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pneumonitis

| Grade of event                                                                      | Alterations to IMP doses                                                                                        |
|-------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------|
| Grade 1                                                                             | PD-0325901: no change Binimetinib: no change PF-02341066: no change                                             |
| Grade 2 ALT, AST 2.6 - 5.0 xN Bilirubin <1.5 x N ALT, AST≤ 2.5 x N Bilirubin normal | PD-0325901: no change Binimetinib: no change PF-02341066: no change                                             |
| Grade 3 ALT, AST 5.1 - 20.0 xN Bilirubin 1.5 - 3.0 x N                              | Withhold until toxicity is grade 1 or better, or has returned to baseline, then  resume treatment -1 dose level |
| Grade 4  ALT, AST > 20.0 x N Bilirubin > 3.0 x N                                    | Off protocol; STOP all study drug agents                                                                        |  
Pneumonitis and Interstitial Lung Disease (ILD) at <1% frequency has been associated with PF-02341066 and Binimetinib. The following guidelines (in absence of disease progression, pulmonary embolism, positive cultures or radiation effect) are recommended:  
| Grade of                             | Clinical presentation                                                                                                                                                                                                                                                                            | Alterations to IMP doses                                                                                                                                                                                                   |
|--------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| event Grade 1                        | Asymptomatic; clinical or diagnostic  observations only; intervention not  indicated.                                                                                                                                                                                                            | PD-0325901: no change Binimetinib: no change PF-02341066: withhold dose until toxicity is  grade 0, i.e. has returned to baseline, then resume treatment at the same dose.  Discontinue permanently if pneumonitis recurs. |
| Grade 2                              | Symptomatic; medical intervention                                                                                                                                                                                                                                                                | PD-0325901: no change                                                                                                                                                                                                      |
| indicated; limiting instrumental ADL | Binimetinib: withhold dose until improves to  grade 0 or 1; then resume at lower dose; if not  resolved within 3 weeks, permanently  discontinue PF-02341066: withhold dose until toxicity is  grade 0, then resume treatment at the same  dose. Discontinue permanently if pneumonitis  recurs. |                                                                                                                                                                                                                            |
| Grade 3                              | Severe symptoms; limiting self-care ADL;                                                                                                                                                                                                                                                         | PD-0325901: no change                                                                                                                                                                                                      |
| oxygen indicated.                    | PF-02341066 or Binimetinib: discontinue  treatment and do not re-treat                                                                                                                                                                                                                           |                                                                                                                                                                                                                            |
| Grade 4                              | Life-threatening respiratory compromise;  urgent intervention indicated (e.g. tracheotomy or intubation).                                                                                                                                                                                        | Off protocol; STOP all study drug agents                                                                                                                                                                                   |
| MErCuRIC1_Protocol_V9.0_29Oct2018    | Protocol Template V3.0_18Feb2013                                                                                                                                                                                                                                                                 |                                                                                                                                                                                                                            |
| Page 63 of 121                       |                                                                                                                                                                                                                                                                                                  |                                                                                                                                                                                                                            |  
Investigators must evaluate thoroughly patients who demonstrate potential signs/symptoms of pneumonitis/pneumonia. If a patient has a potential diagnosis of pneumonitis or drug related lung injury the following evaluations/procedures should be considered to assist or exclude the diagnosis of pneumonitis during this period:
- A sputum gram stain and culture (induced sputum if needed) bacterial, viral, fungal, protozoal, and mycobacteria
- Blood culture should be performed in febrile patients - Thoracenthesis if pleural fluid is present (examined for same pathogens as sputum)
- Bronchoscopy with bronchoalveolar lavage (BAL) if appropriate. The BAL fluid should be sent for culture and cytology (same pathogens as above).  
- Lung biopsy (e.g.open or thorascopic preferable, bronchoscopy with transbronchial biopsy) if appropriate.  
- A plasma sample for BNP (B-type Natriuretic peptide) to evaluate for evidence of CHF,
- For Asian patients or any other in whom it is suspected, a blood sample for β-D-glucan to evaluate for the presence of protozoal pneumonia (e.g. Pneumocystis jerovicii)
If clinically appropriate, high dose corticosteroid treatment should be initiated. Should the event be fatal an autopsy is highly recommended to confirm/exclude the diagnosis. For any case of suspected pneumonitis please contact the Sponsor.
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left ventricular systolic dysfunctions

Decreases of the left-ventricular-ejection-fraction (LVEF) have been observed in subjects receiving PD-0325901 and Binimetinib. LVEF changes are common and the severe, sometimes fatal, events can occur in patients treated with crizotinib. A review by European medicines regulators of data from clinical trials and reports of clinical practice has concluded that this side effect is common (i.e, occurs in between 1 in 10 and 1 in 100 patients who take crizotinib). Up to 25 February 2015, about 14,700 patients worldwide have received crizotinib since licensing. Forty cases of cardiac failure have been reported in the post-marketing setting. In most cases cardiac failure occurred within 1 month of starting treatment with crizotinib, and affected patients with or without pre-existing heart disorders. The reports included some cases with evidence of symptoms of cardiac failure resolving on stopping crizotinib, and cases with evidence of symptoms reoccurring when it was reintroduced.  
| Grade of event                  | Clinical presentation                                                                                               | Alterations to IMP doses   |
|---------------------------------|---------------------------------------------------------------------------------------------------------------------|----------------------------|
| Grade 1                         | -Hold Binimetinib and PF-02341066 and repeat  LVEF within 2 weeks If LVEF recovers (defined as LVEF ≥ 50% or ≥ LLN  and absolute decrease ≤ 10% compared to B/L) in  ≤ 21 days, reduce 1 dose level . Repeat  ECHO/MUGA at 2 weeks after resuming  Binimetinib and PF-02341066, then every 4 weeks  for 12 weeks until resolution If the LVEF does not recover in ≤ 21 days,  permanently discontinue Binimetinib and PF02341066. Closely monitor LVEF until resolution or  for up to 16 weeks                                                                                                                     |                            |
| Grade 2                         | Asymptomatic absolute decrease  of > 10% in LVEF compared to  baseline and the LVEF is below  the institutions' LLN |                            |
| Grade 3 resting  LVEF 39-20% or | Permanently discontinue study treatment                                                                             |                            |
| >20% absolute                   | Consult with cardiologist                                                                                           |                            |
| Symptomatic                     |                                                                                                                     |                            |
| reduction from                  | Repeat ECHO/MUGA after 2, 4, 8, 12 and 16                                                                           |                            |
| baseline                        | weeks or until resolution.                                                                                          |                            |
| Grade 4 resting  LVEF <20%      |                                                                                                                     |                            |  
Symptoms may include: dyspnoea, orthopnoea, and other signs and symptoms of pulmonary congestion and oedema.  
Prolonged QTc interval:
Prolonged QTc interval has been reported as a common side effect in all 3 IMPs.  
| Prolonged QTc interval has been reported as a common side effect in all 3 IMPs. Grade of event Alterations to IMP doses Grade 1 PD-0325901: no change QTc 450-470ms Binimetinib: no change PF-02341066: no change Grade 2 Assess electrolytes and concomitant medications. Correct any  QTc 470-500ms electrolyte or magnesium abnormalities. Continue study treatment at the same dose level. Grade 3 QTc >500ms on at least 2  separate ECG's Interrupt both PF-02341066 and PD-0325901/Binimetinib until  recovery to baseline. Assess electrolytes and concomitant  medications. Correct any electrolyte or magnesium abnormalities.  Resume treatment by reducing one dose level of either PF02341066/PD-0325901 or PF-02341066/Binimetinib if no other  cause for QTc prolongation is found otherwise resume with the  same dose level. Grade 4 QTc >= 501 or >60 ms change  from baseline and Torsade de  pointes or polymorphic ventricular tachycardia or signs/symptoms of  serious arrhythmia Off protocol; STOP all study drug treatment Based on an average QTc (Bazett's) value of triplicate ECGs. For example, if an ECG demonstrates a  prolonged QT interval, obtain 2 more ECGs over a brief period e.g. at least 2 minutes apart each, and then   |
|---|  
Based on an average QTc (Bazett's) value of triplicate ECGs. For example, if an ECG demonstrates a prolonged QT interval, obtain 2 more ECGs over a brief period e.g. at least 2 minutes apart each, and then use the averaged QTc values of the 3 ECGs to determine if study treatments should be interrupted or discontinued.
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bradycardia

For a heart rate <40 beats per minute, evaluate patient fully including an assessment of concomitant medications. Adjust the dosage of any medication known to be associated with bradycardia e.g. beta blockers. If the bradycardia is symptomatic at any time or does not improve within 7 days of adjusting the concomitant medications, hold PF-02341066 and Binimetinib dosing until recovery. Patient may continue treatment only with the agreement of both the sponsor and investigator
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ck elevations

| also as part of a combined therapy. Grade of event Alterations to IMP doses Grade 1 - 2 total CK ≥ 3 × ULN Maintain dose level of Binimetinib and PF-02341066 Measure CK, CK isoenzymes and myoglobin in blood or urine weekly for 3 weeks and if total CK remains ≥ Grade 2, continue to assess CK, CK  isoenzymes and myoglobin along with regularly scheduled clinical chemistry  assessments Grade 3 - If asymptomatic, maintain dose of Binimetinib and PF-02341066 but  total CK ≥ 5 to 10 × ULN monitor closely Measure CK, CK isoenzymes and myoglobin in blood or urine weekly for  3 weeks and if total CK remains ≥ Grade 3, continue to assess CK, CK  isoenzymes and myoglobin along with regularly scheduled clinical chemistry  assessments - If symptomatic (muscle pain/spasms), or asymptomatic with serum  creatinine ≥ 1.5 x baseline creatinine, interrupt Binimetinib only until  MErCuRIC1_Protocol_V9.0_29Oct2018 Protocol Template V3.0_18Feb2013   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
Page 65  
| resolved to Grade ≤ 1 and monitor closely, then:                                                                    |    |                                                                         |
|---------------------------------------------------------------------------------------------------------------------|----|-------------------------------------------------------------------------|
| If resolved in ≤ 21 days, reduce 1 dose level of Binimetinib If not resolved in ≤ 21 days, permanently discontinue Binimetinib and PF02341066                                                                                                                     |    |                                                                         |
| Grade 4                                                                                                             | -  | If asymptomatic , hold Binimetinib only until resolved to Grade ≤ 1 and |
| total CK >10 x ULN                                                                                                  | monitor closely, then: o If resolved in ≤ 21 days, reduce 1 dose level of Binimetinib. PF02341066 no change. - If symptomatic , or asymptomatic withserum creatinine ≥ 1.5 x  baseline creatinine, permanently discontinue Binimetinib and PF02341066    |                                                                         |
| If not resolved in ≤ 21 days, permanently discontinue Binimetinib - Off  protocol; STOP Binimetinib and PF-02341066 |    |                                                                         |
| .                                                                                                                   |    |                                                                         |  
If not resolved in ≤ 21 days, permanently discontinue Binimetinib - Off  
protocol; STOP Binimetinib and PF-02341066  
.  
8.5.2 **Haematological Toxicities:**  
Haematological abnormalities have been observed with all 3 IMPs, are usually of grade 1 and 2 severity and occur in less than 5% of patients.  
Asymptomatic neutropaenia *(ANC)*  
Grade of event Alterations to IMP **doses**  
≤1.5-≥1.0 Continue both drugs, repeat ANC in 1 week  
| <1.0 ≥0.5   | Withhold PF-02341066 and PD-0325901/Binimetinib until toxicity is ≤2, or  has returned to baseline, then resume treatment at the same dose level.   |
|-------------|-----------------------------------------------------------------------------------------------------------------------------------------------------|
| <0.5        | Withhold PF-02341066 and PD-0325901/Binimetinib until toxicity is ≤2, or  has returned to baseline, then reduce dose level -1.                      |
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febrile neutropaenia/neutropenic sepsis

If ANC is ≤ 1.0 with a declining trend and is associated with temperature above 38.0° C on two separate occasions and or associated with signs or symptoms of sepsis, treatment with both drugs should be held.  
Patients should be assessed immediately and treated as in patients with intravenous antibiotics (in accordance with the local hospital neutropenic sepsis guidelines) and supportive treatment as deemed necessary. G-CSF support may be given as deemed appropriate by the physician and in keeping with institutional guidelines (and recorded as concomitant medication). Further treatment is issued after the patient has completely recovered from infection and ANC has resolved to ≥1.5, then reduce dose level -1.  
On subsequent events of neutropaenic sepsis, the same protocol as above is followed and the combination therapy is discontinued.
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lymphopaenia

No dose modification of the combination therapy is necessary if other laboratory parameters are normal and the lymphocyte counts are ≥ 0.5 x 10 9/l (normal reference range 2.0-3.5 x 10 9/l). Consider dose reduction of PD-0325901/Binimetinib or PF-02341066 at physician's discretion if lymphocyte count ≤0.5 x 10 9/l (grade 4).
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anaemia (hb < 8g/dl or

| Grade of event                | Alterations to IMP doses                                                                                                                                     |
|-------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------|
| ≤10 g/dl > 8 g/dl, not        | No change in dose. .                                                                                                                                         |
| symptomatic ≤ 8 g/dl > 6 g/dl | Blood transfusion according to local guidelines. No change in dose.                                                                                          |
| ≤ 6g/dl > 5g/dl               | Blood transfusion according to local guidelines. Withhold till Hb > 8 g/dl.  Dose reduction of PD-0325901 or Binimetinib. Continue PF-02341066 at  same dose |
| ≤ 5g/dl                       | Blood transfusion according to local guidelines. Withhold till Hb > 8 g/dl. Off  protocol; STOP both agents.                                                 |
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8.6 compliance

Patients will be instructed to keep a record of compliance with treatment, by means of using a "patient diary" that will be provided to them.
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8.7 management of overdose

In the event of a PF-02341066 or PD-0325901/Binimetinib overdose (defined as any dose above that specified in the protocol), the investigator should contact the OCTO and the Chief Investigator immediately and closely monitor the patient for AEs/SAEs and laboratory abnormalities. The investigator will use clinical judgment to treat any overdose.  
Information regarding the quantity of the excess dose as well as the duration of the overdosing should be documented in the eCRF for treatment.
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9.2 concomitant medication and non-drug

Concomitant medication may be given as medically indicated. All patients will be asked to provide a complete list of prescription, over-the-counter and complementary and alternative medications that have been taken within the previous 4 weeks prior to the first treatment visit. They must also inform the Investigator about any new medication started while in the trial. Details (including indication, doses, frequency and start / stop dates) of concomitant medication taken during the trial until the completion of the off-study visit must be recorded in the medical record and the appropriate CRF.
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9.3 prohibited therapies

Patients should not be prescribed any other anti-cancer or investigational therapies while participating in this study.
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9.4 (potential) drug interactions pf-02341066

Coadministration of PF-02341066 with strong CYP3A inhibitors may increase PF-02341066 plasma concentrations. The concomitant use of strong CYP3A inhibitors, including but not limited to atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, and voriconazole, should be avoided. Grapefruit or grapefruit juice and Seville oranges, their juice and marmalade containing them may also increase plasma concentrations of crizotinib and should be avoided. Caution should be exercised with concomitant use of moderate CYP3A inhibitors.
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agents that may decrease crizotinib

Coadministration of crizotinib with strong CYP3A inducers may decrease crizotinib plasma concentrations.  
The concurrent use of strong CYP3A inducers, including but not limited to carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, and St. John's Wort, should be avoided.  
Agents Whose Plasma Concentrations May Be Altered By Crizotinib PF-02341066 has been identified as an inhibitor of CYP3A both *in vitro* and *in vivo.* Coadministration of PF-02341066 with CYP3A4 substrates with narrow therapeutic indices associated with life-threatening arrhythmias including, but not limited to dihydroergotamine, ergotamine, pimozide, astemizole, cisapride, and terfenadine must be avoided during PF-02341066 treatment. In addition, caution must be exercised in patients receiving PF-02341066 in combination with other CYP3A4 substrates, particularly those with narrow therapeutic indices, including but not limited to alfentanil, cyclosporine, fentanyl, quinidine, sirolimus, and tacrolimus.  
In addition to drug interactions due to enzyme inhibition and induction, the possibility of an additive pharmacodynamic interaction of PF-02341066 and other negatively chronotropic medications (e.g., betablockers and non-dihydropyridine calcium-channel blockers) should be considered. Co-administration of PF-02341066 with these medications may lead to significant decreases in heart rate.
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pd-0325901

Drug interaction studies have not been conducted for PD-0325901 in humans. Based on *in vitro* studies, PD0325901 and its circulating metabolite, PD-0315209, have a low potential to inhibit CYP2D6, CYP3A4, CYP1A2, and CYP2C19. However, the metabolite (PD-0315209) has the potential to inhibit CYP2C8 and CYP2C9. Caution should be exercised when co-administering PD-0325901 with drugs that are substrates for CYP2C8 or CYP2C9. Patients taking warfarin should be switched to low molecular weight heparin for the duration of the study. Other interactions may exist that are as yet unknown.
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binimetinib

A human ADME study identified direct glucuronidation as a main metabolic pathway of Binimetinib, and in vitro studies identified UGT1A1 as the main enzyme mediating direct glucuronidation. The impact of UGT1A1 inhibitors or inducers has not been assessed to date; therefore, inhibitors or inducers of UGT1A1 should be co-administered with caution. *In vitro* solubility data indicates that Binimetinib's solubility is pH dependent. Currently, the impact of pH modifying agents (such as proton pump inhibitors) on the PK of Binimetinib is unknown. If a patient is prescribed a pH modifying agent, it is recommended that patients take the pH modifying agent at least two hours after Binimetinib administration. Binimetinib has been shown to be a substrate for P-gp and BCRP *in vitro*. The impact of P- gp/BCRP inhibitors on the PK of Binimetinib in vivo is unknown; therefore, it is recommended that P-gp and BCRP inhibitors are dosed with caution. Patients taking warfarin should be switched to low molecular weight heparin for the duration of the study. Other interactions may exist that are as yet unknown.
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10 drug management

10.1 **Drug supplies**
PF-02341066 will be provided as clinical stock by Pfizer. PF-02341066 is formulated as capsules containing 200 or 250 mg of study medication and packaged in HDPE bottles.  
PD-0325901 will be supplied as clinical stock by Pfizer. PD-0325901 is provided in 1 and 5 mg strength hard gelatin capsules (42 capsules per bottle). Both IMPs will be manufactured and QP released to the specifications of an existing IMPD (Investigational Medicinal Product Dossier) under strict GMP conditions.  
For both their IMPs, Pfizer provides these as bulk stock and repackaging, labelling, QP release and distribution to the local hospital pharmacies will be performed free of charge by Almac Clinical Services.  
Binimetinib will be provided as clinical stock by Array. Binimetinib is provided in 15mg strength tablets and packaged in HDPE bottles (70 tablets per bottle). Array provides this stock as bottled, labelled and QP
released to Almac Clinical Services who will then store and distribute the stock, free of charge, to the participating site local pharmacies. All supportive medication is to be sourced and funded locally. Drugs will be prescribed, tracked, and dispensed according to the local policy for investigator initiated studies.
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10.2 drug ordering

Initial supplies of PF-02341066 and PD-0325901 or Binimetinib are distributed by Almac Clinical Services after they have been informed by the Trials office that all approvals are in place. Re-supply of PF-02341066, PD-0325901 and Binimetinib will be managed by the Trials office. If any supplies of PF-02341066, PD0325901 or Binimetinib are damaged the pharmacist should contact the Trials office for replacement patient supplies.
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10.3 imp receipt

Upon receipt of each drug delivery, the site must complete and return the scanned enclosed acknowledgement of receipt by email within 24 hours.  
If supplies are damaged on arrival, please contact OCTO promptly.  
10.4 **Handling and storage**
The investigator or an approved representative (e.g. pharmacist) will ensure that all study drugs are stored in a secured area, under recommended storage conditions in accordance with applicable regulatory requirements
. PF-02341066 should be stored at room temperature (15°C - 30°C) and there are no specific restrictions.  
PD-0325901 capsules are stored at 15°C - 25°C and there are no specific restrictions. Binimetinib tablets are stored at 15°C - 25°C and there are no specific restrictions
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10.5 labelling

PF-02341066, PD-0325901 and Binimetinib will be supplied to participating sites appropriately labelled in accordance with all applicable regulatory requirements.  
10.6 **Dosing dispensing**
PF-02341066 is formulated as capsules containing 200 or 250 mg of study medication and packaged in HDPE bottles and will be provided as 60 capsules per bottle for the 200mg strength and 60 capsules per bottle for the 250mg strength. PD-0325901 is formulated as 1 and 5 mg strength hard gelatin capsules and will be supplied as 42 capsules per bottle. The number of bottles to be dispensed must be sufficient for the cycle of treatment. Patient specific details and the number of capsules to be taken per day must be added to the label prior to dispensing.  
Binimetinib drug product is supplied as film-coated tablets in a-dosage strength of 15 mg. The film coatedtablets consist of Binimetinib drug substance; colloidal silicon dioxide/silica colloidal anhydrous; croscarmellose sodium; lactose monohydrate; magnesium stearate; microcrystalline cellulose/cellulose, microcrystalline; and a commercial film coating. The tablets are yellow to dark yellow and capsule shaped. The number of bottles to be dispensed must be sufficient for the cycle of treatment. Patient specific details and the number of tablets to be taken per day must be added to the label prior to dispensing.
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10.7 drug accountability

Full drug accountability records must be maintained for PF-02341066, PD-0325901 and Binimetinib using the Drug Accountability Logs provided. Sites can use their own logs provided their use is approved in advance by the Trials office.  
The Drug Accountability Logs should be kept up to date and have to contain the following information; patient identifier, date and quantity received at site, date and quantity dispensed, date and quantity returned/destroyed at site.  
The Drug Accountability Logs must be available for inspection by the Sponsor or its representative at every monitoring visit.  
At the conclusion of the study the overall numbers of drug shipped to the centre, the number dispensed and the number destroyed or returned will be provided by the pharmacy. An account must be given of any discrepancy.
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10.8 drug returns from patients

Patients will be asked to return all bottles, whether empty or not, to the hospital. Unused PF-02341066, Binimetinib and PD-0325901 must be returned to pharmacy for counting and recording in the patient's Drug Accountability Log. Returns must be retained until permission to destroy is given by the trial office at the end of the study.  
| Sponsor, as per the following table: Expired drug   | At the end of the study, once authorised to do so by the  Sponsor, any unused drug should be destroyed by the site.  A signed & dated Drug Destruction form must be completed  scanned and emailed to OCTO.                                                                                                  |
|-----------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Drug left unused/not dispensed                      | At the end of the study, once authorised to do so by the  Sponsor, any unused drug should be destroyed by the site.  A signed & dated Drug Destruction form must be completed  scanned and emailed to OCTO.                                                                                                  |
| Patient returns                                     | Upon receipt, number of capsules returned to be recorded  on patient's Drug Accountability Log. At the end of the study, once authorised to do so by the  Sponsor, any unused drug should be destroyed by the site.  A signed & dated Drug Destruction form must be completed  and scanned and emailed OCTO. |
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10.10 occupational safety

The product is not expected to pose an occupational safety risk to site staff under normal conditions of use and administration.
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11 evaluation of response

11.1 **Measurement of disease for solid tumour**
Objective disease response must be measured according to the RECIST version 1.1 criteria given in Appendix 4. In the dose escalation and expansion phase, radiological tumour response with CT scan chest/abdomen/pelvis will be evaluated prior to study entry and then after 2nd, 4th, 6th cycle, and every 2 cycles thereafter, until intolerable toxicity or progressive disease.
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11.2 tumour assessment

A clinical and CT-graphic evaluation of malignancy, as judged appropriate by the Investigator, and in line with the protocol, must be performed before starting the study treatment. The same methods that detect lesions at baseline will be used to follow these lesions throughout the study. To ensure compatibility, the radiological assessments used to assess response must be performed using identical techniques.
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11.2.1 baseline evaluations

These will include radiological measurements of the extent of disease by CT chest/abdomen/pelvis or CT chest with MRI abdomen/pelvis). All areas of disease present must be mentioned (even if specific lesions are not going to be followed for response) and the measurements of all measurable lesions must be recorded on the scan reports. Any non-measurable lesions must be stated as being present. For clinical measurements, documentation by colour photography including a ruler to estimate the size of the lesion is recommended to aid external independent review of responses. All patients with at least one measurable lesion are included in the trial.
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11.2.2 evaluations during treatment and

Tumour assessment will be repeated as per the schedule of events given or more frequently if clinically indicated. All lesions measured at baseline must be measured at subsequent disease assessments, and recorded on the scan reports. All non-measurable lesions noted at baseline must be reported as present or absent. Investigators must ensure that their radiologists are aware of the requirement to follow up and measure every target lesion mentioned at baseline and comment on the non-target lesions in accordance with RECIST 1.1 criteria.
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11.3 tumour response

All patients included in the study must be assessed for response to treatment, even if there is a major protocol treatment deviation or if they are ineligible, or not followed/re-evaluated. Each patient will be assigned one of the following categories: complete response, partial response, stable disease, progressive disease, early death from malignant disease, early death from toxicity, early death from other cause or unknown (not assessable, insufficient data). Response duration will be measured from the time measurement criteria for CR/PR (whichever is first recorded) are first met until the first date that recurrent or progressive disease is objectively documented. Date of progression is defined as the first day when RECIST (version 1.1) PD is observed. Early death is defined as any death occurring before the first per protocol time point of tumour re-evaluation.  
The responsible investigator will decide if the cause of death is malignant disease, toxicity or other cause.  
Patients for whom response is not confirmed will be classified as "unknown", unless they meet the criteria for stable disease (or the criteria for partial response in case of an unconfirmed complete response). Patients' response will also be classified as "unknown" if insufficient data were collected to allow evaluation per these criteria.  
Should rapid tumour progression occur before the completion of 8 weeks treatment the patient will be classified as having early progression (EP).  
Tumour response should be classified as "not evaluable" (NE), only when it is not possible to classify it under another response category, e.g., when baseline and/or follow-up assessment is not performed or not performed appropriately.  
The applicable overall response category for each visit that includes disease assessment must be recorded in the medical record for inclusion in the appropriate CRF in OpenClinica.
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11.4 other definitions of outcome

Toxic death: Any death to which drug toxicity is thought to have a major contribution.  
Early death: Death during the first three weeks of treatment that is not a toxic death.
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12 assessment of safety

The Investigator will monitor each patient for clinical and laboratory evidence of adverse events on a routine basis throughout the study. Should an Investigator become aware of any study drug related SAEs following this period these must also be reported as stated below. Adverse event monitoring starts from the time the patient consents to the study until they complete the trial. All reportable AEs will be followed to a satisfactory conclusion. Any reportable AEs that are unresolved at the patient's last visit in the study are followed up by the Investigator for as long as medically indicated, but without further recording in the CRF.  
All AEs reported to the trial office will be processed according to internal SOPs. The trial office may request additional information for any AE as judged necessary.
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12.1 adverse event definitions

An Adverse Event or experience (AE) is any untoward medical occurrence in a study subject temporally associated with the administration of an investigational medicinal product (IMP) or a comparator product, whether or not considered related to the IMP or a comparator product. An AE can therefore be any unfavourable and unintended sign, symptom, disease (new or exacerbated) and /or significant abnormal laboratory or physiological observation temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e. lack of efficacy), abuse or misuse. This includes any newly occurring event, or a previous condition that has increased in severity or frequency since the administration of study drug. An abnormal laboratory value will not be reported as an AE unless that value leads to discontinuation or delay in treatment, dose modification, therapeutic intervention, or is considered by the investigator to be a clinically significant change from baseline. A **Serious Adverse Event (SAE)** is any AE, regardless of dose, causality or expectedness, that:  
| - Results in death                                                                      | This refers to an event in which the subject was at risk of death  at the time of the event. It does not refer to an event, which                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |                                                            |       |           |                                                            |
|-----------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------|-------|-----------|------------------------------------------------------------|
| - Is life-threatening                                                                   | hypothetically might have caused death, if it were more severe. In general, hospitalisation signifies that the subject has been  admitted (usually involving at least an overnight stay) at the  hospital or emergency ward for observation and/or treatment  that would not have been appropriate in the physician's office or  out-patient setting. Complications that occur during  hospitalisation are AEs. If a complication prolongs  hospitalisation or fulfils any other serious criteria, the event is  serious. When in doubt as to whether hospitalisation occurred  or was necessary, the AE should be considered serious. |                                                            |       |           |                                                            |
| - Requires in-patient  hospitalisation  or prolongs existing inpatient  hospitalisation | This means a substantial disruption of a person's ability to  conduct normal life functions. It does not include experiences of  relatively minor medical significance or accidental trauma (e.g.  sprained ankle), which does not constitute a substantial  disruption.                                                                                                                                                                                                                                                                                                                                                               |                                                            |       |           |                                                            |
| -                                                                                       | Is a congenital anomaly or  birth defect                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |                                                            |       |           |                                                            |
| -                                                                                       | Results in persistent or  significant incapacity or  disability                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | Defined as an event that may jeopardise the patient or may |       |           |                                                            |
| -                                                                                       | Is                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | any                                                        | other | medically | require intervention to prevent one of the outcomes listed |
| important event                                                                         | above. Any new primary cancer must be reported as an SAE.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |                                                            |       |           |                                                            |  
Clarification should be made between a serious AE (SAE) and an AE that is considered severe in intensity
(Grade 3 or 4), because the terms serious and severe are NOT synonymous. The general term severe is often used to describe the intensity (severity) of a specific event; the event itself, however, may be of relatively minor medical significance (such as a Grade 3 headache). This is NOT the same as serious, which is based on patient/event outcome or action criteria described above, and are usually associated with events that pose a threat to a patient's life or ability to function. The seriousness criteria in the table above should be used to determine if the event is serious.  
An Adverse Drug Reaction (ADR) is a response to a medicinal product which is noxious and unintended.  
Response in this context means that a causal relationship between a medicinal product and an adverse event is at least a reasonable possibility.  
An Unexpected Drug Reaction is an adverse drug reaction, the nature or severity of which, is not consistent with applicable reference safety information section (referring to SPC or IB).  
A Suspected Unexpected Serious Adverse Drug Reaction (SUSAR) is a serious adverse drug reaction, the nature or severity of which is not consistent with the applicable product information (e.g. Investigator's Brochure for an unapproved investigational product or SPC for an approved product).
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12.2 clinical laboratory abnormalities and

Abnormal laboratory findings (e.g., clinical chemistry, haematology, urinalysis) or other abnormal assessments (e.g., ECGs, X-rays and scans) that are judged by the investigator as clinically significant will be recorded as AEs or SAEs if they meet the definitions given above. The investigator will exercise his or her medical and scientific judgment in deciding whether an abnormal laboratory finding or other abnormal assessment is clinically significant.  
12.3 **Determining adverse event causality**
The Investigator will assess and classify the relationship of an AE to the trial IMP ((PF-02341066 (Crizotinib)
and PD-0325901 or PF-02341066 (Crizotinib) and Binimetinib)) as follows:  
| Classification                                   | Relationship                                            | Definition - Starts within                                                                                | a                                                       | time       | related   | to      | the   | study   | drug   |      |
|--------------------------------------------------|---------------------------------------------------------|-----------------------------------------------------------------------------------------------------------|---------------------------------------------------------|------------|-----------|---------|-------|---------|--------|------|
| Definitely related                               | administration and                                      |                                                                                                           |                                                         |            |           |         |       |         |        |      |
| -                                                | No obvious alternative medical explanation.             |                                                                                                           |                                                         |            |           |         |       |         |        |      |
| -                                                | Starts                                                  | within                                                                                                    | a                                                       | time       | related   | to      | the   | study   | drug   |      |
| administration and                               |                                                         |                                                                                                           |                                                         |            |           |         |       |         |        |      |
| Probably related                                 | -                                                       | Cannot                                                                                                    | be                                                      | reasonably | explained | by      | known |         |        |      |
| characteristics of the patient's clinical state. |                                                         |                                                                                                           |                                                         |            |           |         |       |         |        |      |
| drug-related                                     | -                                                       | Starts                                                                                                    | within                                                  | a          | time      | related | to    | the     | study  | drug |
| administration and                               |                                                         |                                                                                                           |                                                         |            |           |         |       |         |        |      |
| Possibly related                                 | -                                                       | A causal relationship between the study drug and the  adverse event is at least a reasonable possibility. |                                                         |            |           |         |       |         |        |      |
| -                                                | The time association or the patient's clinical state is |                                                                                                           |                                                         |            |           |         |       |         |        |      |
| Probably not                                     | such that the study drug is not likely to have had an   |                                                                                                           |                                                         |            |           |         |       |         |        |      |
| related                                          | association with the observed effect.                   |                                                                                                           |                                                         |            |           |         |       |         |        |      |
| not drug  related                                | Definitely not                                          | -                                                                                                         | The AE is definitely not associated with the study drug |            |           |         |       |         |        |      |
| related                                          | administered.                                           |                                                                                                           |                                                         |            |           |         |       |         |        |      |  
The Investigator must endeavour to obtain sufficient information to confirm the causality of the adverse event
(i.e. relation to surgery, study drug, background treatment, other illness, progressive malignancy etc) and give their opinion of the causal relationship between each AE and study drug. This may require instituting supplementary investigations of significant AEs based on their clinical judgement of the likely causative factors and/or include seeking a further specialist opinion.
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12.4 expected adverse events

Section 6.2 of the IB for PD-0325901 lists all the expected side effects associated with the use of PD0325901. Section 6.0 of the IB for MEK 162 (Binimetinib) lists all the expected side effects associated with the use of Binimetinib. Section 4.8 of the SmPC for PF-02341066 lists all the expected side effects associated with the use of PF-02341066. A copy of the current, approved version of RSI documents for each IMP must be held in the Site File for reference. Please note that the list of expected side effects for PF02341066 (Crizotinib) in the SmPC are those listed for advanced non-small cell lung carcinoma (NSCLC)
patients. It should also be noted that the side effects for Binimetinib in the SmPC are those listed for advanced unresectable or metastatic NRAS mutation-positive melanoma. It is therefore possible that in this study population other side effects may occur, or the patient might suffer a more severe reaction.
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12.5 suspected unexpected serious adverse

All SUSARs must be reported to the responsible Authority and main REC within very tight deadlines depending on the outcome, so it is imperative that sites report potential SUSARs to the trials office without delay. OCTO will report SUSARs according to their SOPs. In addition, other safety issues qualify for expedited reporting where they might materially alter the current risk assessment of an IMP or be sufficient to change IMP administration or the overall conduct of the trial. Responsibility for expedited safety reporting will be assigned by the Sponsor.  
OCTO must ensure that all SUSARs are reported to the competent authorities of the EU countries in which the trial is taking place
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12.6 expedited reporting of saes

The following SAE reporting requirements apply regardless of the Investigator's assessment of the causality of the SAE (See section 12.9 for exceptions). All SAEs should be reported on the trial SAE report form (see SAE report form and instructions for completion). Please note that the SAE report form is a paper form and these data cannot be entered into the eCRF system (OpenClinica). The SAE form must be completed, scanned and emailed to the Oxford MErCuRIC Pharmacovigilance Team at OCTO: octo-safety@oncology.ox.ac.uk :
SAE forms must be completed with all critical information as soon as possible and submitted within 24hrs of becoming aware of the event by scanning the report and sending as an attachment in email to:
octo-safety@oncology.ox.ac.uk.  
If the SAE has not been reported within the specified timeframe, a reason for lateness must be provided when sending the SAE Report Form.  
Investigators should also adhere to their local policy for incident and SAE reporting in research.  
Safety issues that qualify for expedited reporting where they might materially alter the current risk-benefit assessment of an IMP or be sufficient to change the IMP administration or the overall conduct of the trial. For instance:
- Single case reports of an expected serious adverse reaction with an unexpected outcome.  
- An increase in the rate of occurrence of an expected serious adverse reaction, which is judged to be clinically important.  
- Post study SUSARS that occur after the patient has completed a clinical trial and are reported by the investigator to OCTO.  
- New event relating to the conduct of the trial or the development of the IMP likely to affect the safety of the subjects.
OCTO will send all SAE reports to Pfizer (or designee) and Array Biopharma (or designee) within 24 hours of receipt as per any agreement.  
12.7 **Follow-up of Serious Adverse Events**
If new or amended information on a reported SAE becomes available, the Investigator should report this on a new SAE form or update the existing form, without obscuring any initial information. All new data must be initialled and dated so that all changes are clearly identified. . .  
Follow up will continue until all the necessary safety data for the event has been gathered. Any SAE that is ongoing when a subject completes his/her participation in the trial must be followed until any of the following occurs:
- The event resolves or stabilizes;
- The event returns to baseline condition or value (if a baseline value is available);
- The event is attributed to other agent(s) or to factors unrelated to study conduct.
AEs which are serious must be reported to OCTO from the first dose of PF-02341066 (Crizotinib) and PD-0325901 and up to and including 30 days after administration of the last dose of PF-02341066
(Crizotinib) and PD-0325901 or PF-02341066 (Crizotinib) and Binimetinib . Any SAE that occurs at any time after completion of PF-02341066 (Crizotinib) and PD-0325901 or PF-02341066 (Crizotinib) and Binimetinib treatment, or after the designated follow-up period that the investigator considers to be related to any study drug, must be reported.
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12.8 reporting adverse events on

All AEs, including Serious AEs, occurring during treatment and within 30 days after the last protocol treatment must be recorded on the case report forms (CRF) for that patient. The information provided will include date of onset, event diagnosis (if known) or sign/symptom, severity, time course, duration and outcome and relationship of the AE to study drug. Any concomitant medications or other any therapy used to treat the event must be listed. The Investigator will provide an "other" cause for serious AEs considered to be unrelated to the study drug. Sites should ensure data entered into the CRF is consistent with the SAE
report information where applicable. Each separate AE episode must be recorded. For example, if an AE resolves completely or resolves to baseline and then recurs or worsens again, this must be recorded as a separate AE. For AEs to be considered intermittent, the events must be of similar nature and severity.
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adverse events reporting requirements

Subjects having adverse events will be monitored with relevant clinical assessments and laboratory tests as determined by the Investigator. All adverse events must be followed to satisfactory resolution or stabilization of the event(s) including the investigation for the likely causative factor. Any actions taken and follow-up results must be recorded in the subject's source documentation. Follow-up laboratory results should be filed with the subject's source documentation. For all adverse events which require the subject to be discontinued from the study, relevant clinical assessments and laboratory tests will be repeated, on at least a weekly basis, until final resolution or stabilisation of the event(s).
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12.9 events exempt from being

Clinically significant abnormal laboratory findings or other abnormal assessments that are detected during the study or are present at baseline and significantly worsen following the start of the study will be reported as AEs or SAEs. However, clinically significant abnormal laboratory findings or other abnormal assessments that are associated with the disease being studied, unless judged by the investigator as more severe than expected for the patient's condition, or that are present or detected at the start of the study and do not worsen, should not be reported as AEs or SAEs
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progression of underlying disease

Disease progression and resultant death will be captured on the CRF. An event that is part of the natural course of the disease under study (i.e., disease progression or admission for standard treatment) should not be reported as an AE/SAE. However, if the progression of the underlying disease is greater than that which would normally be expected, or if the investigator considers that there may be a causal relationship between the IMP or protocol design/procedures and the disease progression, then it must be reported.  
Every effort should be made to document the objective progression of underlying malignancy. In some cases, the determination of clinical progression may be based on symptomatic deterioration. For example, progression may be evident from clinical symptoms, but is not supported by tumour measurements. Or, the disease progression is so evident that the investigator may elect not to perform further disease assessments.
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death on study

Death due to disease under study is to be recorded on the Death CRF form providing the death is not unexpected or if a causal relationship suspected. The investigator must clearly state whether the death was expected or unexpected and whether a causal relationship to the study IMP or other protocol treatment intervention is suspected. Elective admissions and supportive care Elective admissions to hospital for patient convenience or for planned procedures or investigations or treatment as specified in this protocol and standard supportive care are not SAEs, and do not require SAE
reporting. Hospital admission for the following supportive care procedures are considered standard for this patient group and should not be reported as SAEs:
- insertion of stent
- insertion of Port-A-Cath, PICC line etc.  
- admission for hydration - admission for transfusion
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12.10 development safety update reports

DSURs will be co-ordinated by OCTO and prepared in collaboration with the CI and submitted in parallel to the regulatory authority and responsible Research Ethics Committee within 60 days of the anniversary of the date of regulatory approval. A copy of each report will be provided to Pfizer, Array Biopharma and the sponsor.
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12.11 informing investigators of new

OCTO or the Chief Investigator will ensure that all investigators are kept informed in a timely manner, as new safety profile information becomes available. Investigators are responsible for briefing their study team and onward transmission to R&D office as appropriate.
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13 pregnancy and breast feeding

Pregnancies (in a participant or partner) occurring within 6 months of treatment dosing with PF-02341066, PD-0325901 or Binimetinib must be reported using the Pregnancy Notification Form which should be scanned and emailed to OCTO within 24 hours of receipt of information at octo-safety@oncology.ox.ac.uk.  
In the event that the pregnancy results in an abnormal outcome and meets the criteria for immediate classification as a serious adverse event, (i.e. spontaneous abortion, still birth, neonatal death or congenital anomaly), the investigator should follow the procedures for reporting serious adverse events. **Note:**
Pregnancy itself is only considered an AE/SAE if there is reason to believe it may be the result of an interaction between the study IMP and the contraceptive used.  
Women who become pregnant should be withdrawn from treatment at the earliest opportunity. All reported pregnancies should be followed up until the outcome. Pregnancy outcome must be recorded in the medical record and in the follow-up section of the Pregnancy Notification Form. Any abnormal outcome (other than elective abortion) for the mother or child should also be reported as a SAE. Pfizer should also be informed by OCTO of any pregnancy arising in a study participant or his/her partner whilst taking part in the trial or during a stage where the foetus could have been exposed to the medicinal product. Following inclusion of the Binimetinib into this trial, Array Biopharma should also be informed by OCTO of any pregnancy arising in a study participant or his/her partner whilst taking part in the trial or during a stage where the foetus could have been exposed to the medicinal product.
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14 defining the end of

For this study the end of the trial is defined as the last visit of the last patient undergoing the trial (LPLV).  
The study will be stopped when:
- The stated number of patients to be recruited is reached.  
AND
- All patients have discontinued treatment with either PD-0325901 in combination with PF-02341066 or Binimetinib in combination with PF-02341066.  
The sponsor, Chief Investigator in consultation with the trial committee, reserve the right to terminate the study earlier at any time. In terminating the study, they must ensure that adequate consideration is given to the protection of the participants' best interests.
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15 statistical considerations

| Table 1 Sample size calculation for dose expansion phase design RAS MT RAS WT/cMET amplified   | RAS WT/cMET overexpressed                                                    |                                                        |
|------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------|--------------------------------------------------------|
| Simon minimax: response then (conditionally)                                                   |                                                                              |                                                        |
| RCT: primary: PFS, secondary: OS                                                               | Simon optimal: response                                                      | Simon optimal: response                                |
|                                                                                                | p1=0.1                                                                       |                                                        |
|                                                                                                | p2=0.25                                                                      |                                                        |
| Power=80% Alpha=5%                                                                             | p1*=0.1 p2*=0.3                                                              |                                                        |
| Power=80% Alpha=5%                                                                             | p1*=0.1 p2*=0.3                                                              |                                                        |
| Power=80% Alpha=5%                                                                             |                                                                              |                                                        |
| Stage 1: If at least 2 responder in first  22 patients, then continue to stage 2               | Stage 1: If 2/10 responders,  then continue to Stage 2                       | Stage 1: If 2/10 responders,  then continue to Stage 2 |
| Stage 2: If at least 7 responders in 40  patients, then continue to phase II                   | Stage 2: If 6/29 responders,  then continue to collect  samples for MErCuRIC |                                                        |
| translational WPs and generate  evidence for future clinical trials  after MErCuRIC            |                                                                              |                                                        |
| 40 patients                                                                                    | 29 patients                                                                  | 29 patients                                            |
| Stage 2: If 6/29 responders,  then continue to collect  samples for MErCuRIC                   |                                                                              |                                                        |
| translational WPs and generate  evidence for future clinical trials  after MErCuRIC            |                                                                              |                                                        |
| MErCuRIC1_Protocol_V9.0_29Oct2018                                                              | Protocol Template V3.0_18Feb2013                                             |                                                        |
| Page 77 of 121                                                                                 |                                                                              |                                                        |
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15.1 sample size

Phase I dose escalation using PF-02341066 *in combination with PD-0325901* Between 2 and 24 patients will be recruited to this phase I dose escalation part of the trial in a rolling 6 design to establish an MTD as explained in earlier sections of the protocol. The dose escalation is agreed between the CI's at the recruiting centres based on the definitions in this protocol.
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phase i dose escalation using

Up to 25 patients will be recruited to this phase I dose escalation part of the trial in a rolling 6 design to establish an MTD as explained in earlier sections of the protocol. The dose escalation is agreed between the CI's at the four recruiting centres based on the definitions in this protocol.
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dose expansion

a) RASMT expansion phase statistical plan:
A Simon Minimax design was proposed for the RASMT patients, as these patients should be easier to recruit as they comprise 50% of the total CRC population and there is a shortage of competing therapeutic options. If 7/40 responders are observed in the RASMT group, we will continue to the randomised phase II trial (WP2).  
b) RAS WT/cMET amplified or mutated expansion phase statistical plan c) RAS WT/cMET overexpressed expansion phase statistical plan A Simon optimal design will be used for both the RASWT/cMET+ groups. This design will give a rapid indication if an effect is not observed, allowing a timely decision to stop that group continuing in the trial
(thereby involving fewer patient) or continue the trial (motivating further recruitment). RASWT/cMET patients are rare, hence recruitment to this group will be slower than RASMT. Due to the rarity of RASWT/cMET patients and delays in the project timelines due to replacement of PD-0325901 with Binimetinib with ,
consequential delays due to protocol amendment, ethics/regulatory approval, Binimetinib supply delay) and lengthy phase Ia dose escalation for Binimetinib/Crizotinib (higher than anticipated number of patients requiring replacement), inclusion of RASWT/cMET patients in the randomised phase II trial is not achievable. Nonetheless, this design will be the first study that aims to: (a) find these RASWT MET aberrant cases, and
(b) define the role of MET inhibition in these two separate MET-dependent groups.
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15.2 statistical analysis plan

A statistical analysis plan written adhering to the current OCTRU standard operating procedures will be signed off for this trial prior to analysis of primary or secondary aims. Inclusion in analysis Toxicity analysis will be on all patients who received at least some of at least one of the treatments in the combination.
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dose escalation for both combination

All evaluable patients will be analysed for dose escalation, which is those completing cycle 1 or who withdraw early for experiencing a DLT. The variables that define the DLTs and safety variables will be summarized by descriptive statistics with patients grouped according to dose level received. Number (with percentages) of patient with and without DLT will also be presented according to dose level.
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dose expansion

All patients recruited to the dose expansion phase will be analysed as intention to treat.  
This means that patients will be analysed as they are consented irrespective of the amount of treatment actually received. The intention-to-treat population will include all patients who have given their informed consent. It is therefore important that every effort is made to encourage patients, including those patients who do not receive/complete their allocated treatment, to attend for follow-up clinic visits and complete tests to avoid bias in the analysis of the results. Results will be given separately for the three genetic subgroups.
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subgroup analysis

No subgroup analyses are planned beyond those inherent in the dose expansion cohort.
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interim analyses

No interim analyses of primary or secondary endpoints are planned beyond those inherent in the rolling 6 design.  
Procedures for reporting any deviation(s) from the original statistical plan Sites must report any deviations/violations to OCTO according to the procedure outlined during site initiation.  
These will be noted in the statistical report.
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final analysis

All patients enrolled in the study, will be accounted for. The number of patients who were not evaluable, who died or withdrew before treatment began will be recorded. The distribution of follow-up time will be described and the number of patients lost to follow-up will be given. Follow-up for progression-free and overall survival will be performed.  
Variables will be analysed to determine whether the criteria for the study conduct are met. This will include a description of patients who did not meet all the eligibility criteria, an assessment of protocol violations, study drug accountability and other data that impact on the general conduct of the study.  
Baseline characteristics will be summarised for all evaluable patients. Treatment related toxicity will be tabulated by type and grade of toxicity for cycle 1 alone and all cycles. All trial treatment and efficacy information will be summarised.
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primary objectives

Dose Escalation The variables that define the DLTs and safety variables will be summarized by descriptive statistics with patients grouped according to dose level received. Number (with percentages) of patients with and without DLTs will also be presented according to dose level. Dose Expansion Safety and toxicity variables will be summarized by descriptive statistics within each genetically defined subgroup to investigate the safety and feasibility of expanded cohort patients at RPII dose.
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16 trial committees 16.1 trial

The Chief Investigator will chair a TMG with responsibility for overseeing the successful conduct and publication of the trial in accordance with the protocol. The TMG will review safety and dose escalations with advice from the Independent Early Phase Trial Oversight Committee (IEPTOC) (see section 16.2). It will provide regular progress reports as required by the applicable steering committees and governance bodies.  
Members of the TMG will include:
- Chief Investigator
- Trial management staff from OCTO
- Trial Statistician
- Principal Investigators from participating sites.
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16.2 data and safety monitoring

There is no Data and Safety Monitoring Committee. The IEPTOC will be in place to monitor the safety and progress of the trial.
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16.3 trial steering committee

The role of the Trial Steering Committee will be fulfilled by the IEPTOC.
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17 data management

17.1 **Database considerations**
Data management will be performed via a web-based, bespoke trial database (OpenClinica). OpenClinica is a dedicated and validated clinical trials database designed for electronic data capture. See: http://www.openclinica.org The Chief Investigator will act as Data Custodian for the trial. A guide explaining how to use OpenClinica will be provided to every site. Relevant OCTO staff will have overview of all entered data.  
17.2 Case report **forms (CRFs)**
The Investigator and study site staff will ensure that data collected on each subject is recorded in the CRFs within OpenClinica as accurately and completely as possible. The CRFs will not contain any source data. All appropriate laboratory data, summary reports and Investigator observations will be transcribed into the CRFs from the relevant medical record(s). Please ensure that:
- the relevant CRFs are completed.  
- all CRF data are verifiable in the source documentation or the discrepancies must be explained. - CRF sections are completed in a timely fashion, i.e. within 7-14 days of the study visit or reported event..  
- Data queries are resolved and documented by authorised study staff, giving a reason for the change or correction where appropriate.  
The above considerations also apply to patients who are withdrawn early. If a patient withdraws from the study, the reason must be noted on the appropriate form and the patient must be followed-up as per protocol.
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17.3 accounting for missing unused

Missing data found will be chased up and supplemented where possible after consultation with the investigator. The control of the correctness of the data is performed with ranking tests, validity tests and consistency checks. Unused data will be retained as for used data.
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18 clinical study report

All clinical data will be presented at the end of the study as data listings. These will be checked to confirm the lists accurately represents the data collected during the course of the study. The trial data will then be locked and a final data listing produced. The clinical study report will be based on the final data listings. The locked trial data may then be used for analysis and publication.
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19 study site management

19.1 **Study site responsibilities**
The Principal Investigator (the PI or lead clinician for the study site) has overall responsibility for conduct of the study, but may delegate responsibility where appropriate to suitably experienced and trained members of the study site team (e.g. drug supplies will be monitored by the on-site pharmacist, trial forms completed by the Data Manager, etc.). All members of the study site team must complete the delegation log or the Staff Contact Responsibility Sheet provided prior to undertaking any study duties. The PI must counter sign and date each entry in a timely manner, authorising staff to take on the delegated responsibilities. The Principal Investigator must ensure that all staff involved in the study are adequately trained and their duties have been logged on the forms provided. All Principal Investigators and Co-Investigators must have valid and up to date GCP training.  
For further information on trial responsibilities, please refer to the ICH GCP guideline (E6).
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19.2 study site set up

A Principal Investigator should lead the study at each site, providing the local study office with all core documentation and attend 'Site Training Call' organized by the trial office or visit before the site becomes activated (usually carried out as a telephone conference call or personal visit). The Trial Office will call to check that the site has all the required study information/documentation and is ready to recruit. The site will then be notified once they are activated on the MErCuRIC database and able to recruit.
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19.3 arrangements for sites outside

Within each country (except the UK) the lead site will co-ordinate the applications to the necessary competent authority and other bodies (e.g. ethics) in line with national regulations. Each participating centre will be responsible for obtaining any local approvals needed. Any changes to the protocol or other supporting documents must be agreed with the Sponsor. Agreements will be put in place with each site/country which includes an appropriate delegation of responsibilities which will include producing translations into local language(s) of all patient documents.  
19.4 **Study documentation**
OCTO will provide an Investigator File and Pharmacy File (where applicable) to each investigational site including: contact details, study procedures and all other documents required for completion of the study. Further copies of documents are available from OCTO as appropriate. The trial office must review and approve any local changes made to any study documentation including patient information and consent forms prior to use. Additional documentation generated during the course of the trial, including relevant communications must be retained in the site files as necessary to reconstruct the conduct of the trial. A screening log must be kept of all patients considered for the study and subsequently excluded; the reason for exclusion must be recorded on this form. A copy of the screening log without patient identifiers should be sent through to OCTO on a monthly basis, or as requested by OCTO. The original must be retained on site.
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20 regulatory and ethical considerations

The Sponsor and Investigators will ensure that this protocol will be conducted in compliance with the European Clinical Trials Regulations, the Principles of Good Clinical Practice (GCP)3 and the applicable policies of the sponsoring organisation. Together, these implement the ethical principles of the Declaration of Helsinki (1996) and the regulatory requirements for clinical trials of an investigational medicinal product under the European Union Clinical Trials Directive.  
20.1 **Ethical conduct of the trial and ethics approval**
The protocol, patient information sheet, consent form and any other information that will be presented to potential trial patients (e.g. advertisements or information that supports or supplements the informed consent) will be reviewed and approved by an appropriately constituted, independent Research Ethics Committee (REC) or equivalent for non-UK countries (IRB etc.). Principal Investigators will be approved by the relevant national and/or local body.
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20.2 regulatory authority approval

Approval to conduct the study will be obtained from the relevant Competent Authority in each participating country prior to initiating the study. In the UK the study will be conducted under a Medicines and Healthcare products Regulatory Agency (MHRA) Clinical Trial Authorisation (CTA).  
20.3 **Local Approvals**
Investigators are responsible for ensuring they obtain appropriate local approvals to conduct the trial in accordance with local arrangements and policies.  
20.4 **Protocol amendments**
Amendments are changes made to the research following initial approval. A 'substantial amendment' is an amendment to the terms of the Responsible Authority application (if applicable), the REC application, or to the protocol or any other supporting documentation, that is likely to affect to a significant degree:  
- the safety or physical or mental integrity of the subjects of the trial;
- the scientific value of the trial; - the conduct or management of the trial; or
- the quality or safety of the investigational medicinal product(s) used in the trial.
Non-substantial amendments are those where the change(s) involve only minor logistical or administrative aspects of the study.  
All amendments will be generated and managed according to the trial office standard operating procedures to ensure compliance with applicable regulation and other requirements. Written confirmation of all applicable REC, regulatory and local approvals must be in place prior to implementation by Investigators.  
The only exceptions are for changes necessary to eliminate an immediate hazard to study patients (see below). It is the Investigator's responsibility to update patients (or their authorised representatives, if applicable)
whenever new information (in nature or severity) becomes available that might affect the patient's willingness to continue in the trial. The Investigator must ensure this is documented in the patient's medical notes and the patient is re-consented if appropriate.
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20.5 urgent safety measures

The sponsor or Investigator may take appropriate urgent safety measures to protect trial participants from any immediate hazard to their health or safety. Urgent safety measures may be taken without prior authorisation. The trial may continue with the urgent safety measures in place. **The Investigator must** inform the Oxford MErCuRIC team **IMMEDIATELY if the study site initiates an urgent safety measure:**
Tel: +44 (0)1865 227194 Email: octo-MERCURIC@oncology.ox.ac.uk  
The notification must include:
- Date of the urgent safety measure;
- Who took the decision; and
- Why the action was taken.
The Investigator will provide any other information that may be required to enable the trial office to report and manage the urgent safety measure in accordance with the current regulatory and ethical requirements for expedited reporting and close out. The Trials office will follow written procedures to implement the changes accordingly.  
20.6 **Temporary halt**
The sponsor and Investigators reserve the right to place recruitment to this protocol on hold for short periods for administrative reasons or to declare a temporary halt. A temporary halt is defined as a formal decision to:
- interrupt the treatment of subjects already in the trial for safety reasons;
- stop recruitment on safety grounds; or - stop recruitment for any other reason(s) considered to meet the substantial amendment criteria, including possible impact on the feasibility of completing the trial in a timely manner.  
The trial office will report the temporary halt via an expedited substantial amendment procedure. The trial may not restart after a temporary halt until a further substantial amendment to re-open is in place. If it is decided not to restart the trial this will be reported as an early termination.  
20.7 **Serious Breaches**
The Medicines for Human Use (Clinical Trials) Regulations require the Sponsor to notify any "serious breaches" to the MHRA within 7 days of the sponsor becoming aware of the breach. A serious breach is defined as "A breach of GCP or the trial protocol which is likely to effect to a significant degree:
- the safety or physical or mental integrity of the subjects of the trial; or
- the scientific value of the trial" Investigators must notify the trials office at once if any serious breach of GCP is suspected.
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20.8 reports progress safety and

This protocol will comply with all current applicable Regulatory Authority, Research Ethics Committee and Sponsor requirements for the provision of periodic study safety and progress reports. Any additional reports will be provided on request. Reporting will be managed by the trials office according to internal SOPs. Sites will be urged to return as much data as possible before each database lock point.  
The trial office will determine which reports need to be circulated Principal Investigators and other interested parties according to internal SOPs. Study sites are responsible for forwarding trial reports they receive to their local Institutions as required.
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21 expenses and benefits

Each participating centre will follow local regulations and policy on reimbursement of travel expenses.
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22 quality assurance 22.1 risk

The study will undergo a risk assessment prior to study start to determine the extent and nature of site monitoring. Risk assessments will be performed throughout the duration of the study on an ad hoc need basis and in line with any substantial amendments and any significant findings that might change the risk/benefit balance of the study. Monitoring plans will be amended accordingly. Monitoring (on-site and central) will be performed according to the plan and trial office SOPs.
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on-site monitoring

Data will be evaluated for compliance with the protocol and accuracy in relation to source documents.  
Monitoring visits reports will be sent to the site in a timely fashion.
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central monitoring

Study sites will be monitored centrally by both programmed validation within the data collection database and manual checking of incoming data for compliance with the protocol, data consistency, missing data and timing. All changes to data that could influence the outcome will be queried with and approved by the study site in a timely manner. For all other data, where there is no doubt about the source of any errors, clear changes to data will be made internally by OCTO staff without referring back to the study site. Study staff will be in regular contact with site personnel to check on progress and deal with any queries that they may have including those arising from queries raised by OCTO.
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22.2 audit and regulatory inspection

All aspects of the study conduct may be subject to internal or external quality assurance audit to ensure compliance with the protocol, GCP requirements and other applicable regulation or standards. It may also be subject to a regulatory inspection. Such audits or inspections may occur at any time during or after the completion of the study. Investigators and their host Institution(s) should understand that it is necessary to allow auditors/inspectors direct access to all relevant documents, study facilities and to allocate their time and the time of their staff to facilitate the audit or inspection visit. Anyone receiving notification of a Regulatory Inspection that will (or is likely to) involve this trial must inform the trial office without delay.
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23 records retention & archiving

During the clinical trial and after trial closure the Investigator must maintain adequate and accurate records to enable the conduct of a clinical trial and the quality of the research data to be evaluated and verified. These essential documents, detailed in the trial office SOP must be stored in such a way that ensures that they are readily available, upon request, to the sponsor or the Regulatory Agency, for the minimum period required by national legislation or for longer if needed. The medical files of trial subjects shall be retained in accordance with national legislation and in accordance with the host institution policy. It is the University of Oxford's policy to store research data for a minimum of 5 years. Retention and storage of laboratory records for clinical trial samples will follow national guidelines.  
Retention and storage of central laboratory records supporting PK or PD endpoints and the disposition of samples donated via the trial must also comply with applicable legislation and Sponsor requirements.  
It is the University of Oxford's policy to store data for a minimum of 5 years. Investigators may not archive or destroy study essential documents or samples without written instruction from the trial office.
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24 patient confidentiality

Personal data recorded on all documents will be regarded as confidential, and to preserve each patient's anonymity, only their patient study number, initials and date of birth (or other identified as appropriate to country regulations and agreed with the Sponsor) will be recorded on the CRFs.  
The Investigator site must maintain the patient's anonymity in all communications and reports related to the research. The Investigator site team must keep a separate log of enrolled patients' personal identification details as necessary to enable them to be tracked. These documents must be retained securely, in strict confidence. They form part of the Investigator Site File and are not to be released externally.
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25 study funding

This trial is being organised by the Oncology Clinical Trials Office (OCTO) at the University of Oxford and is being funded by the European Commission. The trial is part of the NIHR portfolio, and any additional NHS clinical service support costs of patient care while on study should be met by the host study site.
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26 sponsorship and indemnity

26.1 **Sponsorship**
The Sponsor will provide written confirmation of Sponsorship and authorise the trial commencement once satisfied that all arrangements and approvals for the proper conduct of the trial are in place. A separate study delegation agreement, setting out the responsibilities of the Chief Investigator and Sponsor will be put in place between the parties.
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26.2 insurance

The University has a specialist insurance policy in place: - Newline Underwriting Management Ltd, at Lloyd's of London - which would operate in the event of any participant suffering harm as a result of their involvement in the research.
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26.3 contracts/agreements

This trial is subject to the Sponsor's policy requiring that written contracts/agreements are agreed formally by the participating bodies as appropriate. A Clinical Trial Agreement (CTA) will be placed between the Sponsor and participating sites prior to site activation. The Sponsor will also set up written agreements with any other external third parties involved in the conduct of the trial as appropriate.
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27 publication policy

Ownership and publication policy will be as per the MErCuRIC consortium agreement.  
Authors shall acknowledge that the study was sponsored by the University of Oxford and funded by the MErCuRIC EU 7th Framework Programme (Grant agreement number 602901-2).
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appendix 1 ecog performance scale

| Activity Performance Description                                                                                                                     | Score   |
|------------------------------------------------------------------------------------------------------------------------------------------------------|---------|
| Fully active, able to carry out all on all pre-disease performance without restriction.                                                              | 0       |
| Restricted in physically strenuous activity but ambulatory and able to carry out work of a light                                                     | 1       |
| or sedentary nature, e.g. light housework, office work. Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and | 2       |
| about more than 50% of waking hours.  Capable of only limited self-care. Confined to bed or chair more than 50% of waking hours.                     | 3       |
| Completely disabled. Cannot carry out any self-care. Totally confined to bed or chair.                                                               | 4       |
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appendix 2 cockcroft and gault

The estimated GFR is given by:
Males: 1.25 x (140 - age) x weight (kg)
serum creatinine (μmol/l)
Females: 1.05 x (140 - age) x weight (kg)
serum creatinine (μmol/l)
- This formula usually under-estimates GFR by 10-30% compared with EDTA or measured 24-hour creatinine clearance, so is used in this trial as a screening test.  
•
- A Cockcroft and Gault estimate of ≥50 ml/min is accepted as evidence of adequate renal function.  
•
- Patients with a Cockcroft and Gault estimate of <50 ml/min prior to randomisation should have formal GFR measurement with EDTA or 24 urinary creatinine, which must be within the normal range. The corrected EDTA clearance should be ≥50ml/min.  
•
- After the start of treatment, if the Cockcroft and Gault estimate falls by >25% from baseline or to below 50 ml/min, the EDTA measurement or 24 hour urinary creatinine should be re-checked.
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appendix 3 nci-ctcae v4.0 criteria

| Toxicity                         | 1                                               | 2                                                                            | 3                                                                          | 4                        |
|----------------------------------|-------------------------------------------------|------------------------------------------------------------------------------|----------------------------------------------------------------------------|--------------------------|
| Grade Neurological Neuro-sensory | mild paresthesias, loss of deep tendon reflexes | mild or moderate objective sensory loss; moderate paresthesias               | severe objective sensory loss or paresthesias that interfere with function | -                        |
| Neuro-motor                      | subjective  weakness; no objective findings     | mild objective weakness without significant impairment of function           | objective weakness with impairment of function                             | paralysis                |
| Neuro-cortical                   | mild somnolence or                              | moderate                                                                     |                                                                            |                          |
| agitation                        | somnolence or agitation                         | severe  somnolence, agitation,  confusion, disorientation, or hallucinations | coma, seizures,  toxic psychosis                                           |                          |
| Neuro-cerebellar                 | slight incoordination, dysdiadochokinesia       | intention tremor, dysmetria, slurred speech, nystagmus                       | locomotor ataxia                                                           | cerebellar necrosis      |
| Neuro-mood                       | mild anxiety or                                 | moderate anxiety                                                             |                                                                            |                          |
| depression                       | or depression                                   | severe anxiety or                                                            | suicidal ideation                                                          |                          |
| depression                       |                                                 |                                                                              |                                                                            |                          |
| Neuro --                         | mild                                            | moderate or severe                                                           | unrelenting and                                                            | -                        |
| headache                         | but transient                                   | severe                                                                       |                                                                            |                          |
| Neuroconstipation                                  | mild                                            | moderate                                                                     | severe                                                                     | ileus >96 hrs            |
| Neuro-hearing                    | asymptomatic, hearing loss on audiometry only   | tinnitus                                                                     | hearing loss interfering with function but correctable with hearing aid    | deafness not correctable |
| Neuro-vision                     | -                                               | -                                                                            | symptomatic subtotal loss of vision                                        | blindness                |
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appendix 4 measurement of disease

Objective tumour response and time of progression will be measured according to the RECIST (Response Evaluation Criteria In Solid Tumours) criteria (version 1.1). Response criteria are essentially based on a set of measurable lesions identified at baseline as target lesions, and - together with other lesions that are denoted as non-target lesions - followed until disease progression. The following paragraphs are a quick reference to the RECIST criteria (version 1.1). The complete criteria are included in the published RECIST document:
Eisenhauer, EA, Therasse, P, Bogaerts, J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-247 Up to date details are available at: http://www.eortc.be/RECIST
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appendix 5 medications to be

NB. This list is not exhaustive and the absence of a drug from the list does not imply that its combination with PF-02341066 is safe. Please contact the Trials office if further clarification is required.  
DRUGS AFFECTING CYTOCHROME P450 Potent inhibitors of CYP3A4/5: may increase exposure to PF-02341066 **by more than 3-fold**
The following drugs should not be combined with PF-02341066. Recommended withdrawal periods for patients who have recently received treatment with these agents are indicated in the table. For example, it is recommended that patients should not have received clarithromycin for at least 7 days before treatment with PF-02341066 is started.  
| Contra-indicated Drug                                                          | Inhibits   | Minimum washout period prior  to PF-02341066 administration   |
|--------------------------------------------------------------------------------|------------|---------------------------------------------------------------|
| Ketoconazole, Ritonavir, Atazanavir, Saquinavir,                               | CYP3A4/5   | 2 days                                                        |
| Indinavir, Nefazodone, Nelfinavir Itraconazole, Clarithromycin, Erythromycin*, | CYP3A4/5   | 7 days                                                        |
| Fluconazole>400 mg Diltiazem                                                   | CYP3A4/5   | 2 Weeks                                                       |
| * Topical use of erythromycin is permitted during treatment with PF-02341066   |            |                                                               |  
Moderate Inhibitors of CYP3A4/5: may increase exposure to PF-02341066 Caution should be exercised in combining the following drugs with PF-02341066.  
| Warning of possible interaction Drug Inhibits Verapamil CYP3A4    | These drugs are permitted but caution should be  exercised and patients monitored closely for possible drug  interactions.   |                                                                                                                                                                                                                                                                                                                                                     |
|-------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Grapefruit juice                                                  | CYP3A4                                                                                                                       | Patients should abstain from eating large amounts of  grapefruit and Seville oranges (and other products  containing these fruits, e.g. grapefruit juice or marmalade)  during the study. Please do not have more than a small  glass of grapefruit juice (120 mL) or half a grapefruit or 1-2  teaspoons (15 g) of Seville orange marmalade daily. |
| Seville oranges (and other  products containing Seville  oranges) | CYP3A4                                                                                                                       |                                                                                                                                                                                                                                                                                                                                                     |  
Potent Inducers of CYP3A4/5: may reduce exposure to PF-02341066 **by more than 3-fold** The following drugs should not be combined with PF-02341066. Recommended withdrawal periods for patients who have recently received treatment with these agents are indicated in the table. For example; it is recommended that patients should not have received carbamazepine for at least 2 weeks before treatment with PF-02341066 is started  
| Contra-indicated Drug                  | Minimum washout period prior to  PF-02341066 administration   |
|----------------------------------------|---------------------------------------------------------------|
| Barbiturates,Carbamazepine, Phenytoin, | 2 Weeks                                                       |
| Rifampicin, Rifabutin, St John's Wort  |                                                               |  
Substrates **of CYP3A4/5: PF-02341066 may increase exposure** The following drugs should not be given with PF-02341066  
| Contra-indicated Drug Dihydroergotamine, Ergotamine Pimozide, Astemizole, Cisapride Terfenadine   | CYP3A4/5 substrates with narrow therapeutic  indices associated with life-threatening  arrhythmias, and must be avoided during  PF-02341066 administration   |
|---------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------|  
The following drugs may be given with PF-02341066, but caution is advised  
| Contra-indicated Drug Alfentanil, Cyclosporin,  Fentanyl, Quinidine,  Sirolimus, Tacrolimus   | CYP3A4/5 substrates with narrow therapeutic  indices, caution must be exercised   |
|-----------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------|  
The following bradycardic agents (e.g. beta-blockers, non-dihydropyridine calcium channel blockers) should not be given with PF-02314066  
| Contra-indicated Drug Verapamil, Diltiazem Clonidine, Digoxin   | Increased risk of symptomatic bradycardia   |
|-----------------------------------------------------------------|---------------------------------------------|
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drugs that may prolong qt

The drugs listed in this section are taken from information provided by The Arizona Center for Education and Research on Therapeutics and The Critical Path Institute, Tucson, Arizona and Rockville, Maryland. http://www.arizonacert.org/medical-pros/drug-lists/drug-lists.htm The following drugs are known to prolong QT interval or induce Torsades de Pointes and should not be combined with PF-02341066. Recommended withdrawal periods for patients who have recently received treatment with these agents are indicated in the following table.  
| Contraindicated drug                                                                                                        | Withdrawal period                                                            |
|-----------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------|
| Droperidol, Procainamide                                                                                                    | 2 days                                                                       |
| Cisapride Clarithromycin, Disopyramide, Dofetilide, Domperidone, Erythromycin**,                                            | 7 days                                                                       |
| Ibutilide, Quinidine, Sotalol, Sparfloxacin, Thioridazine Bepridil, Chlorpromazine, Halofantrine, Haloperidol, Mesoridazine | 14 days                                                                      |
| Levomethadyl, Methadone, Pimozide                                                                                           | 4 weeks                                                                      |
| Arsenic trioxide                                                                                                            | 6 weeks*                                                                     |
| Pentamidine                                                                                                                 | 8 weeks                                                                      |
| Amiodarone, Chloroquine                                                                                                     | 1 year                                                                       |
| *                                                                                                                           | Estimated value as pharmacokinetics of arsenic trioxide has not been studied |
| **                                                                                                                          | Topical use of erythromycin is permitted during treatment with PF-02341066   |
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binimetinib (mek162) dose modifications

Patients will be monitored for adverse events at each visit with the NCI CTCAE version 4.03 used for all grading. Doses of MEK162 should be adjusted for AEs throughout the study. In general, doses should not be reduced or interrupted for Grade 1 AEs unless the AE is a specific treatmentrelated ocular AE. Treatment to control symptoms should be provided as appropriate. All dose modifications should be based on the worst preceding toxicity (CTCAE version 4.03).  
An individual patient may have their dose of MEK162 reduced to the dose levels specified in Table 6. When the AE that resulted in a dose reduction improves to and remains stable at the patient's Baseline for a minimum of 14 days, the dose can be re-escalated to the next dose level at the discretion of the Investigator, provided there are no other concomitant MEK162-related toxicities that would prevent drug re-escalation. There is no limit to the number of times the patient can have their dose reduced or re escalated (in 15 mg increments); however, no dose re escalation is allowed after a dose reduction due to LVEF dysfunction or prolonged QTcF ≥ 501 msec. A dose reduction below 30 mg BID is not allowed (Table 6). Patients requiring additional reductions must be discontinued from study treatment. Dose interruptions of more than 21 days are not allowed.  
| Table 1CTCAE grading for eye disorders Grade Description 1 Asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not  indicated 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age appropriate  instrumental ADL 3 Severe or medically significant but not immediately sight threatening; Hospitalization or prolongation of existing hospitalization indicated; disabling; limiting selfcare ADL 4 Sight-threatening consequences; urgent intervention indicated; blindness (20/200 or worse)  in the affected eye ADL= activities of daily living   |
|---|  
Eye disorders should be graded according to CTCAE version 4.03 as described below in Table 1.  
| Table 2                                                                                | CTCAE grading for retinal detachment                                                                                                    |
|----------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------|
| Grade                                                                                  | Description                                                                                                                             |
| 1                                                                                      | Asymptomatic                                                                                                                            |
| 2                                                                                      | Exudative and visual acuity 20/40* or better                                                                                            |
| 3                                                                                      | Rhegmatogenous or exudative detachment; operative intervention indicated; decline in  vision (worse than 20/40*but better than 20/200*) |
| 4                                                                                      | Blindness (20/200* or worse) in the affected eye                                                                                        |
| * Please refer to Appendix 7 for Snellen Equivalence (Visual Acuity Conversion Chart). |                                                                                                                                         |  
Retinal detachment should be graded according to the CTCAE version 4.03 as described below in Table 2.  
Uveitis should be graded according to the CTCAE version 4.03 as described below in Table 3.  
Table 3 CTCAE grading for uveitis Grade **Description**
1 Asymptomatic; clinical or diagnostic observations only 2 Anterior uveitis; medical intervention indicated 3 Posterior or pan-uveitis 4 Blindness (20/200* or worse) in the affected eye
* Please refer to Snellen Equivalence (Visual Acuity Conversion Chart).  
Hand Foot Skin Reaction should be graded according to CTCAE version 4.03 as described below in Table 4.  
Table 4 **CTCAE grading of Hand foot skin reaction (HFSR)a**  
| Grade                          | Descriptionb                                                                                                                             |
|--------------------------------|------------------------------------------------------------------------------------------------------------------------------------------|
| 1                              | Minimal skin changes or dermatitis (e.g., erythema, edema, numbness, dysesthesia,  paresthesia, tingling or hyperkeratosis) without pain |
| 2                              | Skin changes (e.g.,peeling, blisters, bleeding, edema, or hyperkeratosis) with pain; limiting  instrumental ADL                          |
| 3                              | Severe skin changes (e.g., peeling, ulceration, blisters, bleeding, edema, or  hyperkeratosis) with pain; limiting self-care ADL         |
| ADL=activities of daily living |                                                                                                                                          |  
1 Minimal skin changes or dermatitis (e.g., erythema, edema, numbness, dysesthesia,  
paresthesia, tingling or hyperkeratosis) without pain  
2 Skin changes (e.g.,peeling, blisters, bleeding, edema, or hyperkeratosis) with pain; limiting  
instrumental ADL  
3 Severe skin changes (e.g., peeling, ulceration, blisters, bleeding, edema, or  
hyperkeratosis) with pain; limiting self-care ADL  
ADL=activities of daily living  
aHFSR or palmar-plantar erythrodysaesthesia syndrome, a disorder characterized by redness, marked  
discomfort, swelling, and tingling in the palms of the hands or the soles of the feet; bMore specifics examples to grade 1 and grade 3 are added to facilitate proper grading [from the sorafenib  
package insert (West Haven, CT: Bayer Pharmaceuticals Corporation; 2007); Porta et al 2007].  
Diarrhea should be graded according to CTCAE version 4.03 as described below in Table 5.  
Table 5 CTCAE grading of diarrhea  
Grade **Description** 1 Increase of < 4 stools per day over baseline; mild increase in ostomy output compared to  
baseline  
2 Increase of 4-6 stools per day over baseline; moderate increase in ostomy output  
compared to baseline  
1-2  
Complicated  
Definition as above with the following complicating signs/symptoms:  
- Moderate to severe cramping  
- Grade ≥ 2 nausea/vomiting  
- Decreased performance status - Fever - Sepsis - Neutropenia - Frank bleeding - Dehydration  
- Unresolved diarrhea after 48 hours of treatment with loperamide (including high dose  
administration) and initiation of second-line treatment  
3 Increase of ≥ 7 stools per day over baseline; hospitalization indicated; severe increase in  
ostomy output compared to baseline; limiting self-care ADL  
4 Life threatening consequences; urgent intervention indicated ADL=activities of daily living  
Dose modification and dose delay for MEK162
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table 6 dose reduction for

| 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), interrupt binimetinib until  resolved to Grade ≤ 1 and monitor closely, then: o If resolved in ≤ 21 days, reduce 1 dose leveld of binimetinib o If not resolved in ≤ 21 days, permanently discontinue  binimetinib  Grade 4 - If asymptomatic, interrupt binimetinib until resolved to Grade ≤ 1  and monitor closely, then: o If resolved in ≤ 21 days, reduce 1 dose leveld of binimetinib o If not resolved in ≤ 21 days, permanently discontinue  binimetinib - If symptomatic, permanently discontinue binimetinib |                                   |  
| 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 6a updated recommended dose

Guidelines - *Binimetinib (MEK162)*
Recommended Dose Modifications Version 2 11 November 2015 - *updated to guidelines Mar 2017*
untitled h1
binimetinib (mek162) dose modifications

Patients will be monitored for adverse events at each visit with the NCI CTCAE version 4.03 used for all grading. Doses of MEK162 should be adjusted for AEs throughout the study. In general, doses should not be reduced or interrupted for Grade 1 AEs unless the AE is a specific treatmentrelated ocular AE. Treatment to control symptoms should be provided as appropriate. All dose modifications should be based on the worst preceding toxicity (CTCAE version 4.03). An individual patient may have their dose of MEK162 reduced to the dose levels specified in Table 6. When the AE that resulted in a dose reduction improves to and remains stable at the patient's Baseline for a minimum of 14 days, the dose can be re-escalated to the next dose level at the discretion of the Investigator, provided there are no other concomitant MEK162-related toxicities that would prevent drug re-escalation. There is no limit to the number of times the patient can have their dose reduced or re escalated (in 15 mg increments); however, no dose re escalation is allowed after a dose reduction due to LVEF dysfunction or prolonged QTcF ≥ 501 msec. A dose reduction below 30 mg BID is not allowed (Table 6). Patients requiring additional reductions must be discontinued from study treatment. Dose interruptions of more than 21 days are not allowed.  
| Table 1                         | CTCAE grading for eye disorders                                                                                 |
|---------------------------------|-----------------------------------------------------------------------------------------------------------------|
| Grade                           | Description                                                                                                     |
| 1                               | Asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not  indicated            |
| 2                               | Moderate; minimal, local or noninvasive intervention indicated; limiting age appropriate  instrumental ADL      |
| 3                               | Severe or medically significant but not immediately sight threatening; Hospitalization or prolongation of existing hospitalization indicated; disabling; limiting selfcare ADL                                                                                                                 |
| 4                               | Sight-threatening consequences; urgent intervention indicated; blindness (20/200 or worse)  in the affected eye |
| ADL= activities of daily living |                                                                                                                 |  
Eye disorders should be graded according to CTCAE version 4.03 as described below in Table 1.  
Retinal detachment should be graded according to the CTCAE version 4.03 as described below in Table 2.  
| Table 2                           | CTCAE grading for retinal detachment                                                                                                    |
|-----------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------|
| Grade                             | Description                                                                                                                             |
| 1                                 | Asymptomatic                                                                                                                            |
| 2                                 | Exudative and visual acuity 20/40* or better                                                                                            |
| 3                                 | Rhegmatogenous or exudative detachment; operative intervention indicated; decline in  vision (worse than 20/40*but better than 20/200*) |
| MErCuRIC1_Protocol_V9.0_29Oct2018 | Protocol Template V3.0_18Feb2013                                                                                                        |  
| Grade                                                                                  | Description                                      |
|----------------------------------------------------------------------------------------|--------------------------------------------------|
| 4                                                                                      | Blindness (20/200* or worse) in the affected eye |
| * Please refer to Appendix 7 for Snellen Equivalence (Visual Acuity Conversion Chart). |                                                  |  
Uveitis should be graded according to the CTCAE version 4.03 as described below in Table 3. Table 3 CTCAE grading for uveitis  
Grade **Description**  
| 5   | Asymptomatic; clinical or diagnostic observations only   |
|-----|----------------------------------------------------------|
| 6   | Anterior uveitis; medical intervention indicated         |
| 8   | Blindness (20/200* or worse) in the affected eye         |  
7 Posterior or pan-uveitis  
* Please refer to Snellen Equivalence (Visual Acuity Conversion Chart).  
Hand Foot Skin Reaction should be graded according to CTCAE version 4.03 as described below in Table 4.  
Table 4 **CTCAE grading of Hand foot skin reaction (HFSR)a**  
Grade **Descriptionb**  
1 Minimal skin changes or dermatitis (e.g., erythema, edema, numbness, dysesthesia,  
paresthesia, tingling or hyperkeratosis) without pain  
2 Skin changes (e.g.,peeling, blisters, bleeding, edema, or hyperkeratosis) with pain; limiting  
instrumental ADL  
3 Severe skin changes (e.g., peeling, ulceration, blisters, bleeding, edema, or  
hyperkeratosis) with pain; limiting self-care ADL  
ADL=activities of daily living  
aHFSR or palmar-plantar erythrodysaesthesia syndrome, a disorder characterized by redness, marked  
discomfort, swelling, and tingling in the palms of the hands or the soles of the feet;  
bMore specifics examples to grade 1 and grade 3 are added to facilitate proper grading [from the sorafenib  
package insert (West Haven, CT: Bayer Pharmaceuticals Corporation; 2007); Porta et al 2007].  
Diarrhea should be graded according to CTCAE version 4.03 as described below in Table 5.  
Table 5 CTCAE grading of diarrhea  
Grade **Description**  
1 Increase of < 4 stools per day over baseline; mild increase in ostomy output compared to  
baseline  
2 Increase of 4-6 stools per day over baseline; moderate increase in ostomy output  
compared to baseline  
1-2 Complicated  
Definition as above with the following complicating signs/symptoms:  
- Moderate to severe cramping  
- Grade ≥ 2 nausea/vomiting  
- Decreased performance status - Fever - Sepsis - Neutropenia - Frank bleeding - Dehydration  
- Unresolved diarrhea after 48 hours of treatment with loperamide (including high dose  
administration) and initiation of second-line treatment  
| Grade                          | Description                                                                                                                                             |
|--------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------|
| 3                              | Increase of ≥ 7 stools per day over baseline; hospitalization indicated; severe increase in  ostomy output compared to baseline; limiting self-care ADL |
| 4                              | Life threatening consequences; urgent intervention indicated                                                                                            |
| ADL=activities of daily living |                                                                                                                                                         |