchymal to epithelial cells is activated by HGFA. C-MET kinase activation results in auto-phosphorylation and binding of adaptor proteins, forming scaffolds for recruitment and activation of signalling proteins. Activation of downstream signalling results in   
activated by HGFA. C-MET kinase activation results in auto-phosphorylation and binding of adaptor proteins, forming scaffolds for recruitment and activation of signalling proteins. Activation of downstream signalling results in increased proliferation, survival, migration and metastasis.
Targeting c-MET in colorectal cancer, rationale and progress. The tight regulation of HGF and MET signalling that is observed in development and regeneration is lost in cancer at multiple levels. Functional crosstalk of c-MET with the receptor tyrosine kinases EGFR, ERBB2, ERBB3 or insulin-like growth factor 1 receptor has been reported in several systems and has emerged as a major mechanism for cancer progression and resistance to therapy (Engelman et al., 2007). Recent data, including studies from this consortium, indicate that c-MET overexpression correlates with poor overall survival and resistance to cetuximab in RASWT CRC (Inno et al., 2011). These data further suggest that c-MET is an attractive target in a significant subpopulation of CRC patients. Currently, multiple agents targeting HGF or c-MET are in phase I-III clinical trials. These targeted therapies can be HGF-competitive analogs (competing for ligand for receptor binding), decoy c-MET compounds, antibodies against HGF (eg.  
Rilotumumab, Ficlatuzumab, TAK-701), antibodies against cMET (eg. MetMab or Onartuzumab, LY2875358) and small molecule tyrosine kinase inhibitors (eg. Crizotinib, tivantinib, foretinib) (Figure 2). With respect to CRC, a phase Ib/II trial in patients with RASWT CRC, found that the combination of panitumumab plus rilotumumab was superior in term of response rate to panitumumab alone (31% versus 21%) (Eng et al.  
J Clin.Oncol. 29 (Suppl.), abstract 3500).
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patient selection for treatment with

"One-size-fits-all" approaches have been standard practice in CRC treatment, but with our increased understanding of the molecular/genetic heterogeneity of CRC, it is clear that novel treatments must be developed and tested in selected subgroups to maximize the benefit of this new knowledge. In Chronic Myeloid Leukaemia (CML), the anti-apoptotic BCR-ABL fusion protein provides a disease specific target for the tyrosine kinase inhibitor imatinib mesylate. Since its introduction in 2001, Imatinib Mesylate and second and third generation TKIs directed against BCR-ABL have become the gold standard therapy in CML, replacing allogeneic stem cell transplantation (Kantarjian et al., 2002). In Non-Small Cell Lung Cancer (NSCLC), tumours harbouring an EGFR mutation are selected for gefitinib treatment, (Lynch et al., 2004)
while recent exciting data has demonstrated that patients carrying an EML4-ALK fusion gene respond to small molecule TKIs such as crizotinib, again demonstrating how molecular stratification informs state-of-theart treatment in patients with poor prognosis disease (Camidge et al., 2012). In this regard, the c-MET-HGF
axis represents a viable target for molecular stratification, with a number of retrospective studies indicating benefit from molecularly targeted agents, particularly in patients whose tumour has high expression (amd/or amplification) of c-MET (Okamoto et al., 2012). Investigators of the randomized phase Ib/II study of rilotumumab with panitumumab versus panitumumab alone found that CRC tumours that overexpressed MET were more likely to respond to the combination of rilotumumab and panitumumab. Other studies in NSCLC and gastric cancer with Moab directed against MET and rilotumumab respectively have also indicated that the best responses are observed in patients expressing high levels of c-MET in the tumour
(Spigel et al. J Clin Oncol: suppl; abstract 7505).  
Recent pilot data from the consortium (QUB, BHSCT)1 has led to an increased understanding of aberrant MET in RASWT CRC patients, which can be used to better define cohorts in the MErCuRIC clinical trials. This data indicates: (1) there is discordance between MET expression status as defined by immunohistochemistry (IHC) and RNA scope, (2) the prevalence of high MET (3+) defined with combination of IHC and RNA scope is ∼ 1%, (3) MET amplification is not always associated with high MET measured by IHC or RNA scope, and (4) there is clear evidence that MET amplified patients might benefit from crizotinib treatment, however the data for high MET IHC or RNA scope as predictive markers for anti-cMET therapies is less clear. In addition, new data2 has arisen over the last year showing the role of c-MET mutations (exon 14 skipping) as a determinant of response to anti c-MET targeted therapies in Non-Small Cell Lung Carcinoma (NSCLC). Thus, there remains uncertainty as to which precise molecular alterations in cMET will drive sensitivity: is a structural alteration in the gene by mutation or copy number amplification required, or is over-expression as measured at RNA or protein level an acceptable biomarker? In this study, we will therefore enter patients into two parallel cMET altered cohorts defined as below.
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1.5 primary hypothesis of the

Combined MEK/MET inhibitor treatment is well tolerated and results in superior response and progression free survival of patients with either a) RASMT CRC or b) RASWT CRC with amplification or mutation c-MET gene or c) RASWT CRC with over-expression of c-MET on protein or mRNA compared to standard chemotherapy treatment.  
This study, which is the first component of the overall MErCuRIC programme, will evaluate safety, toxicity, and anti-tumour activity of the combination of PD-0325901 with PF-02341066, as well as the combination of Binimetinib with PF-02341066.  
Expansion phases will be undertaken in the three molecular cohorts to determine clinical activity measured by response to combined Binimetinib with PF-02341066:
a) RASMT CRC or b) RASWT CRC with amplification or mutation c-MET gene or c) RASWT CRC with over-expression of c-MET on protein or mRNA The outputs from this trial will inform a further study to compare the effect of combined MEKi/METi treatment (experimental arm) with standard therapy in any of these molecular cohorts where sufficient activity to warrant further investigation as defined in the statistical plan is observed. As part of this clinical trial we will develop, validate and apply a comprehensive diagnostic assay for assessing *c-MET* dysregulation. This will enable us to apply "smart recruiting" protocols for selection of future trial participants. Based on NGS data obtained during the trial, the MErCuRIC Consortium will also develop a customised NGS-CRC gene assay to predict response/resistance to combination MEKi/METi.
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2 trial design

2.1 Outline This is a phase I combination study of the MET inhibitor PF-02341066 with the MEK inhibitors PD-0325901 or Binimetinib. There was an initial dose escalation phase using patients with advanced solid tumours receiving the combined study treatment of PF-02341066 with PD-0325901. Following the discontinuation of PD-0325901, the study design has been updated to include a further short dose escalation phase using patients with advance solid tumours receiving the combined study treatment of PF-02341066 with Binimetinib. This will be followed by a dose expansion phase recruiting patients with RASMT and RASWT/cMET over-expressing metastatic CRC.  
In the initial dose escalation study using PF-02341066 with PD-0325901, 25 patients were recruited. In the further dose escalation study using PF-02340166 in combination with Binimetinib, 20 patients were recruited. In the dose expansion phase an additional 42-98 patients with biopsiable metastatic disease will be treated at the RPII dose to further evaluate safety, PK, PD and treatment response. In the dose expansion phase additional biopsy and blood samples will be obtained to define mechanisms of response/resistance to PF02341066/Binimetinib therapy.  
Early closure of recruitment: Recruitment to the trial closed on 23Oct2018 with a total of 82 patients recruited, 45 patients to the dose escalation phases and 37 patients to the dose expansion phase.  
Significant difficulties were encountered in recruiting to the RAS WT CRC patient cohorts and it was decided that the dose expansion phase patient recruitment target of 42-98 patients was non-feasible within the constraints of the EU grant supporting the trial. The decision was made with the support of the TMG, FP7 consortium members and trial sponsor, the University of Oxford.
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2.2 treatment schedule and duration

In this first dose escalation phase of the study, patients with advanced solid tumours will be recruited. It is anticipated that 12-24 patients will be required for the dose escalation phase of the study, which uses a rolling six design. This method minimises delays in the dose escalation phase and up to six patients can be enrolled concurrently onto the study. Accrual to the study will only be suspended when awaiting data from six patients and/or a decision from the Trial Management Group. Decisions as to whether to enrol a new patient onto the current, next highest, or next lowest dose level will be made based on available data at the time of new patient enrolment.  
Figure 3. Schema for dose levels in the escalation phase using PF-02341066 **in combination with PD0325901**  
  
Dose levels Dose levels are summarised in the table below, and may include an intermediate dose level dependent on the emergent clinical data and dose limiting toxicities. Dose levels 2a and 3a may only be investigated if either dose level 2 or dose level 3 respectively is determined to be the MTD.  
| Dose Level   | PD-0325901   | PF-02341066   |
|--------------|--------------|---------------|
| 1            | 2mg BD       | 250mg OD      |
| 2            | 2mg BD       | 200mg BD      |
| 2a           | 4mg BD       | 250mg OD      |
| 3            | 4mg BD       | 200mg BD      |
| 3a           | 8mg BD       | 250mg OD      |
| 4            | 8mg BD       | 200mg BD      |  
Dose level assignment will be based on the number of patients currently enrolled in the cohort, the number of dose limiting toxicities (DLTs) observed, and the number of patients at risk for developing a DLT (i.e.  
patients enrolled but who are not yet evaluable for toxicity ) . For example, when three patients are enrolled onto a dose cohort, if toxicity data are available for all three when the fourth patient enters and there are no DLTs, the dose will be escalated and the fourth patient will be enrolled to the subsequent dose level. If data are not yet available for one or more of the first three patients, or if one DLT has been observed, the new patient will be entered at the same dose level. Lastly, if two or more DLTs have been observed, the dose level will be de-escalated. The process will be repeated for patients five and six. When patients are nonevaluable for toxicity, they will be replaced with the next available patient if escalation or de-escalation rules have not been fulfilled at the time the next available patient enrols in the study. Once the maximum tolerated dose (MTD) has been exceeded the cohort at the next lowest dose level will be expanded to six patients. If the MTD is not defined at the highest dose level to be explored (Dose Level 4, Figure 3), then this dose level will be defined as the RPII dose. The definition of MTD is outlined in the protocol section 8.4.2 and will be discussed and agreed at regular teleconferences throughout the dose escalation phase of the study. Once the MTD has been defined, dosing at a higher level must not occur.
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2.2.2 dose escalation phase of

In this second dose escalation phase of the study, patients with advanced solid tumours will be recruited. It is now anticipated that up to 25 patients will be required for this dose escalation phase of the study to provide for exploring the tolerability of the combination at intermediate dose levels from those previously envisaged, based upon the emerging tolerability and safety profile. The rolling six design is the method that minimises delays in the dose escalation phase and up to six patients can be enrolled concurrently onto the study. Accrual to the study will only be suspended when awaiting data from six patients and/or a decision from the Trial Management Group. Decisions as to whether to enrol a new patient onto the current, next highest, or next lowest dose level will be made based on available data at the time of new patient enrolment. Figure 4. Schema for dose levels in the escalation phase using PF-02341066 in combination with  
 Binimetinib
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dose levels

Dose levels are summarised in the table below. PF-02341066 250mg BD is the recommended dose level and dose level 7 has been included in this dose escalation phase as we wish to extend dosing to that level if the toxicity profile permits. Dose levels 5a and 6a may be explored if BD dosing of the combination drug treatment is not well tolerated. There may also be a requirement to reduce the frequency of the Binimetinib dosing schedule from continuous dosing throughout the study period to days 1 to 21 every 28 days dependent on emergent clinical data.  
| Dose Level   | Binimetinib   | PF-02341066   |
|--------------|---------------|---------------|
| 5            | 30mg BD       | 200mg BD      |
| 5a           | 30mg BD       | 250mg OD      |
| 6            | 45mg BD       | 200mg BD      |
| 6a           | 45mg BD       | 250mg OD      |
| 7            | 45mg BD       | 250mg BD      |  
Dose level assignment will be based on the number of patients currently enrolled in the cohort, the number of dose limiting toxicities (DLTs) observed, and the number of patients at risk for developing a DLT (i.e. patients enrolled but who are not yet evaluable for toxicity ) . For example, when three patients are enrolled onto a dose cohort, if toxicity data are available for all three when the fourth patient enters and there are no DLTs, the dose will be escalated and the fourth patient will be enrolled to the subsequent dose level. If data are not yet available for one or more of the first three patients, or if one DLT has been observed, the new patient will be entered at the same dose level. Lastly, if two or more DLTs have been observed, the dose level will be de-escalated. The process will be repeated for patients five and six. When patients are nonevaluable for toxicity, they will be replaced with the next available patient if escalation or de-escalation rules have not been fulfilled at the time the next available patient enrols in the study. Once the maximum tolerated dose (MTD) has been exceeded the cohort at the next lowest dose level will be expanded to six patients. If the MTD is not defined at the highest dose level to be explored (Dose Level 7,), then this dose level will be defined as the RPII dose. The definition of MTD is outlined in the protocol section 8.4.2 and will be discussed and agreed at regular teleconferences throughout the dose escalation phase of the study. Once the MTD has been defined, dosing at a higher level must not occur.
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2.2.3 dose expansion phase of

Once the RPII dose has been identified, up to 40 patients with biopsiable RASMT CRC or up to 29 with biopsiable RASWT CRC with amplification or mutation in the *MET* gene or 29 patients with biopsiable RASWT CRC with over-expression of c-MET protein or mRNA
will be enrolled in the dose expansion phase to further evaluate the safety, PK, PD and treatment response. Figure 5: Schema for dose expansion phase  
  
Note: Simon staging is further explained in the protocol sample size sec 15.1 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: C*ohort (b) RASWT CRC with amplification or mutation in the-*MET* gene or Cohort c) RASWT CRC with over-expression of c-MET on protein or mRNA)
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2.3 projected number of subjects

The study will be conducted in 4-5 EU centres for the dose escalation phase, increasing to 8-10 for the dose expansion phase. It was anticipated that 12-24 patients would be required for the initial dose escalation phase of the study. 25 patients were actually recruited for this initial dose escalation phase using PF02341066 in combination with PD-0325901. In the further dose escalation study using PF-02341066 in combination with Binimetinib it was anticipated that up to 25 patients would be required. 20 patients were actually recruited as required for the the exploration of the tolerability of the combination at intermediate dose levels from those previously envisaged, based upon the emerging tolerability/safety profile. For the dose expansion phase of the study it was anticipated that 42 - 98 patients would be required, bringing the expected total patient number for the trial to between 92 and 148, not counting any replacements. This target patient number will now not be realised for lack of feasibility of recruiting to the specific RAS WT CRC
patient cohorts.
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2.4 replacement of subjects

In the dose escalation phase if a patient comes off treatment due to a DLT they will not be replaced. If however, they withdraw for reasons other than safety before completing the first treatment cycle they will need to be replaced. Patients withdrawing will not receive further PF-02341066 or PD‐0325901, in the initial dose escalation phase, nor will they receive any further PF-02341066 or Binimetinib in the further dose escalation phase. These patients will be followed up for progression free and overall survival unless they withdraw their consent to do so. If the protocol mandated skin and tumour biopsies in the dose escalation and expansion phases cannot be completed for whatever reason, then the patient will be replaced.
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2.5 post-trial care and follow-up

Following the end of study visit, patients will receive subsequent standard active, clinical trial, supportive and palliative care as appropriate. All patients will be followed up for post-progression survival (PFS and OS), with details of further lines of treatment.
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3 objectives and endpoints

| Primary Objective                                                                                                                                                                                                                                     | Endpoints or                                                                                                                                                          |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| (Dose Escalation)                                                                                                                                                                                                                                     | Outcome Measures                                                                                                                                                      |
| To assess the safety and toxicity profile of PD0325901 /PF-02341066 or Binimetinib/ PF02341066 combinations in patients with advanced  solid tumours using the NCI CTCAE V4.03, and  determine the maximum tolerated dose (MTD).                                                                                                                                                                                                                                                       | Maximal tolerated dose (MTD) of PD-0325901 or  Binimetinib with PF-02341066 according to toxicities  graded by NCI CTCAE V4.03 in cycle 1 of treatment.               |
| Primary Objective  (Dose Expansion) To investigate the response to treatment with RPII  dose of PF-02341066 in combination with  Binimetinib in patients with a) RASMT CRC or b)  RASWT/c-METmut/amplified CRC or c)  RASWT/c-MET over-expressed CRC. | Clinical and radiological response to Binimetinib with  PF-02341066 as defined by stable, partially or  completely responding disease using RECIST  version 1.1.      |
| Secondary Objectives  (Dose Escalation) To define the recommended phase II (RPII) dose  and schedule of PD-0325901 or Binimetinib in  combination with PF-02341066.                                                                                   | Recommended phase II (RPII) dose and schedule,  guided by safety, PK and PD data.                                                                                     |
| To investigate the pharmacokinetics (PK) of PD0325901 or Binimetinib with PF-02341066 when  administrated in combination.                                                                                                                                                                                                                                                       | Determine plasma Cmax, Cmin, AUC, oral clearance  and t1/2 etc for PF-02341066, PD‐0325901 (and its  metabolite) and Binimetinib.                                     |
| To investigate pharmacodynamic (PD) biomarkers  of PD-0325901 or Binimetinib with PF-02341066 in  paired skin biopsies, tumour biopsies (where  possible), in serum and PBMCs.                                                                        | ELISA for soluble c-MET and HGF in plasma; ERK  phosphorylation (pERK) in PBMC;  Immunohistochemistry (IHC) for pERK1/2, cMETY1234/1235 in (mandatory) skin and (optional)  tumour biopsies.                                                                                                                                                                       |
| To preliminarily assess the efficacy of RPII dose of  PF-02341066 in combination with PD‐0325901 or  Binimetinib.                                                                                                                                     | Objective response using CT scan and modified  RECIST version 1.1 and progression free and overall  survival.                                                         |
| Secondary Objectives  (Dose Expansion) To assess the efficacy of RPII dose of PF02341066 in combination with Binimetinib in  patients with a) RASMT CRC or b) RASWT/cMETmut/amplified CRC or c) RASWT/c-MET overexpressed CRC.                                                                                                                                                                                                                                                       | Progression free survival using RECIST version 1.1. and overall survival.                                                                                             |
| To further investigate the safety and toxicity  profile/tolerability of Binimetinib/ PF-02341066  combinations.                                                                                                                                       | Adverse events according to NCI CTCAE v4.03  across all treatment cycles.                                                                                             |
| To investigate pharmacokinetic (PK) biomarkers of                                                                                                                                                                                                     | Determine plasma Cmax, Cmin, AUC, oral clearance                                                                                                                      |
| PF-02341066 and Binimetinib in blood.                                                                                                                                                                                                                 | and t1/2 etc. for PF-02341066 and Binimetinib.                                                                                                                        |
| To measure pharmacodynamic (PD) effect of PF02341066 in combination with Binimetinib in paired  skin biopsies, tumour biopsies (where possible),  plasma and PBMCs.                                                                                                                                                                                                                                                       | ELISA for soluble c-MET and HGF in plasma;  Western blotting for pERK1/2 in skin ( 10 patients).                                                                      |
| Tertiary and  Exploratory Objectives To identify molecular signatures of response and  resistance to combined PD-0325901 /PF-02341066  or Binimetinib/ PF-02341066 treatment.                                                                         | Whole exome sequencing and miRNA profiling on  tumour biopsies taken prior to treatment and upon  resistance to PF-02341066 and PD‐0325901 or  Binimetinib treatment. |
| Develop a liquid biopsy platform for routine                                                                                                                                                                                                          | Gene sequencing outputs from ctDNA in serially                                                                                                                        |
| assessment of therapeutic efficacy                                                                                                                                                                                                                    | collected plasma samples from mCRC patients in the  dose expansion phase                                                                                              |
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4 patient selection

Written informed consent must be obtained before any study specific procedures are performed. The Investigator will determine patient eligibility based on the following criteria. Dose escalation: Adult patients with pathologically proven advanced solid tumours. This will include patients with any solid tumour for whom the drug combination is considered a reasonable treatment option in the opinion of the clinical investigator. Dose expansion: Adult patients with pathologically proven colorectal cancer with a) RASMT CRC or b) RASWT/c-METmut/amplified CRC or c) RASWT/c-MET over-expressed CRC in a metastatic lesion. This will include CRC patients who received prior lines of cytotoxic drug treatment or targeted therapies.  
Subjects must meet all the inclusion/exclusion criteria listed below.  
4.1 **Inclusion Criteria**
(Inclusion criteria for the completed initial dose escalation phase using PF-02341066/PD-0325901 is listed in Appendix 7.) A patient will be eligible for inclusion in this study if all of the following criteria apply.
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4.1.1 all patients

- Age ≥ 16 years
- ECOG performance status 0-1 (Appendix 1) - Adequate respiratory function on clinical assessment.  
- Left ventricular ejection fraction (LVEF) ≥ 50% as determined by a multigated acquisition (MUGA)
scan or echocardiogram.  
- Able to give informed consent prior to any screening procedures being performed and be capable of complying with the protocol and its requirements.  
- Haematological and biochemical indices within the ranges shown below:
o Haemoglobin (Hb) ≥ 9g/dl (transfusion to achieve this allowed),
o Neutrophils≥ 1,500/µl, o Platelet count ≥ 100,000/µl, o AST or ALT ≤ 2.5 x ULN, patient with liver metastases ≤ 5 ULN, Alkaline phosphatase ≤ 5 x ULN,
o Serum Bilirubin ≤ 1.5 x ULN,
o Creatinine Clearance ≥ 50ml/min (Calculated by Cockcroft Gault equation, or by EDTA)
(Appendix 2)
- Able to swallow oral medication - Life expectancy of at least 3 months.
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4.1.2 dose escalation phase

- Patients with any advanced solid tumours - Patients for whom the combination of PF-02341066 with Binimetinib is a reasonable option.
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4.1.3 dose expansion phase

Patients will be eligible for pre-screening for MErCuRIC provided that:
- They have given informed consent to screening. - They are willing to undergo a biopsy for assessment of tumour RAS mutation status and c-MET
assessment
- 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 or c) RASWT/c-MET over-expressed with progressive disease on or within 6 months of completion of adjuvant therapy or after chemotherapy/targeted therapies for metastatic disease.  
- Prior treatment with an EGFR targeted monoclonal antibody for patients with RASWT/c-METmutated or amplified CRC or RASWT/c-MET over-expressed CRC.  
- No evidence for a mutation in BRAF at codon600
- Metastases accessible for biopsy on 2-3 occasions
- At least one other measurable lesion (according to RECIST v1.1). - Unsuitable for potential curative resection.  
┼For non-UK territories: if ECHO cannot be performed, a MUGA scan may be performed in compliance with local policy, applicable national legislation and relevant approvals. Cardiac ejection fraction must **be determined as** measured by echocardiogram (ECHO) in the UK.  
4.2 **Exclusion criteria**
(Exclusion criteria for the completed initial dose escalation phase using PF-02341066/PD-0325901 is listed in Appendix 7.)
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4.2.1 all patients

- Unstable ischemic heart disease, cardiac dysrhythmias, coronary/peripheral artery bypass graft or cerebrovascular accident within 6 months prior to starting treatment.  
- Uncontrolled arterial hypertension despite medical treatment.  
- Ongoing congestive heart failure or cardiac dysrhythmias of NCI CTCAE Grade ≥2 or uncontrolled atrial fibrillation.  
- History of extensive disseminated/bilateral or known presence of Grade 3 or 4 interstitial fibrosis or interstitial lung disease, including a history of pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease (ILD), obliterative bronchiolitis, and pulmonary fibrosis. A history of prior radiation pneumonitis is allowed.  
- Any active central nervous system (CNS) lesion (i.e., those with radiographically unstable, symptomatic lesions) and/or leptomeningeal metastases. However, patients treated with stereotactic radiotherapy or surgery are eligible if the patient remained without evidence of CNS disease progression ≥ 3 months. Patients must be off corticosteroid therapy for ≥ 3 week
- Patients who have neuromuscular disorders that are associated with elevated CK (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy);
- Patients who are planning on embarking on a new strenuous exercise regimen after first dose of study treatment. NB: Muscular activities, such as strenuous exercise, that can result in significant increases in plasma CK levels should be avoided while on Binimetinib treatment
- Spinal cord compression unless treated with the patient attaining good pain control and stable or recovered neurologic function.  
- Carcinomatous meningitis or leptomeningeal disease.  
- History of hypoalbuminaemia, or patients with peritoneal disease or pleural disease, where there is a requirement for ascitic or pleural taps.  
- History of retinal vein occlusion, intraocular pressure > 21 mmHg or patient considered at risk of retinal vein thrombosis (e.g. history of hyperviscosity or hypercoagulability syndromes).  
- History of retinal degenerative disease.  
- History of Gilbert's syndrome. - Active infections (including chronic hepatitis type B or C and HIV infection if status known), severe immunologic defect, compromised bone marrow function
- Other severe acute or chronic medical (including severe gastro-intestinal disorders e.g. partial bowel obstruction, malabsorption, active inflammatory bowel disease) or psychiatric conditions or  
laboratory abnormalities that the investigator considers would make the patient a poor trial candidate, would impart excess risk associated with study participation or drug administration or could interfere with protocol compliance or the interpretation of trial results.  
- Patients who have undergone major surgery ≤ 3 weeks prior to starting study drug or who have not recovered from side effects of such procedure
- Use of drugs or foods that are known potent CYP3A4 inhibitors or inhibitors or are CYP3A4 substrates with narrow therapeutic indices (see Appendix 5)
- Radiotherapy (except for palliative reasons), endocrine therapy, immunotherapy or chemotherapy during the previous four weeks (six weeks for nitrosoureas, Mitomycin-C) and four weeks for investigational medicinal products before treatment. Patients with prostate cancer may continue to receive endocrine therapy to maintain castrate levels of androgens.  
- Resting ECG with QTc >480msec at 2 or more time points within a 24h period (using Fredericia correction).  
- Requirement for medication known to prolong QT interval (see Appendix 5).  
- History of other malignancy less than 3 years before the diagnosis of current cancer, EXCLUDING
the following: Non-melanoma skin cancer, in situ carcinoma of the cervix treated surgically with curative intent, other malignant tumours that have been treated curatively and patient is deemed disease-free
- Women with the ability to become pregnant (or already pregnant or lactating). However, those female patients who have a negative serum pregnancy test before enrolment and agree to use one highly effective form of contraception (oral, injected or implanted hormonal contraception or intrauterine device) in addition to condom plus spermicide, for four weeks before entering the trial, during the trial and for six months afterwards are considered eligible.  
- Male patients with partners of child-bearing potential unless they agree to take measures not to father children by using one form of highly effective contraception including: oral, injected or implanted hormonal contraception or intra-uterine device in addition to condom plus spermicide, during the trial and for six months afterwards). Men with pregnant or lactating partners should be advised to use barrier method contraception (condom plus spermicidal gel) during the trial and for six months afterwards to prevent exposure to the foetus or neonate.  
- Prior exposure to any of a HGF, cMET or a MEK inhibitor.
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4.3 protocol deviations and waivers

Protocol adherence is a fundamental part of the conduct of a clinical study. Changes to the approved protocol need prior approval unless for urgent safety reasons.  
Systems for prospectively approving protocol deviations, in order to effectively widen the scope of a protocol should not be used. Doing so might erode the scientific and ethical value of the protocol and its authorisation and might have an impact on the processes put in place for the care and safety of the study subjects.  
Investigators must contact the MErCuRIC Office to obtain guidance and/or clarification as necessary if unsure whether the patient satisfies all the entry criteria and to clarify matters of clinical discretion. OCTO will contact the chief investigator or clinical coordinators as necessary. Investigators should not request a protocol waiver to enter a patient who does not satisfy the selection criteria.  
Investigators should not deviate from the protocol for the management of enrolled subjects deliberately unless essential to protect the rights or safety of the individual. Examples might include the addition or deletion of tests, dosing, duration of treatment etc. It may be necessary to withdraw the patient from further study. All waivers and deviations should be fully documented/ justified and reported to the trial office without delay.
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4.4 re-screening if patient does

If a patient does not meet the list of key inclusion/exclusion criteria first time round, he/she can be rescreened, as long as dose escalation or dose expansion phase is recruiting. Patients who fail at rescreening are ineligible and may not be rescreened.
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4.5 patient registration procedure

Patients will be recruited from those referred to oncology services at participating sites for management of their advanced solid cancers (escalation phase) or colorectal cancer (expansion phase). A screening log must be kept of all patients considered for the study including any that are subsequently excluded; the reason for exclusion must be recorded on this form. A copy of the screening log should be sent to the trial office on request, but without patient identifiers. The original must be retained on site.  
Before entering a patient onto the study the Principal Investigator or designee will confirm eligibility. If in any doubt the Chief Investigator must be consulted before entering the patient. Details of the query and outcome of the decision must be documented on the registration/ eligibility checklist.  
After completing suitability checks, Informed Consent Form for trial participation and Informed Consent Form for blood and tissue sample collection, the site staff will scan and email the Registration Form, where applicable, to confirm the patient's eligibility.
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registration of patients

OCTO Registration by email to octo-MErCuRIC.ox.ac.uk The patient will then be registered. Once the Investigator / research nurse has a study number for the patient, they will be asked to provide the original Registration Form along with c-MET and RAS mutation status report and a copy of the histology report (expansion phase) to the Trials office
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5 trial assessments and procedures

Written informed consent will be obtained to perform RAS mutational status on archival tumour tissue (if not already known) and to perform a biopsy of representative CRC metastasis for c-MET status assessment
(using mutation, amplification and immunohistochemistry) before seeking consent for the main study. The Investigator will explain the principles and rationale for evaluating c-MET and RAS mutational status using patient information and consent form A. Patients may give consent to c-MET and RAS screening testing without the usual 24 hour period for consideration if they wish. This is to reduce the time required to obtain cMET and RAS mutational status, and to minimise delays in evaluating patients' suitability for the protocol.  
Once the patient has consented to tRAS and cMET screening demographic information and medical history will be recorded. No further study specific investigations will be made until the RAS and cMET status is known. Patients whose RAS mutational status on primary tumour is already known do not require re-testing of primary tumour; however, these patients still require biopsy of CRC metastasis for c-MET status. The Investigator must ensure that a copy of the relevant test report is obtained and held in the medical record.  
Patients consenting to RAS and cMET trial screening tests must be logged with the trials office in order to obtain a screening number before the sample is dispatched (see 7.5). The responsible analytical laboratory will provide the Investigator with a written report within 5 working days of receipt of a suitable sample. The study site will maintain a log of all patients screened for RAS and c-MET status along with details of the outcome and date of the test result. A copy of this log must be provided to the trial office on request. Patients will only be eligible for the main study if the RAS mutational status and cMET report confirms a RAS
mutant or RASWT/c-MET+ status. If the result is inconclusive the patient is not eligible for the dose expansion phase. Note that the responsible laboratory will assess the sample quality and perform the assay and any re-test in accordance with their internal standard operating procedures. Hence any inconclusive result is final and no further re-testing will be done for the trial.  
Once the patient RAS and c-MET status is confirmed to be a) RAS mutant, b) RASWT/c-MET mutated or amplified or c) RASWT/c-MET over-expressed status the trial entry procedures detailed below (for the dose expansion phase) may start.
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5.2 informed consent for main

Potential participants will be given a current, approved version of the patient information sheet. They will also receive clear verbal information about the study detailing no less than: the nature of the study; the implications and constraints of the protocol; the known side effects and any risks involved in taking part. It will be explained that they will be free to withdraw from the study at any time, for any reason, without prejudice to future care, and with no obligation to give a reason for withdrawal. They will have at least 24 hours to consider the information provided and the opportunity to question the Investigator, their GP or other independent parties before deciding whether to participate.  
The Investigator (or delegate) who obtains consent must be suitably qualified and experienced. All delegates working on behalf of the investigator must be authorised by the PI. The Investigator is responsible for ensuring that the trial consent procedures comply with current applicable GCP Regulatory and ethical requirements. Informed consent discussions and outcomes must be well documented in the medical record.  
The Investigator (or delegate) must be satisfied that the patient has made an informed decision before taking consent. The patient and the Investigator (or delegate) must personally sign and date the current approved version of the informed consent form in each other's presence. A copy of the information and signed consent form will be given to the participant. The original signed form will be retained in the Site File, whilst a copy is to be filed in the medical record. A copy of the signed and dated consent form is to be sent to the MErCuRIC
Office, for the purpose of central monitoring. If patients agree to donate samples to the licenced tissue bank a copy of the signed consent form is to be sent to the tissue bank. If local policies differ from the above, the site should discuss this at the stage of site activation before the trial is opened.
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contraceptive/ pregnancy counselling

All participants must be advised on the need to use reliable methods of contraception during the study. The advice should include:
(1) The acceptable methods, including: male or female sterilization, implants, injectables, combined oral contraceptives, some intrauterine devices (IUDs), and abstinence.  
(2) Male patients with partners of child-bearing potential unless they agree to take measures not to father children by using one form of highly effective contraception (oral, injected or implanted hormonal contraception or intra-uterine device) in addition to condom plus spermicide during the trial and for six months afterwards). Men with pregnant or lactating partners should be advised to use barrier method contraception (condom plus spermicidal gel) during the trial and for six months afterwards to prevent exposure to the foetus or neonate. A barrier method (condom with spermicide) should be used in addition to a highly effective form of contraception.  
(3) Males should continue to take these precautions for a minimum 6 months after the last dose of study drug.  
(4) Females should continue to take these precautions a minimum of 6 months after the last dose of study drug.  
(5) That any pregnancy (also applies to females partners of male trial subjects) occurring within six months of the last administration of study drug / other trial intervention will be followed up and the outcome of all pregnancies (spontaneous miscarriage, elective termination, normal birth or congenital abnormality) will be reported and followed up even if participant is discontinued from the study.
5.3 Informed consent for translational sub-studies Patients, who agree to participate in the dose escalation part of the trial, will also be informed of the MErCuRIC translational studies. Subjects who agree to donate samples for the sub-study will have these taken during the screening period, and a biopsy of a representative metastasis taken upon developing resistance to either the PF-02341066/PD-0325901 or PF-02341066/Binimetinib treatment. The translational component is fundamental to the dose expansion part of the trial and participation is therefore mandatory.  
Note: Study procedures 5.4 - **5.8 below refer to participants treated with the combination of PF02341066 with Binimetinib. For participants treated with PF-02341066 with PD-0325901, these study**
procedures are detailed separately in Appendix 8.
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5.4 main screening pre-dosing evaluations

The following must be performed/obtained within the 28 days before the patient receives the first administration of study drug. All patients
- Written informed consent
- Demographic details - Medical history (including prior diagnosis, prior treatment, concomitant diseases, concomitant medications, therapies received by patient within 28 days prior to cycle 1, day1, known ophthalmologic medical history).  
- ECOG Performance Status (PS) - Full physical examination
- Clinical and radiological (CT chest/abdomen/pelvis or CT chest with MRI abdomen/pelvis) disease assessment
- Vital signs (systolic/diastolic blood pressure, pulse, body temperature), height and weight.  
- Ophthalmic assessment, including visual acuity, pressure, perimetry, slit lamp examination, fundoscopy with digital photography, optical coherence tomography (OCT).  
- Safety blood laboratory examination Haematology: haemoglobin, white blood cells (WBC) with differential count and platelets; Clinical chemistry: sodium, potassium, calcium, phosphate, urea, creatinine, total protein, albumin, bilirubin, alkaline phosphatase (alk phos), AST and/or ALT and LDH; Coagulation screen: APTT, PT)
- Blood for assessment of tumour markers (if appropriate)
- Cardiac muscle/enzymes levels - CK and troponin - Urinalysis - Serum pregnancy test for women of childbearing potential.  
- 12-lead electrocardiogram - Echocardiography or MUGA
- Review of inclusion and exclusion criteria
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dose escalation phase

- Obtain archived tumour tissue for biomarker analysis - Draw blood sample for germline DNA - Obtain fresh skin biopsy for PD assessment
- Obtain fresh tumour biopsy for PD assessment, where additional consent has been given.
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dose expansion phase

- Obtain archived tumour tissue for biomarker analysis - Draw blood sample for germline DNA - Obtain fresh skin biopsy for PD assessment (first 10 patients only) - Obtain fresh biopsy of metastases for biomarker assessment
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5.5 evaluations during dosing

Cycle 1 **day 1**
All patients
- ECOG PS - Record of concomitant medications - Full physical examination - Vital signs (systolic/diastolic blood pressure, pulse, body temperature) and weight. - ECG (12-lead)
- Blood for assessment of haematology, clinical chemistry, cardiac/muscle enzymes - CK and troponin status and coagulation status,
- Urinalysis
- Serum or urine Human Chorionic Gonadotropin (HCG) pregnancy test for women of childbearing potential.  
- Plasma samples for biomarkers; blood draws as per section 7.4. - Assessment of adverse events - Start dosing with PF-02341066 and Binimetinib.
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dose expansion phase only

- Obtain blood sample for ctDNA as per section 7.5.  
Cycle 1 day 8
- ECOG PS
- Record of concomitant medications
- Full physical examination
- Vital signs (systolic/diastolic blood pressure, pulse, body temperature) and weight. - Assessment of adverse events
- Dosing with PF-02341066 and Binimetinib.  
Cycle 1 day 15
- ECOG PS - Record of concomitant medications - Full physical examination
- Vital signs (systolic/diastolic blood pressure, pulse, body temperature) and weight. - ECG (12-lead)
- Blood for assessment of haematology, clinical chemistry, cardiac/muscle enzymes - CK and troponin status and coagulation status
- Urinalysis
- Plasma samples for biomarkers; blood draws as per section 7.4.  
- Assessment of adverse events - Dosing with PF-02341066 and Binimetinib
- 3-6 hours post-dose fresh skin biopsy for PD assessment (for dose escalation phase and initial cohort of 10 patients in dose expansion phase)
- 3-6 hours post-dose fresh tumour biopsy for PD assessment (for patients in the dose expansion phase and those patients who have consented to the biopsy in the escalation phase).  
Cycle 1 day 21
- ECOG PS - Record of concomitant medications
- Full physical examination
- Vital signs (systolic/diastolic blood pressure, pulse, body temperature) and weight. - Echocardiography or MUGA - PK sampling: blood draws as per section 7.3. - Assessment of adverse events
- Dosing with PF-02341066 and Binimetinib.
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cycle 1 day 22

- PK sampling (24 hour sample)
- Dosing with PF-02341066 only and Binimetinib (if continuous dosing)
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cycle 2 day 1 all

- ECOG PS - Record of concomitant medications - Full physical examination - Vital signs (systolic/diastolic blood pressure, pulse, body temperature) and weight.  
- ECG (12-lead)
- Blood for assessment of haematology, clinical chemistry, cardiac/muscle enzymes - CK and troponin status and coagulation status
- Plasma samples for biomarkers; blood draws as per section 7.4. - Serum or urine Human Chorionic Gonadotropin (HCG) pregnancy test for women of childbearing potential.  
- Urinalysis
- Assessment of adverse events
- Dosing with PF-02341066 and Binimetinib
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cycle 2 onwards day 8

- ECOG PS - Record of concomitant medications - Full physical examination
- Vital signs (systolic/diastolic blood pressure, pulse, body temperature). - Assessment of adverse events
- Dosing with PF-02341066 and Binimetinib
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cycle 2 onwards day 15

- ECOG PS
- Record of concomitant medications - Full physical examination - Vital signs (systolic/diastolic blood pressure, pulse, body temperature).  
- Assessment of adverse events - Plasma samples for biomarkers; blood draws as per section 7.4 (cycle 2 only).  
- Dosing with PF-02341066 and Binimetinib
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cycle 2 onwards day 21

- ECOG PS - Record of concomitant medications - Full physical examination - Vital signs (systolic/diastolic blood pressure, pulse, body temperature).  
- PK sampling: blood draws as per section 7.3 (trough level and 2h after morning dosing, cycles 2, 4, 6, 8, 10 and 12).  
- Assessment of adverse events
- Ophthalmic assessment, including visual acuity, pressure, perimetry, slit lamp examination, and fundoscopy with digital photography
- Dosing with PF-02341066 and Binimetinib
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cycle 3 onwards day 1

- ECOG PS - Record of concomitant medications
- Full physical examination
- Clinical and radiological (CT chest/abdomen/pelvis or CT chest with MRI abdomen/pelvis) disease assessment
- Vital signs (systolic/diastolic blood pressure, pulse, body temperature) and weight. - ECG (12-lead)
- Blood for assessment of haematology, clinical chemistry, cardiac/muscle enzymes - CK and troponin status and coagulation status
- Serum or urine Human Chorionic Gonadotropin (HCG) pregnancy test for women of childbearing potential.  
- Blood for assessment of tumour markers (if appropriate)
- Plasma samples for biomarkers; blood draws as per section 7.4.  
- Urinalysis
- Assessment of adverse events - Dosing with PF-02341066 and Binimetinib
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5.6 end of treatment evaluations

- ECOG PS
- Record of concomitant medications
- Full physical examination - Assessment of adverse events - Vital signs (systolic/diastolic blood pressure, pulse, body temperature) and weight. - ECG (12-lead)
- Urinalysis
- Serum or urine Human Chorionic Gonadotropin (HCG) pregnancy test for women of childbearing potential.  
- Blood for cardiac/muscle enzymes - CK and troponin status - Blood for assessment of haematology, clinical chemistry, and coagulation status
- Blood for assessment of tumour markers (if appropriate) - Ophthalmic assessment, including visual acuity, pressure, perimetry, slit lamp examination, fundoscopy with digital photography, optical coherence tomography and fluorescin angiography
(OCT and flourescin angiography only if required).  
- Tumour assessment: CT scan chest/abdomen/pelvis (or CT chest with MRI abdomen/pelvis) using RECIST v1.1.  
Dose expansion phase
- Blood for ctDNA
- Biopsy of representative metastases for molecular profiling (optional)
5.7 Post treatment follow-up - **evaluations**
All patients
- Assessment of adverse events - Record of post-trial therapy - Patients will be followed up every 3 months for survival status until death or study closure, whichever happens first.  
Dose expansion phase
- Tumour biopsy (optional)
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5.8 evaluations on early withdrawal

If the patient is withdrawn from treatment, for any of the reasons indicated in section 6, a final off-study visit assessment should be performed 28 - 30 days after the last administration of PF-02341066 and Binimetinib. The following assessments will be done:
- ECOG PS - Record of concomitant medications
- Full physical examination
- Assessment of adverse events - Vital signs (systolic/diastolic blood pressure, pulse, body temperature) and weight. - ECG (12-lead) - Urinalysis
- Blood for cardiac/muscle enzymes - CK and troponin status
- Blood for assessment of haematology, clinical chemistry, and coagulation status If the patient is withdrawn from the trial and declines attendance for a final off-study visit, then a withdrawal assessment should be performed, if possible on the day the decision is made to take the patient off-study or as soon as possible. Telephone review is permitted in these circumstances. These patients will be followed up for progression and overall survival.
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6. early patient withdrawal 6.1

During the course of the trial, a patient may withdraw early from treatment. This may happen for a number of reasons, including:
- Unacceptable toxicity, including but not limited to:
- Life threatening grade 4 toxicity. - Repetition of non-life threatening grade 4 toxicity despite per protocol dose reduction. - Delay of a treatment cycle for more than 3 consecutive weeks beyond the due date
- Objective evidence of progressive disease as determined by CT scan and/or X-ray and/or ultrasound and/or clinical examination
- Clinical decision by the investigator that continued participation in the trial is contrary to the patient's best interests
- Patient decision to discontinue treatment (as opposed to participation in all aspects of the study)
When a patient stops treatment early, an 'End of Treatment' Form should be completed, and any other relevant form (for example a SAE Form). The reason for withdrawing from treatment early should be clearly documented in the medical records. An off-study visit assessment should be performed and the results of the evaluations and observations reported in the CRF.
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6.2 withdrawal of consent

Withdrawal of consent means that a patient has expressed a wish to withdraw from the study altogether.  
Under these circumstances, the site needs to document all relevant discussions in the patient notes and notify the Trials Office. Under these conditions, ongoing SAEs require follow up until resolution.
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6.3 patient evaluability and replacement

In the dose escalation phase, if a patient comes off treatment due to a DLT, they will not be replaced. If however, a patient withdraws, for reasons other than safety/toxicity, prior to the end of cycle 1, they will need to be replaced and will not receive any further PF-02341066/PD‐0325901 or PF-02341066/Binimetinib. All withdrawn patients will no longer receive the study drugs and will be followed up for progression free and overall survival unless they withdraw their consent.  
In the dose expansion phase patients who are non-evaluable for the primary end-point of response to treatment will be replaced. This does not include patients who progress early on treatment so as to be unable to undergo cross-sectional imaging, who will be classified as progressing on treatment.
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- samples for laboratory analysis

Samples for haematology, biochemistry and coagulation analysis will be labelled with standard patient identifiers and sent to the local hospital diagnostic laboratory. Results will be processed in the standard way and entered into the routine hospital reporting system. Samples will be stored, held, reported and subsequently destroyed in accordance with standard local laboratory practice.
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pathology

The routine diagnostic pathology samples taken at participating centres will also be labelled, processed and reported according to local hospital protocols. With regard to the dose expansion study, an H&E section will be obtained from each FFPE core of each of the 2-3 tumour biopsies prior to and during treatment and also upon resistance (where consent provided) to confirm the presence of tumour.  
RAS mutational analysis *–dose expansion phase* RAS mutational analysis will be determined on primary tumour using the applicable local technique according to local policies.
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7.2 samples to be sent

Details of sample preparation, labelling and despatch are provided in the sample handling manual for the MErCuRIC1 protocol.  
The following samples will be sent to the CCRCB Molecular pathology lab (Prof Manuel Salto-Tellez):
- Block of FFPE core from the pre-screening biopsy, during treatment and end of treatment biopsy
(optional) to evaluate cMET expression, amplification and mutation (only in dose expansion study)
- Pharmacodynamic FF tumour and skin samples for pERK1/2 by Western blotting - Pharmacodynamic blood samples to measure soluble HGF and MET
- Fresh frozen cores for DNA extraction and molecular profiling. DNA extraction will be performed by QUB NI-MPL and DNA send to PDUM lab for analysis of MET amplification and mutational status.  
- Blood samples for germ-line DNA
The following blood samples will be sent according to the procedures described in the sample handling manual:
- Pharmacokinetic studies for PF-02341066, PD-0325901 and M15, Binimetinib - Pharmacodynamics blood samples to measure soluble c-MET
Blood samples for ctDNA analysis will be sent to Professor A. Bardelli's lab (UNITO).
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7.3 pharmacokinetic assays pf-02341066 in

Analysis of plasma samples for the determination of PF-02341066, PD‐0325901, M15 will be carried out to ensure that the putative target levels to inhibit cMET and ERK1/2 signalling pathways respectively are met when PF-02341066 is combined with PD‐0325901.  
Blood samples for the determination of PF-02341066 and PD‐0325901, and M15 levels will be collected predose, 1, 2, 4, 6, 8, 10 and 24 hours post morning dose of PF-02341066 and PD‐0325901 on cycle 1 days -
1/1, cycle 1 days 21/22 and cycle 1 days 28/29 (cycle 2 day 1). The levels being determined at the various time points are summarised in the table below:  
| Pre-dose and, 1, 2 , 4,  6, 8, 10 (hours postmorning  dose) Cycle  1 Day -1                   | Pre-dose, 1,  2 , 4, 6, 8, 10 (hours postmorning  dose) Cycle 1 Day 21   | Pre-dose, 1,  2 , 4, 6, 8, 10 (hours postmorning  dose) Cycle 1 Day 28   |    |    |
|-------------------|---|---|----|----|
| 24 hours  (premorning  dose) Cycle 1  Day 1                   | 24 hours  (premorning  dose) Cycle 1  Day 22   | 24 hours (premorning dose) Cycle 1 Day  29/Cycle 2 Day 1   |    |    |
| PF-02341066       | X | X | X  | X  |
| PD-0325901 +  M15 | X | X | X  | X  |  
PK trough samples will also be collected pre-dose and 2 hours post morning dose of PF-02341066 and PD‐
0325901 on cycle 2 day 21, cycle 4 day 21, cycle 6 day 21, cycle 8 day 21, cycle 10 day 21 and cycle 12 day 21.  
Blood samples will be centrifuged to generate plasma. Plasma concentrations of PF-02341066, PD‐0325901 and M15 will be determined using validated HPLC-MS/MS assays following solid-phase extraction of the plasma sample.
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pharmacokinetic assays for pf-02341066 in

Analysis of plasma samples for the determination of PF-02341066 and Binimetinib will be carried out to ensure that the putative target levels to inhibit cMET and ERK1/2 signalling pathways respectively are met when PF-02341066 is combined with Binimetinib.  
Blood samples for the determination of PF-02341066 and Binimetinib levels will be collected pre-dose, 1, 2, 4, 6, 8, 10 hours post morning dose of PF-02341066 and Binimetinib on cycle 1 day 21 and immediately prior to dosing on the morning of day 22. Further PK profiling on Cycle 1 Day 28/29 is not required for the dose escalation and dose expansion phases using PF-02341066 with Binimetinib as the study drugs are being taken together. The levels being determined at the specified time points are summarised in the table below:  
| Pre morning dose Cycle 1 day 21,  And at 1, 2 , 4, 6, 8, 10 hours post morning dose on Cycle 1 Day 21   | 24 hours (pre morning dose) On Cycle 1 Day 22   |    |    |
|---------------------------------------------------------------------------------------------------------|-------------------------------------------------|----|----|
| PF-02341066                                                                                             |                                                 | X  | X  |
| Binimetinib                                                                                             |                                                 | X  | X  |  
PK trough samples will also be collected pre-dose and 2 hours post morning dose of PF-02341066 and Binimetinib on cycle 2 day 21, cycle 4 day 21, cycle 6 day 21, cycle 8 day 21, cycle 10 day 21 and cycle 12 day 21. Blood samples will be centrifuged to generate plasma. Plasma concentrations of PF-02341066 and Binimetinib will be determined using validated HPLC-MS/MS assays following solid-phase extraction of the plasma sample.
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7.4 pharmacodynamic assays

Pre-dose and post-dose fresh skin biopsy. Samples will be collected at site and the sections will be forwarded to the central laboratory where the Western Blotting technique will be used for for analysis of pERK1/2. These samples will be collected at screening and Cycle 1, day 15 (+/- 7 days) during the Dose Escalation phase and from the first 10 patients during the Dose Expansion phase.
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pre-dose and post-dose fresh tumour

Samples will be fixed in formalin and paraffin embedded at site. Sections will be forwarded to QUB, where immunohistochemistry for pERK1/2 and pcMETY1234/1235 will be performed. These will be collected at screening and Cycle 1, day 15 (+/- 7 days) as mandatory for the Dose Expansion phase, but optional for the Dose Escalation phase. A further optional metastatic tumour biopsy will be collected at disease progression during the Dose Expansion phase only. Plasma sample for soluble biomarkers. c-MET ectodomain and HGF scatter factor will be analysed using commercially available Invitrogen ELISAs. Blood samples will be collected to assess biomarkers pre-dose and 6 hours post-dose (morning dose) on days 1 and 15 of Cycle 1; pre-dose and 6 hours post-dose (morning dose) on day 1 and 15 of Cycle 2; pre-dose and 6 hours post-dose (morning dose) on day 1 of cycles 3 through to 6.
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7.5 samples for molecular analysis

Fresh frozen cores from pre-dose and post-dose fresh tumour biopsies will be processed for DNA
extraction and molecular profiling. Where sufficient material exists fresh frozen cores may also be used to develop xenografts. Blood samples will be processed for **germ-line DNA** and ctDNA.
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7.6 summary of samples/assays to

Assay/sample handling and storage will be managed according to separate written instructions. The following summarises the arrangements for collection, close to patient handling, timings, and analytical laboratories responsible. Research assays will be performed according to separate laboratory SOPs.
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7.7 samples for biobanking

Participants in this trial will be invited to permit the long term retention of samples left over after protocolspecified analyses for use in possible other future research linked to trial data. Consent to participate in this aspect of the trial is optional and not a requirement of participation in the main study.
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7.8 labelling and confidentiality of

All samples sent to analytical laboratories will be labelled with the trial code, trial patient number, dosing cohort and date/time taken. Should a laboratory receive any samples carrying unique patient identifiers the recipient must immediately obliterate this information and re-label the samples. The study site will be informed of their error.
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7.9 clinical reporting of exploratory

The results of the MErCuRIC trial research assays are exploratory and are not intended to influence the individual patient's medical care. Findings for exploratory research assays will not be reported routinely in real time to the responsible clinician.
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7.10 trial sample retention at

The Chief Investigators have overall responsibility for custodianship of the trial samples. Laboratories are instructed to retain any surplus samples pending instruction from the Chief Investigators on use, storage or destruction. It is possible that new or alternative assays may be of future scientific interest. At the end of the research study any surplus samples may be retained for use in other projects that have received ethical approval. Hence, any surplus study samples may be transferred to a licensed tissue bank where they will be managed in accordance with applicable host institution policies and the Human Tissue Act (HTA)
requirements.
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7.11 withdrawal of consent for

A patient may withdraw consent to provide samples for research at any time without giving a reason. The Investigator must ensure that their wishes are recorded in the medical record and will inform the trials office accordingly. The investigator should discuss with patients the valuable use of samples that have already been provided and under circumstances where these samples have already been processed and anonymised, it would not be possible to destroy such samples.
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8.2 treatment dose

Dose escalation phase: PF-02341066 *in combination with PD-0325901* PF-02341066 (Crizotinib): 250mg orally, once a day or 200mg orally, twice a day continuously.  
PD-0325901: 2mg orally, twice a day to 8mg orally twice a day. Run-in day -7 to day -1, then days 1 to 21 every 28 days.
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dose escalation phase pf-02341066 in

PF-02341066 (Crizotinib): 250mg orally once or twice a day or 200mg orally twice a day, continuously.  
Binimetinib: 30mg orally, twice a day or 45mg orally twice a day continuously or for 1 to 21 days every 28 days.
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dose expansion phase

PF-02341066 (Crizotinib) at recommended phase II dose continuously. Binimetinib at recommended phase II dose either continuously or for 1- 21 days every 28 days..
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8.3 duration of treatment

Treatment will be given continuously until  
- Disease progression
- Intercurrent illness that in the judgment of the investigator would affect patient safety, the ability to deliver treatment or the primary study endpoints.  
- In case of unacceptable toxicity
- At the patient's request.  
- Physician's decision for any other reasons (which should be clearly justified or documented)
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8.4 management of drug administration

Patients will receive the morning dose of PF-02341066 and/or PD-0325901 without regard to meals. .  
Patients should take the capsules at approximately the same time each day. For BD evening dosing PF02341066 will be administered approximately 12 hours following the morning dosing.  
In case of BD administration, doses of PF-02341066 and PD-0325901 should be taken approximately 12 hours apart. Wherever possible doses should not be missed but if a dose is missed then the next dose should be taken at the allotted time and the missed dose should not be made up. If the patient vomits shortly after taking PF-02341066 or PD-0325901, the dose should be replaced only if the vomited capsules can actually be seen and counted. Compliance with PF-02341066and PD-0325901 dosing will be evaluated by capsule count during scheduled visits to the trial site by pharmacy staff.
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dose escalation phase and dose

Binimetinib:
Patients will receive the morning dose of PF-02341066 and Binimetinib. In case of BD administration, doses of PF-02341066 and Binimetinib should be taken approximately 12 hours apart and, wherever possible, at approximately the same time every day, without regard to meals. Doses should not be missed, but, if a dose is missed, then the next dose should be taken at the allotted time and the missed dose should not be made up. If the patient vomits shortly after taking PF-02341066 or Binimetinib, the dose should be replaced only if the vomited capsules or tablets can actually be seen and counted. Compliance with PF-02340166 and Binimetinib dosing will be evaluated by capsule/tablet count during scheduled visits to the trial site by pharmacy staff.
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8.4.1 dose limiting toxicity (dlt)

The dose limiting toxicity (DLT) and maximum tolerated dose (MTD) are defined using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. DLTs identified during the first cycle will inform the decision to dose escalate through the increasing dose levels.  
A DLT is defined as an almost certainly or probably drug-related adverse event to PF-02341066 and/or PD-0325901 or Binimetinib.  
- neutropenia Grade 4 for ≥5 days duration *(See note)  
- febrile neutropenia (without clinically or microbiologically documented infection) with an absolute neutrophil count <1000/mm3 and a single temperature of >38.3˚C or a sustained temperature of
≥38˚C for more than one hour.  
- infection (documented clinically or microbiologically) with Grade 3 or 4 neutropenia (ANC <1.0 x 109/L)
- thrombocytopenia Grade 4:
a) for ≥5 days duration * (See note), or  
b) associated with active bleeding, or c) requiring platelet transfusion.  
- CK elevation ≥ Grade 3 associated with an increase in creatinine ≥ 1.5 × the patient's Baseline screening creatinine.  
- Grade 2 pneumonitis
- Total bilirubin Grade ≥ 3 - AST or ALT Grade ≥ 3 in conjunction with total bilirubin Grade ≥ 2 of any duration
- AST or ALT Grade 3 for > 7 consecutive days - AST or ALT Grade 4
- Serum creatinine Grade ≥ 3
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- grade 3 or 4

Should any change be made to the grade or causality of an AE during the trial that may alter its DLT status, OCTO must be informed immediately as this may affect dose escalation decisions.
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8.4.2 maximum tolerated dose (mtd)

If two out of up to six patients at the same dose level experience a DLT in the first cycle of PF-02341066 in combination with PD-0325901, the Maximum Tolerated Dose (MTD) will be determined as the dose level below this. This dose will be determined following discussion of all the relevant toxicity data between OCTO and the TMG. Once the MTD has been defined, dosing at a higher dose must not occur. With the introduction of Binimetinib as the alternative MEKi to PD-0325901, the data accrued from the initial dose escalation phase will not now be used for determining the phase II recommended dose.
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pf-02341066 in combination with binimetinib

If two out of up to six patients at the same dose level experience a DLT in the first cycle of PF-02341066 in combination with Binimetinib, the Maximum Tolerated Dose (MTD) will be determined as the dose level below this. This dose will be determined following discussion of all the relevant toxicity data between OCTO
and the TMG. Once the MTD has been defined, dosing at a higher dose must not occur. The PF-02341066 and Binimetinib recommended phase II dose to be used in the expansion phase and subsequent phase II/III evaluation will be determined based on the MTD, observed safety profile, PK and pharmacodynamic data, but may include drug-related toxicities experienced in sustained dosing after cycle 1 after discussion with the TMG.
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8.5 dose modification a. pf-02341066

Every effort should be made to administer trial treatment on the planned schedule. The toxicity of each cycle of PF-02341066 and PD-0325901 must be recorded before the administration of the next one and graded according to the current version of the Common Terminology Criteria for Adverse Events (CTCAE Version 4.03). If individual patients experience treatment related toxicity, subsequent trial treatment may be delayed, omitted and/or dose modified according to the worst toxicity observed during the previous cycle as described below. Dose reductions are permanent (no intra-patient dose re-escalation is permitted). The following outlines provide guidance for the management of toxicities for patients treated with PF-02341066 and/or PD0325901.  
If > 2/3 or > 2/6 DLTs occur during cycle 1 in the first patient cohort (ie defined as exceeding the MTD), then the planned schedule of PF-02341066 on continuous dosing and/or PD-0325901 on day 1 - 21 every 28 day dosing will be discontinued. In that case, we need to explore:
- alternate intermittent schedules of both oral agents in combination, whereby a substantial amendment will be submitted to the MHRA prior to administering the proposed new dosing schedule.  
- use of a monoclonal antibody directed against HGF (e.g. from AVEO or AMGEN), the ligand of cMET or the ectodomain of c-MET (eg MetMAb from Roche/Genentech) instead of PF-02341066
For grade 3, grade 4 or intolerable grade 2 toxicities, the treatment will be interrupted until recovery to <grade 2 or to base line (in the judgement of the investigator). If the patient fails to recover to this extent within 3 weeks, then trial treatment will be discontinued. If a patient cannot tolerate treatment after two successive dose reductions, trial treatment will be discontinued. This trial investigates the use of combined cMET and MEK inhibition, and so complete cessation of either drug will result in the patient discontinuing all trial treatment. In any of these circumstances, patients then will undergo end of treatment evaluation as per section 5.6 and will be followed up at the end of study visit at day 28-30 following the last treatment. Patients will then be monitored for progression and survival as per section 5.7.
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b. pf-02341066 in combination with

Every effort should be made to administer trial treatment on the planned schedule. The toxicity of each cycle of PF-02341066 and Binimetinib must be recorded before the administration of the next one and graded according to the current version of the Common Terminology Criteria for Adverse Events (CTCAE Version 4.03). If individual patients experience treatment related toxicity, subsequent trial treatment may be delayed, omitted and/or dose modified according to the worst toxicity observed during the previous cycle as described below. Dose reductions are permanent (no intra-patient dose re-escalation is permitted). The following outlines provide guidance for the management of toxicities for patients treated with PF-02341066 and/or Binimetinib. If > 2/3 or > 2/6 DLTs occur during cycle 1 in the first patient cohort (i.e. defined as exceeding the MTD), then the planned schedule of PF-02341066 on continuous dosing and/or Binimetinib on either continuous dosing or day 1 - 21 every 28 day dosing, will be discontinued. In that case, we need to explore alternate intermittent schedules of either or both oral agents in combination, whereby a substantial amendment will be submitted to the MHRA prior to administering the proposed new dosing schedule.  
For grade 3, grade 3 CPK rise associated with creatinine increase of 50% over baseline, grade 4 or intolerable grade 2 toxicities, the treatment will be interrupted until recovery to <grade 2 or to base line (in the judgement of the investigator). If the patient fails to recover to this extent within 3 weeks, then trial treatment will be discontinued. If a patient cannot tolerate treatment after two successive dose reductions, trial treatment will be discontinued. This trial investigates the use of combined cMET and MEK inhibition, and so complete cessation of either drug will result in the patient discontinuing all trial treatment. In any of these circumstances, patients then will undergo end of treatment evaluation as per section 5.6 and will be followed up at the end of study visit at day 28-30 following the last treatment. Patients will then be monitored for progression and survival as per section 5.7.  
Comprehensive information on recommended guidelines for dose modification for Binimetinib is included in Appendix 6 and updated in Appendix 6A.
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8.5.1 non haematological toxicities skin

Maculopapular erythematous (acneiform) rash, similar to that described in patients with EGFR inhibitors, has been noted with MEK inhibitors (LoRusso et al., 2010). While most often of mild or moderate severity, grade 3 rash (associated with pain, ulceration, disfiguration or desquamation) has been noted. Patients should be informed about the frequent related cutaneous adverse reactions associated with PD-0325901 or Binimetinib and the need to avoid the exposure to extreme temperatures, the use of lotions (since lotions can contain alcohol) and direct sunlight (or tanning beds). The employment of preventive topical treatments, such as bathing techniques using bath oils or mild moisturizing soaps and bathing in tepid water may help to prevent the appearance of cutaneous toxicity or reduce its intensity. The use of regular moisturizing creams is also recommended to keep an appropriate skin hydration and humidity, which is useful to reduce the symptoms in case of rash appearance. Rash, including erythematous, macular, papular, and pruritic rash, has been reported in 47 (7%) patients treated with single-agent PF-02341066. All of these cases were Grade 1 or 2 in severity.  
| Grade of AE MaculoPapular rash                                                                                                                                               | Rash severity                                                                                            | Management of rash                                                                                                                                                                                                          | Alterations to IMP doses                                                                                                               |    |              |
|-----------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------|----|--------------|
| Grade 1                                                                                                                                       | Localised Minimally symptomatic No impact on activities of  daily living (ADL) No sign of superinfection | PD-0325901: no change Binimetinib: no change PF-02341066: no change Reassess after 2 weeks; if rash  worsens or does not improve,  proceed as for Grade 2.                                                                  |                                                                                                                                        |    |              |
| Grade 2                                                                                                                                       | Generalized  Mild symptoms (e.g.  pruritis, tenderness) Minimal impact on ADL No sign of superinfection  | Initiate prophylactic  regimen if not already  started. Consider using  moderate strength topical  steroidsa                                                                                                                | PD-0325901                                                                                                                             | or | Binimetinib: |
| Hold until <                                                                                                                                  | grade 1, then                                                                                            |                                                                                                                                                                                                                             |                                                                                                                                        |    |              |
| restart at the same dose level. PF-02341066: no change Reassess after 2 weeks, if rash  worsens or does not improve,  proceed as for Grade 3. |                                                                                                          |                                                                                                                                                                                                                             |                                                                                                                                        |    |              |
| Grade 3                                                                                                                                       | Generalized Severe symptoms (e.g.,  pruritis, tenderness) Significant impact on  ADL                     | Initiate prophylactic  regimen if not already  started, using moderate  strength topical steroidsa Initiate prophylactic  regimen if not already  started, using moderate  strength topical steroidsa plus methylprednisone | PD-0325901 or Binimetinib:  Hold until < grade 1, then  resume with -1 dose level. PF-02341066: Hold until < grade 1, then resume with |    |              |
| MErCuRIC1_Protocol_V9.0_29Oct2018                                                                                                             | Protocol Template V3.0_18Feb2013                                                                         |                                                                                                                                                                                                                             |                                                                                                                                        |    |              |
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| Sign of, or potential for,                                         | dose pack.                                                                                      |    |
|--------------------------------------------------------------------|-------------------------------------------------------------------------------------------------|----|
| superinfection                                                     | Consider obtaining  dermatology consultation.  Manage rash per dermatologist's  recommendation. | same dose level. If rash worsens or does not  improve in 2 weeks,  permanently discontinue PD0325901/Binimetinib and PF02341066.    |
| a Hydrocortisone 2.5% cream or fluticasone proprionate 0.5% cream. |                                                                                                 |    |  
The need for oral or topical antibiotics (e.g., clindamycin cream, oral minocycline or doxycycline etc) and higher strength topical steroids is a clinical decision of the investigator. Oral or topical retinoids are not recommended. It is strongly recommended that subjects who develop rash or other skin toxicities have a consultation with a dermatologist to determine appropriate management.  
- For **pruritic lesions**, the use of cool compresses and oral antihistamine agents may be helpful. - For **fissuring**, the use of Monsel's solution, silver nitrate, or zinc oxide cream is advised.  
- For **desquamation**, thick emollients and mild soap are recommended. - For **paronychia**, antiseptic bath and local potent corticosteroids, in addition to oral antibiotics, are recommended. If no improvement is seen, a dermatology or surgery consultation is recommended.  
For **infected lesions**, bacterial and fungal culturing followed by the appropriate culture-driving systemic or topical antibiotics is indicated.
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fatigue

| majority of these cases of grade 1 or 2 in severity. Grade of  Clinical presentation   | Alterations to IMP doses                      |                                                                     |
|----------------------------------------------------------------------------------------|-----------------------------------------------|---------------------------------------------------------------------|
| event Grade 1                                                                          | Fatigue relieved by rest                      | PD-0325901: no change Binimetinib: no change PF-02341066: no change |
| Grade 2                                                                                | Fatigue not relieved by rest; limiting        | PD-0325901: no change                                               |
| instrumental ADL                                                                       | Binimetinib: no change PF-02341066: no change |                                                                     |
| Grade 3                                                                                | Fatigue not relieved by rest, limiting self   | Hold until grade 1 - resume -1 dose level PD0325901/Binimetinb                                                                     |
| care ADL                                                                               |                                               |                                                                     |
| Grade 4                                                                                | -                                             | Off protocol; STOP all study drug agents                            |
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diarrhoea

Diarrhoea has been reported as a common side effect for all 3 IMPs. The majority of these cases were grade 1 or 2 in severity and can be symptomatically managed with loperamide 2mg PRN.  
| 1 or 2 in severity and can be symptomatically managed with loperamide 2mg PRN. Grade of  Diarrhoea Severity Adverse Event  event Management guidelines Alterations to IMP doses Grade 1 Uncomplicated  diarrhoea Increase of <4 stools  per day over baseline;  mild increase in  colostomy output  compared to baseline. Diet: Stop all lactosecontaining products; eat  small meals, BRAT diet  (bananas, apples, rice, toast)  is recommended. Hydration: 8 to 10 large  glasses of clear liquids per  day (e.g., Gatorade or broth) Loperamide: initially 4mg,  followed by 2mg every 4  hours or after every  unformed stool, to a  maximum of 16mg/ day.  PD-0325901: no change Binimetinib: no change PF-02341066: no change Grade 2 Uncomplicated  diarrhoea Increase of 4-6 stools  per day over baseline;  moderate increase in  colostomy output  compared to baseline. PD-0325901: no change Binimetinib: no change PF-02341066: no change If diarrhoea is Grade 2 for >48  hours, interrupt study treatment  MErCuRIC1_Protocol_V9.0_29Oct2018 Protocol Template V3.0_18Feb2013   |
|---|  
| MErCuRIC1                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | Confidential                                                                       |                                                                                                                                                                                                            |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Continue until diarrhoea-free  for 12 hours. Diarrhoea > 24 hours: Loperamide 2mg every two  hours to a maximum of  16mg/ day. Consider adding  oral antibiotics. Diarrhoea >48 hours:  Loperamide 2mg every two  hours to a maximum of  16mg/ day. Add budesonide  or other 2nd line therapies  (otreotide, or tincture of  opium) and oral antibiotics.                                                                                                                                                                                                                                                                                                 | until resolution to ≤ Grade 1. Restart study treatment at the  current dose level. |                                                                                                                                                                                                            |
| Clinical evaluation is  mandatory. Loperamidec : initially 4mg,  followed by 2mg every 4  hours or after every  unformed stool, to a  maximum of 16mg/ day.  Continue until diarrhoea-free  for 12 hours. Oral antibiotics and 2nd line  therapies should be  implemented if clinically  indicated. Hydration: intravenous fluids  should be administered if  clinically indicated. Antibiotics (oral or iV) should  be administered if clinically  indicated. Interventions should be  continued until the patient is  diarrhoea-free for ≥ 24 hours. Intervention may require  hospitalisation for patients at  risk of life-threatening complications. | Interrupt study treatment until                                                    |                                                                                                                                                                                                            |
| Grade 3 Any  complicated  diarrhoea.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | Increase of ≥7 stools  per day over baseline;  incontinency;  hospitalization  indicated; severe  increase in colostomy  output compared to  baseline; Limiting selfcare ADL.                                                                                    | diarrhoea recovers to ≤ Grade  1. Restart study treatment with a  one dose level reduction.  If 3 dose reductions of study  treatment are clinically  indicated, permanently  discontinue study treatment. |
| Grade 4                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Life threatening  consequences; urgent  intervention indicated.                    | Off protocol; STOP all study  drug agents                                                                                                                                                                  |
| Other, frequent causes for diarrhoea including concomitant medications (e.g., stool softeners, laxatives,  antacids, etc.), infections by C. difficile or other pathogens, partial bowel obstruction, etc., should be clinically                                                                                                                                                                                                                                                                                                                                                                                                                          |                                                                                    |                                                                                                                                                                                                            |  
Other, frequent causes for diarrhoea including concomitant medications (e.g., stool softeners, laxatives, antacids, etc.), infections by *C. difficile* or other pathogens, partial bowel obstruction, etc., should be clinically excluded. Guidelines regarding management and dose reduction for diarrhoea considered to be related to study treatment by the investigator are provided in this Table.  
- Uncomplicated diarrhoea is defined by the absence of symptoms such as cramping, nausea/vomiting
≥Grade 2, decreased performance status, pyrexia, sepsis, neutropenia ≥Grade 3, frank bleeding, and/or dehydration requiring iV fluid substitution.  
- Complicated diarrhoea is defined by the presence of symptoms such as cramping, nausea/vomiting ≥Grade 2, decreased performance status, pyrexia, sepsis, neutropenia ≥Grade 3, frank bleeding, and/or dehydration requiring iV fluid substitution.  
- Loperamide should be made available to the patient prior to the start of study treatment so that loperamide administration can begin at the first signs of diarrhoea. - Escalation of study treatment to the previous dose level is allowed after consultation with the trial coordination team in the absence of another episode of complicated or severe diarrhoea in the 4 weeks subsequent to dose reduction.
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nausea/vomiting

Nausea has been reported as a common side effect for all 3 IMPs. The majority of these cases were grade 1 or 2 in severity and can be symptomatically managed. Standard anti-emetics such as cyclizine may be used for the treatment of vomiting. Taking PF-02341066 with food may reduce nausea. Prophylactic anti-emetics may be used.  
| Grade of               | Clinical presentation                                                                                                                                                                                     | Alterations to IMP doses                                             |
|------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------|
| event Grade 1          | Nausea: Loss of appetite without alteration in eating habits Vomiting: 1-2 episodes (separated by 5 minutes) in 24h                                                                                       | PD-0325901: no change Binimetinib: no change PF-02341066: no  change |
| Grade 2                | Nausea: Oral intake decreased without significant weight loss, dehydration or  malnutrition Vomiting: 3-5 episodes (separated by 5 minutes) in 24 h                                                       | PD-0325901: no change Binimetinib: no change PF-02341066: no change  |
| Grade 3                | Nausea: Inadequate oral caloric or fluid intake; tube feeding, TPN, or hospitalization indicated Vomiting: ≥6 episodes (separated by 5 minutes) in 24 hrs; tube feeding, TPN or hospitalization indicated | Hold until < grade 1 - resume -1 dose level                          |
| Grade 4                | Life-threatening consequences; urgent                                                                                                                                                                     | Off protocol; STOP all study drug agents                             |
| intervention indicated |                                                                                                                                                                                                           |                                                                      |
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visual disturbances/retinal vein occlusion (rvo)

Grade 1-2 visual symptoms, such as blurred vision, photopsia, and halos, generally with preservation of acuity, have been reported for PD-0325901 and also for Binimetinib. All episodes of RVO with PD-0325901 presented quite late, after 13, 15 and 36 weeks of therapy. A retrospective analysis of relevant visual episodes found predisposing factors for retinopathy (hypertension, diabetes, hypercholesterolemia, and glaucoma).  
Diplopia; photopsia; vision blurred; visual brightness; visual field defect; vitreous floaters; visual impairment, mostly grade 1 or 2 have been seen with PF-02341066 (Camidge et al., 2012). Baseline ophthalmologic examination including visual acuity, pressure, perimetry and slit lamp examination with fundoscopy and digital photography should be performed for all patients. Optical coherence tomography and fluorescin angiography should also be performed with PD-0325901, or if clinically indicated. If the patient develops new visual disturbances/symptoms suggestive of RVO, ophthalmologic investigation will be urgently repeated.  
| Grade of                                                               | Eye disorder severity            | Alterations to IMP doses   |      |           |
|------------------------------------------------------------------------|----------------------------------|----------------------------|------|-----------|
| event Grade 1                                                          | Asymptomatic                     | or                         | mild | symptoms; |
| clinical or diagnostic observations only;  intervention not indicated. | a. If the changes are clearly not due to retinal or  retinal vein abnormalities or are clearly  unrelated to study drug(s), (e.g., conjunctivitis),  PD-0325901/Binimetinib and PF-02341066 may  continue with close observation. b. If drug attribution or aetiology is unclear,  immediately refer the patient for an ophthalmic  exam. If an ophthalmic exam cannot be  performed within 7 days of onset of the event,  then interrupt PD-0325901/Binimetinib and PF02341066 until the exam can be performed. c. If a retinal abnormality is noted, interrupt  PD-0325901/Binimetinib immediately and  consider referral to a retinal specialist if  available for further evaluation. d. If RVO is diagnosed, then report as SAE and  permanently discontinue PD                                  |                            |      |           |
| MErCuRIC1_Protocol_V9.0_29Oct2018                                      | Protocol Template V3.0_18Feb2013 |                            |      |           |  
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| 0325901/Binimetinib. e. If CSR is diagnosed,                                                                                                                    | then                                                                                                                                                                                | interrupt                                                                 |           |         |       |    |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------|-----------|---------|-------|----|
| PD-0325901/Binimetinib                                                                                                                                          | until                                                                                                                                                                               | signs                                                                     | and       |         |       |    |
| symptoms                                                                                                                                                        | have                                                                                                                                                                                | resolved.                                                                 | Resume    | PD         |       |    |
| 0325901/Binimetinib                                                                                                                                             | with                                                                                                                                                                                | a                                                                         | 1         | dose    | level |    |
| reduction. f. If there is no evidence of RVO or CSR, then  resume PD-0325901/Binimetinib at the same  dose level.                                               |                                                                                                                                                                                     |                                                                           |           |         |       |    |
| Grade 2                                                                                                                                                         | Moderate,                                                                                                                                                                           | minimal,                                                                  | local     | or      | non       |    |
| invasive intervention indicated; limiting  age-appropriate instrumental ADL.                                                                                    | a.                                                                                                                                                                                  | Immediately                                                               | interrupt | PD         |       |    |
| 0325901/Binimetinib and                                                                                                                                         | PF                                                                                                                                                                                     |                                                                           |           |         |       |    |
| 02341066                                                                                                                                                        | and                                                                                                                                                                                 | refer                                                                     | the       | patient | to    | an |
| ophthalmologist for evaluation. For all patients  with findings consistent with RVO or CSR based  on the ophthalmic exam, consider referral to a  retinal specialist if available for further  evaluation. b. If RVO is diagnosed, then report as SAE and  permanently discontinue PD0325901/Binimetinib and PF-02341066 c. If CSR is diagnosed, then interrupt  PD-0325901/Binimetinib and until signs and  symptoms have resolved. Resume PD0325901/Binimetinib with a 1 dose level  reduction. d. If there is no evidence of RVO or CSR,  interrupt PD-0325901/Binimetinib and PF02341066 until signs and symptoms have  returned to Grade 1 or resolved. Resume PD0325901 or Binimetinib with a 1 dose level  reduction, resume PF-02341066. MEK  inhibition at the initial dose level may be  considered if visual changes are clearly  unrelated to PD-0325901/Binimetinib.                                                                                                                                                                 |                                                                                                                                                                                     |                                                                           |           |         |       |    |
| Grade 3                                                                                                                                                         | Severe or medically significant but not  immediately sight-threatening;  hospitalization or prolongation of  existing hospitalization indicated;  disabling; limiting self-care ADL |                                                                           |           |         |       |    |
| Grade 4                                                                                                                                                         | Sight-threatening consequences; urgent  intervention indicated; blindness  (20/200 or worse) in the affected eye.                                                                   | Off protocol; STOP all study drug agents;  Repeat ophthalmic consultation |           |         |       |    |
| For all visual changes, regardless of grade, a blood sample for pharmacokinetic analysis must be drawn as  close as possible to the time of onset of the event. |                                                                                                                                                                                     |                                                                           |           |         |       |    |
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neurologic toxicity

PD-0325901 has been associated with acute neurotoxicity (balance, gait disorders) in patients receiving
≥15mg BD, regardless of the schedule. Nervous system disorders ( burning sensation; dizziness; dysgeusia; hypoesthesia; hypoaesthesia facial; neuralgia; neuropathy peripheral; paraesthesia; peripheral sensory neuropathy; peripheral motor neuropathy; sensory disturbance), usually grade 1 or 2 have also been seen with PF-02341066 (Appendix 3).  
| Grade of event Neuro-sensory Neuro-motor Neuro-mood Neuro-cortical or  cerebellar   | Clinical presentation                                                                                        | Alterations to IMP doses                                            |
|-------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------|
| (see also Appendix 3)                                                               |                                                                                                              |                                                                     |
| Grade 1                                                                             | Asymptomatic or mild symptoms;  clinical or diagnostic observations only; intervention not indicated         | PD-0325901: no change Binimetinib: no change PF-02341066: no change |
| Grade 2                                                                             | Moderate; minimal, local or Non-invasive intervention indicated;  limiting age-appropriate instrumental  ADL | PD-0325901: no change Binimetinib: no change PF-02341066: no change |
| MErCuRIC1_Protocol_V9.0_29Oct2018                                                   | Protocol Template V3.0_18Feb2013                                                                             |                                                                     |  
Page 62  
Grade 3 Severe or medically significant  
but not immediately life threatening; hospitalization or prolongation of existing hospitalization indicated; disabling; limiting self-care ADL  
| but not immediately life threatening; hospitalization or prolongation of  existing hospitalization indicated; disabling; limiting self-care ADL   | Hold until < grade 1 - resume -1 dose level  Off protocol; STOP all study drug agents   |
|---------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------|
| intervention indicated                                                                                                                            |                                                                                         |
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transaminitis

Transient and mild (grade 1 or 2) elevation of ALT has been reported for PD-0325901, Binimetinib and PF02341066 (Kwak et al., 2010; LoRusso et al., 2010). The following guidelines are recommended: