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dose modification and dose delay

| Table 6                                                                                                 | Dose reduction for MEK162   |                  |
|---------------------------------------------------------------------------------------------------------|-----------------------------|------------------|
| Dose reduction*                                                                                         | Dose (level - 0)            | Dose level - 1** |
| Binimetinib (MEK162)                                                                                    | 45 mg BID                   | 30 mg BID        |
| *Dose reduction should be based on the highest AE grade **Dose reduction below 30 mg bid is not allowed |                             |                  |  
Missed/skipped doses will not be made up (i.e. the patient should not double their dose if the previous dose was missed). When the toxicity that resulted in a dose reduction improves to and remains stable at Grade 1 or less for a minimum of 21 days, the dose can be re-escalated at the investigator's discretion provided there are no other concomitant toxicities. No dose re-escalation is allowed after dose reduction due to left ventricular dysfunction or prolonged QTcF > 500 msec.  
Dose reduction/interruption/discontinuation decisions should be based on the CTCAE grade of the toxicity and the guidelines provided below. All AEs should be followed weekly or as clinically appropriate until stabilization or resolution.  
Please refer to the tables below for dose adjustment recommendations for MEK162 induced toxicities.  
| MEK162 - Recommended dose modifications associated with treatment-related adverse events  Worst Toxicity CTCAE v4.03  Grade (unless  otherwise  specified)  Dose Modification for Binimetinib Eye Disorder - Serous Detachment of the Retina Eventsb,c Grade 1 - Maintain dose level of binimetinib and increase frequency of  ophthalmic monitoring to at least every 14 days until stabilization or  resolution Grade2 - Maintain dose level of binimetinib and refer the patient to  ophthalmologist within 1 week: o If resolved to Grade ≤ 1 in ≤ 21 days, maintain dose of  binimetinib o If not resolved to Grade ≤ 1 in ≤ 21 days, reduce 1 dose leveld of binimetinib or maintain dose of binimetinib based upon the  Investigator's discretion after consultation with the  ophthalmologist Grade 3 - Interrupt binimetinib and refer the patient to ophthalmologist within  1 week: o If resolved to Grade ≤ 1 in ≤ 21 days, reduce 1 dose leveld of  binimetinib o If not resolved to Grade ≤ 1 in ≤ 21 days, permanently  discontinue binimetinib and close follow-up with ophthalmic  monitoring until stabilization or resolution Grade 4 - Permanently discontinue binimetinib and immediate follow-up with  ophthalmic monitoring until stabilization or resolution Eye Disorder - RVOc RVO of any grade - Permanently discontinue binimetinib and immediate follow-up with ophthalmic monitoring until stabilization or resolution Other Eye Disorders (i.e., Non-retinal Events)c Grade 1-2 - Maintain dose level of binimetinib and increase frequency of  ophthalmic monitoring to at least every 14 days until stabilization or  resolution Grade 3 - Interrupt binimetinib and refer patient to ophthalmologist within  1 week: o If resolved to Grade ≤ 1 in ≤ 21 days, reduce 1 dose leveld of  binimetinib o If not resolved to Grade ≤ 1 in ≤ 21 days, permanently  discontinue binimetinib and close follow-up with ophthalmic  monitoring until stabilization or resolution Grade 4 - Permanently discontinue binimetinib and immediate follow-up with ophthalmic monitoring until stabilization or resolution   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
Worst Toxicity  
CTCAE v4.03 Grade  
(unless otherwise specifieda)  
Dose Modification for Binimetinib  
| (unless otherwise specifieda )                                                                                                                        |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |                                                                                                                                                                                                                                          |
|-------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Liver-related Adverse Events Grade 1                                                                                                                  | -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | Maintain dose level of binimetinib                                                                                                                                                                                                       |
| ALT or AST > ULN to 3 × ULN Grade 2 For patients with Baseline  ALT/AST values ≤ ULN: ALT or AST > 3.0 to 5.0 × ULN  and blood bilirubinf ≤ 2.0 × ULN | -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | Interrupt binimetinib until resolved to Grade ≤ 1, then: o If resolved in ≤ 14 days, maintain dose level of binimetinib o If not resolved in ≤ 14 days, reduce 1 dose leveld of  binimetinib                                             |
| -                                                                                                                                                     | Interrupt binimetinib until resolved to Grade ≤ 2, then:                                                                                                                                                                                                                                                                                                                                                                                                                                           |                                                                                                                                                                                                                                          |
| For patients with liver metastases  or ALT/AST Baseline  values >ULN: ALT or AST 3 × Baseline value to  5.0 × ULN and blood bilirubinf ≤ 2.0 × ULN    | o                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | If resolved in ≤ 14 days, maintain dose level of binimetinib                                                                                                                                                                             |
| o                                                                                                                                                     | If not resolved in ≤ 14 days, reduce 1 dose leveld of  binimetinib                                                                                                                                                                                                                                                                                                                                                                                                                                 |                                                                                                                                                                                                                                          |
| -                                                                                                                                                     | Interrupt binimetinib until resolved to Grade ≤ 1, then:                                                                                                                                                                                                                                                                                                                                                                                                                                           |                                                                                                                                                                                                                                          |
| For all patients: ALT or AST > 3.0 to 5.0 × ULN  and blood bilirubinf > 2.0 × ULN                                                                     | o                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | If resolved in ≤ 7 days, reduce 1 dose leveld of binimetinib                                                                                                                                                                             |
| o                                                                                                                                                     | If not resolved in ≤ 7 days, permanently discontinue  binimetinib                                                                                                                                                                                                                                                                                                                                                                                                                                  |                                                                                                                                                                                                                                          |
| Grade 3 ALT or AST > 5.0 to 8.0 × ULN  and blood bilirubinf ≤ 2.0 × ULN                                                                               | -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | Interrupt binimetinib until resolved to Grade ≤ 1 (or Grade ≤ 2 in  case of liver metastasis), then: o If resolved in ≤ 14 days, maintain dose level of binimetinib o If not resolved in ≤ 14 days, reduce 1 dose leveld of  binimetinib |
| ALT or AST > 8.0 ×ULN  and blood bilirubinf ≤ 2.0 × ULN                                                                                               | -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | Permanently discontinue binimetinib                                                                                                                                                                                                      |
| ALT or AST > 5.0 × ULN  and blood bilirubinf > 2.0 × ULN                                                                                              | -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | Permanently discontinue binimetinib                                                                                                                                                                                                      |
| Grade 4                                                                                                                                               | -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | Permanently discontinue binimetinib                                                                                                                                                                                                      |
| ALT or AST > 20.0 × ULN QTc Prolongation                                                                                                              | First Occurrence: - Interrupt binimetinib. Electrolyte abnormalities (if applicable)  should be corrected and any concomitant medication that could  potentially prolong QT should be discontinued - Monitor patient until resolution of the AE. Include a consultation  with a cardiologist, if indicated - Once resolved to Grade ≤ 1, resume binimetinib at 1 reduced dose  leveld Second Occurrence: - If second occurrence is attributed to binimetinib, permanently  discontinue binimetinib |                                                                                                                                                                                                                                          |
| Grade 3 mean triplicate QTcF ≥ 501 msec (confirmed by a separate mean  triplicate ECG)                                                                |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |                                                                                                                                                                                                                                          |  
| Worst Toxicity                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                                   |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------|
| CTCAE v4.03 Grade                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | Dose Modification for Binimetinib |
| (unless otherwise specifieda ) Cardiac Disorders - Left Ventricular Systolic Dysfunctiona Asymptomatic absolute decrease  of > 10% in LVEF compared to  Baseline and the LVEF is below  the institution's LLN (e.g., a  decrease of 60% to 48% is an  absolute decrease of 12%) - Interrupt binimetinib and repeat evaluation of LVEF within 2 weeks: o If the LVEF recovers (defined as LVEF ≥ 50% or ≥ LLN and  absolute decrease ≤ 10% compared to Baseline) in ≤ 21 days,  reduce 1 dose leveld after approval of the Medical Monitor.  Monitor LVEF 2 weeks after resuming binimetinib, every  4 weeks for 12 weeks and subsequently as per protocol o If the LVEF does not recover in ≤ 21 days, permanently  discontinue binimetinib. Closely monitor LVEF until resolution  or for up to 16 weeks Grade 3-4 - Permanently discontinue binimetinib. Closely monitor LVEF until  resolution or for up to 16 weeks Note: Copies of ECHO and/or MUGA scans may be requested to be  available to the Sponsor for patients with absolute decrease of > 10%  in LVEF compared to Baseline and LVEF < LLN CK Elevations Grade 1-2 - Maintain dose level of binimetinib o If total CK ≥ 3 × ULN, measure CK, CK isoenzymes and  myoglobin in blood or urine weekly for 3 weeks and if total CK  remains ≥ Grade 2, continue to assess CK, CK isoenzymes  and myoglobin along with regularly scheduled clinical chemistry  assessments Grade 3  - If asymptomatic, maintain dose of binimetinib and monitor closely > 5.0 to 10.0 × ULN o Measure CK, CK isoenzymes and myoglobin in blood or urine  weekly for 3 weeks and if total CK remains ≥ Grade 3, continue  to assess CK, CK isoenzymes and myoglobin along with  regularly scheduled clinical chemistry assessments - If symptomatic (muscle pain/spasms), or asymptomatic with an increase in creatinine ≥ 1,5 x the patient's Baseline screening  creatinine, interrupt binimetinib until resolved to Grade ≤ 1 and  monitor closely, then: o If resolved in ≤ 21 days, reduce 1 dose leveld of binimetinib o If not resolved in ≤ 21 days, permanently discontinue  binimetinib  Grade 4 - If asymptomatic, interrupt binimetinib until resolved to Grade ≤ 1  and monitor closely, then: o If resolved in ≤ 21 days, reduce 1 dose leveld of binimetinib o If not resolved in ≤ 21 days, permanently discontinue  binimetinib - If symptomatic, or asymptomatic with an increase in creatinine ≥  1,5 x the patient's Baseline screening creatinine , permanently  discontinue binimetinib |                                   |  
| Worst Toxicity                   |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |                                                                                                                       |
|----------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------|
| CTCAE v4.03 Grade                | Dose Modification for Binimetinib                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |                                                                                                                       |
| (unless otherwise specifieda )   |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |                                                                                                                       |
| Rash Grade 1                     | -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | Maintain dose level of binimetinib                                                                                    |
| -                                | Initiate Initial Rash Treatment Regimen if it was not already started  and rash should be closely monitored                                                                                                                                                                                                                                                                                                                                                                                                        |                                                                                                                       |
| Grade 2                          | First Occurrence: - Maintain dose level of binimetinib and rash should be closely  monitored - Initiate Initial Rash Treatment if it was not already started - Reassess within ≤ 14 days. If rash worsens or does not improve,  interrupt binimetinib until resolved to Grade ≤ 1. Resume  binimetinib at current dose level Second Occurrence: - Reassess within ≤ 14 days. If rash worsens or does not improve,  interrupt binimetinib until resolved to Grade ≤ 1. Resume  binimetinib at 1 reduced dose leveld |                                                                                                                       |
| Grade 3                          | First Occurrence: - Interrupt binimetinib until resolved to Grade ≤ 1. Reassess weekly.  Resume binimetinib at current dose level - Consider referral to dermatologist and manage rash per  dermatologist's recommendation Second Occurrence: - Interrupt binimetinib until resolved to Grade ≤ 1. Reassess weekly.  Resume binimetinib at 1 reduced dose leveld - Consider referral to dermatologist and manage rash per  dermatologist's recommendation                                                          |                                                                                                                       |
| Grade 4                          | -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | Permanently discontinue binimetinib                                                                                   |
| Diarrhea Uncomplicated Grade 1-2 | -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | Consider temporary interruption of binimetinib until resolved to  Grade ≤ 1. Resume binimetinib at current dose level |
| Complicated Grade 1-2            | -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | Temporarily interrupt binimetinib until resolved to Grade ≤ 1.  Resume binimetinib at 1 reduced dose leveld           |
| Grade 3                          | -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | Temporarily interrupt binimetinib until resolved to Grade ≤ 1.  Resume binimetinib at 1 reduced dose leveld           |
| Grade 4                          | -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | Temporarily interrupt binimetinib until resolved to Grade ≤ 1.  Resume binimetinib at 1 reduced dose leveld           |  
| Worst Toxicity                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                                   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------|
| CTCAE v4.03 Grade                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | Dose Modification for Binimetinib |
| (unless otherwise specifieda )                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                                   |
| All Other Binimetinib Treatment-related Adverse Events Grade 1-2 - If the event is Grade 1 or non-persistent Grade 2, maintain dose  level of binimetinib and monitor until stabilization or resolution - If the event is a persistent Grade 2 AE not responsive to a specific  therapy, consider binimetinib dose interruption or reductiond Grade 3 - Interrupt binimetinib until resolved to Grade ≤1 or to  pretreatment/Baseline level. If the event resolves ≤ 21 days, then  binimetinib may be resumed at 1 reduced dose leveld based upon  the Investigator's discretion Grade 4 - Permanently discontinue binimetinib e Abbreviations: AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; |                                   |  
Abbreviations: AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BID = twice daily; CK = creatine kinase; CTCAE = Common Terminology Criteria for Adverse Events; ECHO = echocardiogram; LLN = lower limit of normal; LVEF = left ventricular ejection fraction; mg = milligram(s); MUGA = multi-gated acquisition; OCT = optical coherence tomography; RVO = retinal vein occlusion; ULN = upper limit of normal a Not according to CTCAE.  
b Further evaluation with specialized retinal imaging (e.g., OCT [spectral domain OCT recommended] of the macula for non-vascular abnormalities; and color fundus photography of the central 30 degrees and/or fluorescein angiography for vascular abnormalities) is recommended.  
c Images/results of the ophthalmic examinations (at a minimum, OCT, color fundus photography and/or fluorescein angiography) must be made available upon Sponsor request.
d The lowest recommended dose level of MEK162 is 15 mg BID. When the AE that resulted in a dose reduction improves to and remains stable at ≤ Grade 1 for a minimum of 14 days, the dose can be reescalated to the next dose level at the discretion of the Investigator, provided there are no other concomitant toxicities. There is no limit to the number of times the patient can have their dose reduced or re-escalated (in 15 mg increments); however, no dose re escalation is allowed after a dose reduction due to LVEF dysfunction or prolonged QTcF > 500 msec.  
e A patient with a Grade 4 AE may resume treatment at the lower dose level if the AE recovers to Grade
≤ 1 within 21 days of interrupting drug and, if in the opinion of the Investigator and Medical Monitor, the event is not life-threatening, and the patient can be managed and monitored for recurrence of AE. Dose interruptions of more than 21 days are not allowed unless approved by the Investigator, and the Array BioPharma Medical Monitor or designee.  
f Refers to total bilirubin.
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appendix 7 inclusion and exclusion

- **Age ≥ 16 years**
- **ECOG performance status 0-1 (Appendix 1)**
- **Adequate respiratory and cardiac function (left ventricular function WNL on echocardiography)** - **Able to give informed consent and be capable of co-operating with the protocol**
- **Haematological and biochemical indices within the ranges shown below:**
− **Haemoglobin (Hb) ≥9g/dl (transfusion to achieve this allowed),** − Neutrophi**ls≥ 1,500/µl,**
− **Platelet count ≥ 100,000/µl,**
− **AST or ALT ≤ 3 x ULN, alkaline phosphatase ≤ 2 x ULN,**
− **Serum Bilirubin ≤ 1.5 x ULN,** − **Creatinine Clearance ≥ 30ml/min (Calculated by Cockcroft Gault equation, or by EDTA)**
(Appendix 2)
- **Able to swallow oral medication** - **Only well-controlled CNS metastatic disease ie stable for at least 12 weeks after therapy (surgery,**
radiotherapy) for brain metastases.  
- **Life expectancy of at least 3 months.**
- **Patients with any advanced solid tumours**
- Patients for whom the combination of PF-02341066 with PD‐0325901 is a reasonable option.
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exclusion criteria

All patients
- Unstable ischemic heart disease, cardiac dysrhythmias, coronary/peripheral artery bypass graft or cerebrovascular accident within 6 months prior to starting treatment.  
- **Ongoing congestive heart failure or cardiac dysrhythmias of NCI CTCAE Grade ≥2 or**
uncontrolled atrial fibrillation.  
- **History of extensive disseminated/bilateral or known presence of Grade 3 or 4 interstitial**
fibrosis or interstitial lung disease, including a history of pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease (ILD), obliterative bronchiolitis, and pulmonary fibrosis. A history of prior radiation pneumonitis is allowed.  
- **Spinal cord compression unless treated with the patient attaining good pain control and**
stable or recovered neurologic function.  
- **Carcinomatous meningitis or leptomeningeal disease.**
- **History of hypoalbuminaemia, with peritoneael disease or pleural disease, where patient has**
requirement for ascites or pleural taps.  
- **History of retinal vein occlusion, intraocular pressure > 21 mmHg or patient considered at**
risk of retinal vein thrombosis.  
- Active infections (including chronic hepatitis type B or C and HIV infection if status known),
severe immunologic defect, compromised bone marrow function
- **Other severe acute or chronic medical (including severe gastro-intestinal disorders e.g.**
partial bowel obstruction, malabsorption, active inflammatory bowel disease) or psychiatric conditions or laboratory abnormalities that the investigator considers would make the patient a poor trial candidate, would impart excess risk associated with study participation or drug administration or could interfere with protocol compliance or the interpretation of trial results.  
- **Use of drugs or foods that are known potent CYP3A4 inhibitors or inhibitors or are CYP3A4**
substrates with narrow therapeutic indices (see Appendix 5)
- **Radiotherapy (except for palliative reasons), endocrine therapy, immunotherapy or**
chemotherapy during the previous four weeks (six weeks for nitrosoureas, Mitomycin-C) and four weeks for investigational medicinal products before treatment. Patients with prostate cancer may continue to receive endocrine therapy to maintain castrate levels of androgens.  
- **Resting ECG with QTc >480msec at 2 or more time points within a 24h period.** - **Requirement for medication known to prolong QT interval (see appendix 5).** - **History of other malignancy less than 5 years before the diagnosis of current cancer,**
EXCLUDING the following: Non-melanoma skin cancer, in situ carcinoma of the cervix treated surgically with curative intent, other malignant tumours that have been treated curatively and patient is deemed disease-free
- **Women with the ability to become pregnant (or already pregnant or lactating). However,**
those female patients who have a negative serum or urine pregnancy test before enrolment and agree to use two highly effective forms of contraception (oral, injected or implanted hormonal contraception and condom plus spermicide, have an intra-uterine device and condom plus spermicide, diaphragm with spermicidal gel and condom with spermicide) for four weeks before entering the trial, during the trial and for six months afterwards are considered eligible.  
- Male patients with partners of child-bearing potential (unless they agree to take measures not to father children by using two forms of highly effective contraception including oral, injected or implanted hormonal contraception and condom plus spermicide during the trial and for six months afterwards). Men with pregnant or lactating partners should be advised to use barrier method contraception (condom plus spermicidal gel) to prevent exposure to the foetus or neonate.  
- Prior exposure to a HGF or cMET inhibitor and/or a MEK inhibitor.
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appendix 8 study evaluations for

1. Main screening: pre-dosing evaluations The following must be performed/obtained within the 28 days before the patient receives the first administration of study drug.  
- **Written informed consent** - **Demographic details** - Medical history (including prior diagnosis, prior treatment, concomitant diseases, concomitant medications, therapies received by patient within 28 days prior to cycle 1, day minus 7, known ophthalmologic medical history).  
- **ECOG Performance Status (PS)** - **Full physical examination** - Clinical and radiological (CT chest/abdomen/pelvis or CT chest with MRI abdomen/pelvis)
disease assessment
- **Vital signs (systolic/diastolic blood pressure, pulse, body temperature), height and weight.**
- **Ophthalmic assessment, including visual acuity, pressure, perimetry, slit lamp examination,**
fundoscopy with digital photography, optical coherence tomography and fluorescin angiography.  
- **Safety blood laboratory examination [Haematology: haemoglobin, white blood cells (WBC) with**
differential count and platelets; Clinical chemistry: sodium, potassium, calcium, phosphate, urea, creatinine, total protein, albumin, bilirubin, alkaline phosphatase (alk phos), AST and/or ALT and LDH; Coagulation screen: APTT, PT)
- **Serum or urine Human Chorionic Gonadotropin (HCG) pregnancy test for women of childbearing**
potential.  
- **12-lead electrocardiogram** - **Echocardiography**
- **Review of inclusion and exclusion criteria**
- **Obtain archived tumour tissue for biomarker analysis**
- **Draw blood sample for germline DNA**
- **Obtain fresh skin biopsy for PD assessment** - **Obtain fresh tumour biopsy for PD assessment, where additional consent has been given.**
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2. evaluations during dosing cycle

Record of concomitant medications Full physical examination Vital signs (systolic/diastolic blood pressure, pulse, body temperature) and weight. ECG (12-lead) Blood for assessment of haematology, clinical chemistry, and coagulation status Blood for assessment of Carcinoembryonic Antigen (CEA)
PD assessment of ERK phosphorylation according to timings in section 7.4. PD assessment of soluble c-MET and HGF according to timings in section 7.4 Assessment of adverse events Dosing with PD‐**0325901.**
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cycle 1 day minus 1

Blood for PK assessment: blood draws as per section 7.3.  
Dosing with PD-0325901.
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cycle 1 day 1 ecog

Record of concomitant medications Full physical examination Vital signs (systolic/diastolic blood pressure, pulse, body temperature) and weight. ECG (12-lead)
Blood for assessment of haematology, clinical chemistry, and coagulation status Blood for assessment of Carcinoembryonic Antigen (CEA)
PK sampling (24 hour sample) PD assessments according to timings in section 7.4.  
Plasma samples for biomarkers; blood draws as per section 7.4.  
Assessment of adverse events Start PF-02341066 and PD‐**0325901.**
**Obtain blood sample for ctDNA as per section 7.5.**
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cycle 1 day 2

Blood for PD assessment (24 hour sample) as per section 7.4.  
Dosing with PD‐0325901 **and PF-02341066.**
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cycle 1 day 8

ECOG PS
Record of concomitant medications Full physical examination Vital signs (systolic/diastolic blood pressure, pulse, body temperature) and weight. Assessment of adverse events Dosing with PD‐0325901 **and PF-02341066.**
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cycle 1 day 15 ecog

Record of concomitant medications Full physical examination Vital signs (systolic/diastolic blood pressure, pulse, body temperature) and weight.  
ECG (12-lead) Blood for assessment of haematology, clinical chemistry, and coagulation status Blood for assessment of Carcinoembryonic Antigen (CEA)
PD assessments according to timings in section 7.4. Plasma samples for biomarkers; blood draws as **per section 7.4.**
Assessment of adverse events Dosing with PD‐0325901 **and PF-02341066**
4-6 hours post-dose fresh skin biopsy for PD assessment 4-6 hours post-dose fresh tumour biopsy for PD assessment (for patients in the dose expansion phase and those patients who have consented to the biopsy in the escalation phase).
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cycle 1 day 16

Blood for PD assessment (24 hour sample)
Dosing with PD‐0325901 and PF-02341066.
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cycle 1 day 21 ecog

Record of concomitant medications Full physical examination Vital signs (systolic/diastolic blood pressure, pulse, body temperature) and weight. PK sampling: blood draws as per section 7.3.  
Ophthalmic assessment, including visual acuity, pressure, perimetry, slit lamp examination, fundoscopy with digital photography, optical coherence tomography and fluorescin angiography.  
Assessment of adverse events Dosing with PD-0325901 **and PF-02341066**
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cycle 1 day 28 ecog

Record of concomitant medications Full physical examination Vital signs (systolic/diastolic blood pressure, pulse, body temperature) and weight.  
PK sampling: blood draws as per section 7.3 ECG (12-lead)
Blood for assessment of haematology, clinical chemistry, and coagulation status Blood for assessment of Carcinoembryonic Antigen (CEA) Assessment of adverse events Dosing with PF-02341066 only
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cycle 2 day 1 (day

PK sampling (24 hour sample)
Plasma samples for biomarkers; blood draws as per section 7.4. Blood sample for ctDNA (dose expansion phase only)
Dosing with PF-02341066 and restart PD-0325901
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cycle 2 onwards day 8

Record of concomitant medications Full physical examination Vital signs (systolic/diastolic blood pressure, pulse, body temperature).  
Assessment of adverse **events**
Dosing with PD‐0325901 **and PF-02341066**
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cycle 2 onwards day 15

Record of concomitant medications Full physical examination Vital signs (systolic/diastolic blood pressure, pulse, body temperature). Assessment of adverse events Dosing with PD‐0325901 **and PF-02341066**
Plasma samples for biomarkers; blood draws as per section 7.4 (cycle 2 only).
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cycle 2 onwards day 21

Record of concomitant medications Full physical examination Vital signs (systolic/diastolic blood pressure, pulse, body temperature). PK sampling: blood draws as per section 7.3 (trough level and 2h after dosing, cycles 2, 4, 6, 8, 10 and 12).  
Assessment of adverse events Dosing with PD-0325901 and PF-02341066
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cycle 3 onwards day 1

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, and coagulation status Blood for assessment of Carcinoembryonic Antigen (CEA)
Plasma samples for biomarkers; blood draws as per section 7.4.  
Blood sample for ctDNA (dose expansion phase only)
Assessment of adverse events Dosing with PF-02341066 and re-start PD-0325901
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3. end of treatment evaluations

Record of concomitant medications Full physical examination Vital signs (systolic/diastolic blood pressure, pulse, body temperature) and weight.  
Blood for assessment of haematology, clinical chemistry, and coagulation status Blood for assessment of Carcinoembryonic Antigen (CEA)
Blood for ctDNA (dose expansion phase only) Ophthalmic assessment, including visual acuity, pressure, perimetry, slit lamp examination, fundoscopy with digital photography, optical coherence tomography and fluorescin angiography.  
Assessment of adverse events ECG (12-lead) Tumour assessment: CT scan chest/abdomen/pelvis (or CT chest with MRI abdomen/pelvis)
using RECIST v1.1.  
Biopsy of representative metastases for molecular profiling (dose expansion phase only:
optional)
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4. post treatment follow-up -

- Patients will be followed up every 3 months for survival status until death or study closure, whichever happens first.  
5. Evaluations on early withdrawal If the patient is withdrawn from treatment, for any of the reasons indicated in section 6, a final off-study visit assessment should be performed 28 - 30 days after the last administration of PF-02341066 and PD‐
0325901. The following assessments will be done:
- **ECOG PS** - **Record of concomitant medications** - **Full physical examination** - **Vital signs (systolic/diastolic blood pressure, pulse, body temperature) and weight.** - **Blood for assessment of haematology, clinical chemistry, and coagulation status**
- **Assessment of adverse events**
- **ECG (12-lead)**
If the patient is withdrawn from the trial and declines attendance for a final off-study visit, then a withdrawal assessment should be performed, if possible on the day the decision is made to take the patient off-study or as soon as possible. Telephone review is permitted in these circumstances. These patients will be followed up for progression and overall survival.  
| Screening                                | Cycle 1                   | Cycle 2          | Cycle 3   | Cycle 4   | Cycle 5 onwards   | End of  Treatment o   | Post end of  treatment  follow-up   |                        |    |    |    |            |    |       |    |    |    |      |    |    |     |         |    |
|------------------------------------------|---------------------------|------------------|-----------|-----------|-------------------|-----------------------|-------------------------------------|------------------------|----|----|----|------------|----|-------|----|----|----|------|----|----|-----|---------|----|
| Visit Description Visit No               | 1                         | 2                | 3         | 4         | 5                 | 6                     | 7                                   | 8                      | 9  | 10 | 11 | 12         | 13 | 14 15 | 16 | 17 | 18 | 19   | 20 | 21 | 22  | 23      | 24 |
| -28 to                                   | -7                        | -6               | -1        | 1         | 2                 | 8                     | 15                                  | 16                     | 21 | 22 | 28 | 29±3 36 43 | 49 | 57±3  | 64 | 71 | 78 | 85±3 | 92 | 99 | 105 | D 28-30 |    |
| Day                                      | -1                        | after last  dose |           |           |                   |                       |                                     |                        |    |    |    |            |    |       |    |    |    |      |    |    |     |         |    |
| Informed Consent                         | X                         |                  |           |           |                   |                       |                                     |                        |    |    |    |            |    |       |    |    |    |      |    |    |     |         |    |
| Demographics & History                   | X                         |                  |           |           |                   |                       |                                     |                        |    |    |    |            |    |       |    |    |    |      |    |    |     |         |    |
| Concomitant medication                   | X                         | X                | X         | X         | X                 | X                     | X                                   | X                      | X  | X  | X  | X          | X  | X     | X  | X  | X  | X    | X  |    |     |         |    |
| ECOG                                     | X                         | X                | X         | X         | X                 | X                     | X                                   | X                      | X  | X  | X  | X          | X  | X     | X  | X  | X  | X    | X  |    |     |         |    |
| Physical examination a                   | X                         | X                | X         | X         | X                 | X                     | X                                   | X                      | X  | X  | X  | X          | X  | X     | X  | X  | X  | X    | X  |    |     |         |    |
| Tumour Assessment b                      | X                         | X                | X         |           |                   |                       |                                     |                        |    |    |    |            |    |       |    |    |    |      |    |    |     |         |    |
| Vital signs                              | X                         | X                | X         | X         | X                 | X                     | X                                   | X                      | X  | X  | X  | X          | X  | X     | X  | X  | X  | X    | X  |    |     |         |    |
| Height & Weight c                        | X                         | X                | X         | X         | X                 | X                     | X                                   | X                      | X  | X  |    |            |    |       |    |    |    |      |    |    |     |         |    |
| Ophthalmic Exam d                        | X                         | X                | X         |           |                   |                       |                                     |                        |    |    |    |            |    |       |    |    |    |      |    |    |     |         |    |
| Haem &  Clin Chem Bloods e               | X                         | X                | X         | X         | X                 | X                     | X                                   | X                      |    |    |    |            |    |       |    |    |    |      |    |    |     |         |    |
| Pregnancy test                           | X                         |                  |           |           |                   |                       |                                     |                        |    |    |    |            |    |       |    |    |    |      |    |    |     |         |    |
| 12 lead ECG                              | X                         | X                | X         | X         | X                 | X                     | X                                   | X                      |    |    |    |            |    |       |    |    |    |      |    |    |     |         |    |
| Echocardiography f                       | X                         |                  |           |           |                   |                       |                                     |                        |    |    |    |            |    |       |    |    |    |      |    |    |     |         |    |
| Inclusion/exclusion criteria             | X                         |                  |           |           |                   |                       |                                     |                        |    |    |    |            |    |       |    |    |    |      |    |    |     |         |    |
| CEA g                                    | X                         | X                | X         | X         |                   |                       |                                     |                        |    |    |    |            |    |       |    |    |    |      |    |    |     |         |    |
| PK 24 hours profile h                    | X                         | X                | X         | X         | X                 | X                     |                                     |                        |    |    |    |            |    |       |    |    |    |      |    |    |     |         |    |
| PK trough i                              | X                         | X                |           |           |                   |                       |                                     |                        |    |    |    |            |    |       |    |    |    |      |    |    |     |         |    |
| PD PBMC/plasma j                         | X                         | X                | X         | X         | X                 | X                     |                                     |                        |    |    |    |            |    |       |    |    |    |      |    |    |     |         |    |
| AE review                                | X                         | X                | X         | X         | X                 | X                     | X                                   | X                      | X  | X  | X  | X          | X  | X     | X  | X  | X  | X    | X  |    |     |         |    |
| PD-0325901 administration k              | X                         | X                | X         | X         | X                 | X                     | X                                   | X                      | X  | X  | X  | X          | X  | X     | X  | X  | X  | X    | X  | X  | X   |         |    |
| PF-02341066 administration               | Continuous administration |                  |           |           |                   |                       |                                     |                        |    |    |    |            |    |       |    |    |    |      |    |    |     |         |    |
| Survival data (PFS and OS)               | X                         |                  |           |           |                   |                       |                                     |                        |    |    |    |            |    |       |    |    |    |      |    |    |     |         |    |
| Biomarker studies Archival tumour sample | X                         |                  |           |           |                   |                       |                                     |                        |    |    |    |            |    |       |    |    |    |      |    |    |     |         |    |
| Blood sample germline DNA                | X                         |                  |           |           |                   |                       |                                     |                        |    |    |    |            |    |       |    |    |    |      |    |    |     |         |    |
| PD skin biopsy l                         | X                         | X                |           |           |                   |                       |                                     |                        |    |    |    |            |    |       |    |    |    |      |    |    |     |         |    |
| PD tumour biopsy m                       | X                         | X                |           |           |                   |                       |                                     |                        |    |    |    |            |    |       |    |    |    |      |    |    |     |         |    |
| Plasma soluble  biomarkers n             | X                         | X                | X         | X         | X                 | X                     | X                                   | Repeat  cycle 3  and 4 |    |    |    |            |    |       |    |    |    |      |    |    |     |         |    |  
APPENDIX 9: SCHEDULE **OF EVENTS FOR DOSE ESCALATION PHASE USING PF-02341066 WITH PD-0325901**
a To include vital signs (pulse and systolic/diastolic blood pressure, body temperature) and neurological examination. b CT includes chest, abdomen and pelvis. Measurements using modified RECIST 1.1. At screening and after 2nd, 4th, 6th cycle, and every 2 cycles thereafter until intolerable toxicity or progressive disease. c Height to measured only at screening.  
d Ophthalmic exam on Cycle 1 Day 21 time window of +/- 2 days e To include FBC with differential and platelets, Na, K, Ca, phosphate, urea, creatinine, total protein, albumin, bilirubin, alk phos, AST and /or ALT, LDH, coagulation screen, APTT, PT (validity period of bloods is 3 days).  
fECHO will only be repeated as clinically indicated.  
g At same time as CT scan (optional at every cycle) plus Cycle 1 Day 28. h Serum PK measurements will be taken as specified in the protocol (section 7.3). iPK trough sample pre-dose (morning) and 2 hours post dose day 21 of cycles 2, 4, 6, 8, 10 and 12.  
jPD PBMC/Plasma samples will be taken as specified in the protocol (section 7.4)
k Run-in day -7 to day -1 then days 1-21 of each 28 day cycle. lDay 15 +/- 7 days. m At Screening and Day 15 +/- 7 days. Optional biopsy if separate consent obtained. n At each sampling point 4ml of plasma obtained. o Disease progression, intolerance or withdrawal.  
| APPENDIX 10: AMENDMENT HISTORY Amendment  Protocol  No. Version  No. Date issued Author(s) of   | Details of Changes made                                 |           |                                                                     |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |
|-------------------------------------------------------------------------------------------------|---------------------------------------------------------|-----------|---------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| changes                                                                                         |                                                         |           |                                                                     |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |
| 001 substantial                                                                                 | 2.0                                                     | 29Jul2014 | Mark Middleton (CI) Sharon Love (Stats) OCTO Pfizer                 | In response to MHRA NFGNA: clarification  re MTD and dose modification; Protocol and  PIS inclusion of MHRA contraception  guidelines; IMP information correction to  CTA.                                                                                                                                                                                                                                                                                                                                              |
| 004 substantial                                                                                 | 3.0                                                     | 27Jan2015 | Mark Middleton (CI) Sharon Love (Stats) OCTO Pfizer                 | Amend IRAS Dataset updated with changes.  Protocol; Dose Escalation and Dose  Expansion PIS/CFs; Patient Diary Card;  Patient Study Card Belfast site PI - notice of change of status.                                                                                                                                                                                                                                                                                                                                  |
| 007 substantial                                                                                 | 4.0                                                     | 14Jul2015 | Mark Middleton (CI) Sharon Love (Stats) OCTO Pfizer                 | Inclusion of interim dose level. Additional  exclusion criteria. Removal of Ondansetron as recommended  treatment for Vomiting. Correction to ECG event Cycle 1 Day 15                                                                                                                                                                                                                                                                                                                                                  |
| 008 substantial                                                                                 | 5.0                                                     | 13Apr2016 | Mark Middleton (CI) Sharon Love (Stats) OCTO Pfizer Array Biopharma | Include new study drug, MEK inhibitor  Binimetinib as replacement for the MEK  inhibitor PD-0325901. Inclusion of an extra short dose escalation phase using the new combination study drug  Binimetinib with PF-02341066. Change to the study design of the dose  expansion phase to incorporate specific  cohorts of RAS wild type colorectal patients. Additional Investigator Brochure for  Binimetinib Notification of change of investigator at an  existing site, European St Georges  Pompidou Hospital, Paris. |
| 011 substantial                                                                                 | 6.0                                                     | 14Mar2017 | Mark Middleton (CI)                                                 | Clarification to CPK DLT criteria and dose                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |
| OCTO                                                                                            | modification guidelines in Protocol secs 8.5  and 8.5.1 |           |                                                                     |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |
| 012 substantial                                                                                 | 7.0                                                     | 11May2017 | Mark Middleton (CI) Sharon Love (Stats) OCTO Pfizer Array Biopharma | Amendment to protocol, doe expansion  phase patient information and screening  consent form and GP letter.. Update to patient numbers required for  escalation phase as well as total patient  numbers. Update of dose escalation phase site  numbers from 4to 5. Update to dose expansion phase site  numbers from 8 to 8-10 sites. To capture early phase Ib dose expansion  objective responses to study treatment in a)  RASMT CRC and b) RASWT/cMETmut/amplified CRC and c) RASWT/cMET over-expressed CRC. This also  requires an increase in patient number  target. Update to eligibility and exclusion criteria. Update to contraception guidelines. Correction to the sec 3.0 dose expansion  phase secondary endpoints where CT  scanning was listed in addition to the primary                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |
| MErCuRIC1_Protocol_V9.0_29Oct2018                                                               | Page 120 of 121                                         |           |                                                                     |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |  
| endpoint. Revision of dose expansion phase sample  collection to exclude pERK sample collection  in PBMCs and reduction in skin biopsy  samples to include a limited cohort of 10  patients. Change of lab information for processing of  skin biopsies.  Dose Expansion Schedule changes for: i)  clarification of post end of treatment and  follow up and (ii) removal of C1 day 2 and C1  day 16 as no longer required for PD pERK  samples. Update to dose modification guidelines for  AEs (pneumonitis and LVEF) Change to PI at the Vall d'Hebron, Barcelona  site.   |                        |           |                                                                          |                                            |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------|-----------|--------------------------------------------------------------------------|--------------------------------------------|
| 013 substantial                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | 8.0                    | 11Sep2017 | Mark Middleton (CI) OCTO Sandra Van  Schaeybroeck  (Project coordinator) | Amendment to sec 7.2 to include PDUM  facility for evaluation of amplification and cMET expression Clarifications to sec 15.1 and correction to  sample size typographical error Typographical corrections and clarifications  to ensure consistency throughout the  protocol. Screening PIS - clarification to reporting  timeline for RAS genotype                                            |
| 014                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | 8.0                    | 29Aug2018 | Mark Middleton (CI)                                                      | Update to IBs - binimetinib (v Mar2018 and |
| OCTO                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | crizotinib (v Oct2017) |           |                                                                          |                                            |
| 015                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | 9.0                    | 29Oct2018 | Mark Middleton (CI)                                                      | Change of trial statistician details.      |
| OCTO                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | Change in protocol design to include early  patient recruitment closure - protocol  synopsis and sec 2.1 and sec 2.3. Clarification of CPK dose modification  guidelines in sec 8.5.1 and Appendix 6A. Removal of ctDNA sample collection timepoint in Summary Schedule of Events at  screening - dose expansion phase and alsp  sec 5.4 as not required.                        |           |                                                                          |                                            |