Conditions: Advanced Solid Tumors Metastatic Melanoma
Keywords: solid tumor melanoma
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 56
Healthy volunteers: no

Brief summary:
This is an open-label, 3-arm, fixed-sequence study to evaluate the effect of single and multiple oral doses of encorafenib in combination with binimetinib on the single oral dose pharmacokinetics (PK) of cytochrome P450 (CYP) enzyme probe substrates using a probe cocktail, on an organic anion-transporting polypeptide/breast cancer resistance protein (OATP/BCRP) substrate using rosuvastatin and on a CYP2B6 substrate using bupropion. The effect of multiple oral doses of the moderate cytochrome P450 (CYP) inhibitor modafinil on encorafenib in combination with binimetinib will also be assessed. The study will have 2 treatment phases, a drug-drug interaction (DDI) phase followed by a post-DDI phase.

Detailed description:

Arms:
arm 1: Patients will receive a single oral dose of the CYP Probe Cocktail on Day -7, Day 1, and Day 14:

* 25 mg losartan oral tablet
* 30 mg dextromethorphan oral capsule
* 50 mg caffeine oral liquid
* 20 mg omeprazole oral capsule
* 2 mg midazolam oral syrup

encorafenib/binimetinib continuous daily dosing starting Day 1:

* 450 mg (6 x 75 mg) encorafenib oral capsules once daily (QD)
* 45 mg (3 x 15 mg) binimetinib oral tablet twice daily (BID)

All drugs will be taken within 10 minutes. arm 2: Patients will receive a single oral dose of rosuvastatin and bupropion once on Day -7, Day 1 and Day 14:

* 10 mg rosuvastatin oral tablet
* 75 mg bupropion immediate release (IR) oral tablet

encorafenib/binimetinib continuous daily dosing starting Day 1:

* 450 mg (6 x 75 mg) encorafenib oral capsules once daily (QD)
* 45 mg (3 x 15 mg) binimetinib oral tablet twice daily (BID)

All drugs will be taken within 10 minutes. arm 3: Patients will begin encorafenib/binimetinib continuous daily dosing starting Day 1:

* 450 mg (6 x 75 mg) encorafenib oral capsules once daily (QD)
* 45 mg (3 x 15 mg) binimetinib oral tablet twice daily (BID)

then receive continuous treatment of modafinil on Day 15 through Day 21:

\- 400 mg modafinil tablet once daily (QD)

Interventions: intervention 1: losartan intervention 2: dextromethorphan intervention 3: caffeine intervention 4: omeprazole intervention 5: midazolam intervention 6: rosuvastatin intervention 7: bupropion immediate release (IR) intervention 8: encorafenib intervention 9: binimetinib intervention 10: modafinil
Intervention descriptions: intervention 1: taken orally intervention 2: taken orally intervention 3: taken orally intervention 4: taken orally intervention 5: taken orally intervention 6: taken orally intervention 7: taken orally intervention 8: taken orally intervention 9: taken orally intervention 10: taken orally

Protocol document:
Prot_000.pdf: 
Encorafenib/Binimetinib (BRAF/MEK inhibitors)
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Clinical Study ARRAY-818-103; C4221003
An Open-label Phase 1 Study to Evaluate Drug-Drug Interactions of Agents Co-
Administered with Encorafenib and Binimetinib in Patients with BRAF V600-mutant 
Unresectable or Metastatic Melanoma or Other Advanced Solid Tumors
Protocol Version 1.0
Protocol Version 2.0
17 February 2017
28 March 2017
Protocol Version 3.0
14 September 2017
Protocol Version 4.0
15 November 2017
Protocol Version 5.0
15 November 2018
Protocol Version 6.0
Protocol Version 7.0
15 March 2019
27 January 2020
Protocol Version 8.0
07 December 2020
IND Number:
EudraCT
2019-001036-66
Array BioPharma Inc.
(a wholly owned subsidiary of Pfizer Inc.)
3200 Walnut Street
Boulder, CO 80301
Phone: (303) 381-6600
Fax: (303) 386-1240
CONFIDENTIAL INFORMATION
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Array BioPharma Inc. Except as otherwise agreed to in writing, by accepting or reviewing this 
document you agree to hold this information in confidence and not to disclose it to others (except 
where required by applicable law) or to use it for unauthorized purposes. In the event of any actual or 
suspected breach of this obligation, Array BioPharma Inc. should be promptly notified.
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Protocol Synopsis
Title
An Open-label Phase 1 Study to Evaluate Drug-Drug Interactions of 
Agents Co-Administered with Encorafenib and Binimetinib in Patients 
with BRAF V600-mutant Unresectable or Metastatic Melanoma or 
Other Advanced Solid Tumors
Protocol 
Number
ARRAY-818-103; C4221003
Phase
1
Study Center(s)
Approximately 30 centers globally
Objectives
All objectives pertain to the drug-drug interaction (DDI) phase of the 
study only.
Primary: 

To evaluate the effect of single and multiple oral doses of 
encorafenib in combination with binimetinib on the single oral 
dose pharmacokinetics (PK) of the cytochrome P450 (CYP) 
enzyme probe substrates, losartan (CYP2C9), midazolam 
(CYP3A4), caffeine (CYP1A2), omeprazole (CYP2C19), and 
dextromethorphan (CYP2D6) and selected metabolites, in 
patients with BRAF V600-mutant unresectable or metastatic 
melanoma or other advanced solid tumors.

To evaluate the effect of single and multiple oral doses of 
encorafenib in combination with binimetinib on the single oral 
dose PK of rosuvastatin, an organic anion-transporting 
polypeptide (OATP) /breast cancer resistance protein (BCRP) 
substrate, and on the single oral dose PK of bupropion (a 
CYP2B6 substrate) and hydroxybupropion, in patients with 
BRAF V600-mutant unresectable or metastatic melanoma or 
other advanced solid tumors.

To evaluate the effect of multiple doses of modafinil, a 
moderate CYP3A4 inducer, on the multiple oral dose PK of 
encorafenib and its metabolite, LHY746, in patients with 
BRAF V600-mutant unresectable or metastatic melanoma or 
other advanced solid tumors.
Secondary:

To assess the single and multiple dose PK of encorafenib,
LHY746 and binimetinib (and its metabolite, AR00426032) 
after coadministration with a single oral dose of the CYP probe 
cocktail, rosuvastatin, and bupropion.


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•
To assess the safety and tolerability of single and multiple oral 
doses of encorafenib in combination with binimetinib when 
administered with a single oral dose of the CYP probe cocktail,
rosuvastatin and bupropion during the DDI portion of the 
study.
•
To assess safety and tolerability of multiple oral doses of 
encorafenib in combination with binimetinib when 
administered with multiple doses of modafinil during the DDI 
portion of the study.
 
 
 
Endpoints
Primary: 
•
Changes in plasma maximum concentration (Cmax) and area 
under the concentration time curve from time zero to the time 
of last quantifiable concentration (AUClast): midazolam, 1-OH 
midazolam, caffeine, paraxanthine, omeprazole, 5-hydroxy 
omeprazole, rosuvastatin, bupropion and hydroxybupropion.
•
Changes in the amount eliminated via urine over an 8-hour 
period (Ae0-8): losartan and its metabolite (E-3174), 
dextromethorphan and dextrorphan.
•
Changes in plasma encorafenib and LHY746 Cmax and area 
under the concentration time curve (AUC) in Arm 3.
Secondary:
•
Metabolite ratios (MRAUC and MRCmax) for 1-OH 
midazolam/midazolam, paraxanthine/caffeine, 5-hydroxy 
omeprazole/omeprazole, hydroxybupropion/bupropion and 
LHY746/encorafenib and MRAe0-8 for E-3174/losartan and 
dextrorphan/dextomethorphan.
•
Pharmacokinetic parameters (e.g., time to reach Cmax [Tmax], 
AUC from time zero extrapolated to infinity [AUCinf], percent 
of AUC extrapolated [AUC%extrap], apparent terminal 
elimination rate constant [Kel], apparent terminal elimination 
half-life [T1/2], apparent total body clearance after 
extravascular administration [CL/F], and apparent total volume 
of distribution after extravascular administration [Vz/F]) where 
calculable, for midazolam, 1-OH midazolam, caffeine, 
paraxanthine, omeprazole, 5-hydroxy omeprazole,
rosuvastatin, bupropion and hydroxybupropion.
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•
Pharmacokinetic parameters (e.g., urine concentration [Curine], 
quantity of urine excreted during each collection interval 
[Vol], cumulative amount excreted in urine during each 
collection interval [CumA]e, and percentage of dose recovered 
in urine [Fe] %) for losartan, E-3174, dextromethorphan and 
dextrorphan.
•
Pharmacokinetic parameters (e.g., Cmax, AUClast, Tmax, AUCinf, 
AUC%extrap, Kel, T1/2, CL/F, and Vz/F) for encorafenib, 
LHY746, binimetinib and AR00426032 where calculable.
•
Safety will be evaluated by monitoring adverse events (AEs), 
physical examinations, ophthalmic examinations, vital sign 
measurements, 12-lead electrocardiograms (ECGs), 
echocardiogram (ECHO)/multigated acquisition scan 
(MUGA), and clinical laboratory tests.
 
 
Design
This is an open-label, 3-arm, fixed-sequence study. 
Patients will be assigned to the appropriate treatment arm by the 
Sponsor study team based on eligibility. Enrollment to Arm 3 will 
begin once Arm 2 enrollment is complete.
The study will have 2 treatment phases, a DDI phase followed by a 
post-DDI phase for each study arm. 
DDI Phase: 
Arm 1
Twenty patients will be enrolled into Arm 1 (CYP probe cocktail 
arm). Patients will receive a single oral dose of the CYP probe 
cocktail (losartan, dextromethorphan, caffeine, omeprazole, and
midazolam) on Day -7. Encorafenib, administered once daily (QD) 
and binimetinib, administered twice daily (BID) will be initiated on 
Day 1. Patients will then receive a single oral dose of the CYP probe 
cocktail on Day 1 and Day 14. Blood and urine PK sampling will be 
conducted from 0 to 8 hours on Day -7, Day 1 and Day 14.
Arm 2
Ten patients will receive a single oral dose of rosuvastatin and
bupropion on Day -7. Encorafenib, administered QD and binimetinib, 
administered BID will be initiated on Day 1. Patients will then receive 
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a single oral dose of rosuvastatin and bupropion on Day 1 and Day 14. 
Blood PK sampling will be conducted from 0 to 8 hours on Day -7, 
Day 1 and Day 14.
Arm 3
Six to 12 patients will inititate continuous treatment with encorafenib 
QD and binimetinib BID on Day 1. Patients will then receive
continuous treatment of modafinil QD on Day 15 through Day 21. 
Blood PK sampling will be conducted from 0 to 8 hours on Day 14
and Day 21.
PK data will be analysed after the first 6 patients to look for an 
indication that the moderate inducer is having a significant effect on 
encorafenib PK. If there is a ≥ 20% change in geometric mean 
encorafenib AUC then an additional 6 patients will be enrolled to 
more fully characterize the effect.
All Arms
Patients who discontinue or require a dose reduction of study drug(s), 
in particular encorafenib, prior to the final sample collection on 
Day 14 in Arms 1 and 2 or prior to Day 21 in Arm 3 may be 
considered unevaluable for PK analyses and may be replaced. If a 
patient misses 3 or more consecutive doses of encorafenib in any arm 
or 3 or more doses of modafinil in Arm 3 prior to completion of the 
last PK sampling on Day 14 in Arms 1 and 2 or on Day 21 in Arm 3 
due to noncompliance, the patient may remain on treatment but may 
be replaced if limited data are available from the patient. In addition, 
patients who miss any dose of study drugs on any of the PK days, or
who vomit within 4 hours after dosing on any of the PK days, may be 
replaced but may remain on treatment.
Safety Analysis
DDI Phase (through Day 28)
All safety data will be recorded in the patient’s source documents and 
electronic case report forms (eCRFs). Adverse events including 
serious adverse events (SAEs), laboratory profiles (hematology, 
biochemistry, coagulation, cardiac/muscle enzymes, urinalysis), 
physical examination (including vital signs, ophthalmic and 
dermatological examinations), Eastern Cooperative Oncology Group 
(ECOG) performance status (PS) assessment, and cardiac profiles 
(ECG and MUGA or ECHO), concomitant medications and/or 
therapies will be recorded.  


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Post DDI Phase:
If a patient chooses to not continue in the post-DDI phase, the Day 30 
Safety Follow-up Visit assessments will still be performed. 
During the post-DDI phase patients may continue to receive 
encorafenib/binimetinib combination until disease progression, 
unacceptable toxicity, withdrawal of consent, pregnancy, significant 
protocol deviation, lost to follow up, Investigator decision, death, or 
study termination by Sponsor.
It is recommended that safety evaluations occur every 3 to 4 weeks, 
unless otherwise specified. Safety should be monitored by assessing 
physical examination, hematology and chemistry laboratory testing 
and any other pertinent testing required as part of the safety profile of 
the compound (dermatological examinations, ophthalmic exams, 
cardiac profiles) until discontinuation. Adverse events will be 
collected at every visit. Investigators will be required to record all 
Grade 3 or 4 AEs. All SAEs are to be reported to the Sponsor or 
designee using the SAE form.
This study does not formally assess efficacy, however, some efficacy 
assessment is necessary for the Investigator to assess continued 
benefit. The Sponsor recommends assessing efficacy every 8 to 
12 weeks.
Treatment 
Regimens
Treatments are described as follows:
Encorafenib/binimetinib (continuous daily dosing starting on Day 1 
for all arms):
450 mg (6 x 75 mg) encorafenib oral capsules QD
45 mg (3 x 15 mg) binimetinib oral tablet BID
CYP Probe Cocktail (once on Day -7, Day 1 and Day 14 for Arm 1 
only) taken in the following order:
25 mg losartan oral tablet
30 mg dextromethorphan oral capsule
50 mg caffeine as oral liquid
20 mg omeprazole oral capsule
2 mg midazolam as oral syrup
Rosuvastatin and bupropion (once on Day -7, Day 1 and Day 14 for 
Arm 2 only):
10 mg rosuvastatin oral tablet
75 mg bupropion immediate release (IR) oral tablet


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Modafinil (continuous daily dosing starting on Day 15 through Day 21
for Arm 3 only):
400 mg modafinil as oral tablet(s) QD
For each arm, all drugs will be taken within 10 minutes total time.
Study 
Population
Up to approximately 42 patients with BRAF V600-mutant 
unresectable or metastatic melanoma or other advanced solid tumors; 
20 in Arm 1, 10 in Arm 2 and up to 12 in Arm 3.  
Duration of 
Study 
Participation
Prescreening:
Prescreening evaluations must be performed between Day -57 and 
Day -36 in Arms 1 and 2 and between Day -50 and Day -29 in Arm 3.
Screening:
Screening of patients will occur within 28 days prior to the first study
drug dose on Day -7 (Day -35 to Day -8, inclusive) in Arms 1 and 2 
and prior to the first study drug dose on Day 1 (Day -28 to Day -1, 
inclusive) in Arm 3.
DDI Phase:
The duration of the DDI phase in Arms 1 and 2 will be 35 days and 
will include clinic visits on Day -7, Day 1, Day 14, and Day 28. The 
duration of the DDI phase will be 28 days in Arm 3 and will include 
clinic visits on Day 1, Day 14, Day 15, Day 21 and Day 28. 
Post-DDI Phase: 
Patients will be followed by the Investigator following standard 
clinical practice and may continue to receive study treatment until 
discontinuation criteria are met. 
Eligibility 
Criteria
Inclusion Criteria
Patients must meet all of the following inclusion criteria to be eligible 
for enrollment into the study:
1. Signed written informed consent;
2. Male or female patient, age ≥ 18 years;
3. Histologically 
confirmed 
diagnosis 
of 
locally 
advanced, 
unresectable or metastatic cutaneous melanoma or unknown 
primary melanoma American Joint Committee on Cancer (AJCC)
Stage IIIB, IIIC or IV; or other BRAF V600-mutant advanced solid 
tumors;
4. Presence of BRAF V600E and/or V600K mutation in tumor tissue 
prior to enrollment, as determined using a local test;
5. Evidence of measurable or non-measurable lesions as detected by 
radiological or photographic methods according to guidelines based 
on Response Evaluation Criteria in Solid Tumors (RECIST) v. 1.1;


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6. Patient with unresectable locally advanced or metastatic melanoma  
who has received no prior treatment or progressed on or after prior 
systemic therapy
Note: Prior therapy with a BRAF inhibitor (e.g., vemurafenib, 
dabrafenib, encorafenib and XL281/BMS-908662) and/or a MEK 
inhibitor (e.g., trametinib, binimetinib, selumetinib, cobimetinib 
and refametinib) is permitted except in the regimen immediately 
prior to study entry. Progression during prior BRAF/MEK 
inhibitor treatment is not required; 
7. Patient with other (non-melanoma) BRAF V600E and/or V600K -
mutant advanced solid tumors who has progressed on standard 
therapy or for whom there are no available standard therapies
Note: Prior therapy with a BRAF inhibitor and/or a MEK inhibitor 
is permitted except in the regimen immediately prior to study 
entry. Progression during prior BRAF/MEK inhibitor treatment is 
not required; if it occurred, the patient’s circumstances (e.g., ≥ 1 
year since prior BRAF and/or MEK inhibitor, equivocal 
progression, refractory to available therapies) must be discussed 
with the Sponsor prior to enrollment;
8. ECOG PS of 0 or 1;
9. Adequate bone marrow, organ function and laboratory parameters:
a. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L,
b. Hemoglobin (Hgb) ≥ 9 g/dL without transfusions,
c. Platelets (PLT) ≥ 100 x 109/L without transfusions,
d. Aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) ≤ 2.5 × upper limit of normal (ULN); 
patient with liver metastases ≤5 ×ULN,
e. Total bilirubin ≤ 2 × ULN,
f. Creatinine ≤ 1.5 mg/dL, or calculated creatinine clearance 
(determined as per Cockcroft-Gault) ≥ 50 mL/min;
10. Able to take oral medications;
11. Patient is deemed by the Investigator to have the initiative and 
means to be compliant with the protocol (treatment and follow-up);
12. Negative serum beta-human chorionic gonadotropin (β-HCG) test 
(female patient of childbearing potential only) performed within 
72 hours prior to first dose and consent to ongoing urine pregnancy 
testing during the course of the study;
13. Male patients and female patients of childbearing potential must 
agree to use an acceptable method of contraception as defined in the 
study protocol;
ARM 1 ONLY:
1. Non-smoker who has not used nicotine containing products for at 
least 3 months prior to the first dose.


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Exclusion Criteria
Patients meeting any of the following criteria are not eligible for 
enrollment in the study:
1. Symptomatic brain metastasis. Patients previously treated or 
untreated for these conditions who are asymptomatic in the 
absence of corticosteroid and anti-epileptic therapy are allowed. 
Brain metastases must be stable, with imaging (e.g., magnetic 
resonance imaging [MRI] or computed tomography [CT] 
demonstrating no current evidence of progressive brain metastases 
at screening);
2. History of reaction to any of the study medications in the arm the 
patient is enrolled in this trial;
3. Use, within 2 weeks prior to the start of encorafenib/binimetinib 
treatment on Day 1 and through DDI phase (Day 28), of any 
herbal medications/supplements or any medications or foods that 
are moderate or strong inhibitors or inducers of CYP3A4/5;
4. Consumption of grapefruit, pomegranates, star fruits, Seville 
oranges or products containing the juice of each starting from 
Day -14 and through the DDI phase (Day 28), due to potential 
CYP3A4 interaction with the study drugs. Orange juice is allowed;
5. Symptomatic or untreated leptomeningeal disease;
6. History or current evidence of retinal vein occlusion (RVO) or 
current risk factors for RVO (e.g., uncontrolled glaucoma or ocular 
hypertension, history of hyperviscosity or hypercoagulability 
syndromes); 
7. Clinically significant cardiac disease including any of the 
following: 
a. Congestive heart failure requiring treatment (New York Heart 
Association Grade ≥ 2)
b. Left ventricular ejection fraction (LVEF) < 50% as determined 
by MUGA or ECHO
c. Uncontrolled hypertension defined as persistent systolic blood 
pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg 
despite current therapy
d. History or presence of clinically significant ventricular 
arrhythmias or atrial fibrillation
e. Clinically significant resting bradycardia
f. Unstable angina pectoris ≤ 3 months prior to start of study drug
g. Acute myocardial infarction ≤ 3 months prior to start of study 
drug


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h. QT interval corrected for heart rate using the Fridericia formula 
(QTcF) > 480 msec at screening;
8. Impaired hepatic function as defined by Child-Pugh class B or C;
9. Impaired gastrointestinal function or disease which may 
significantly alter the absorption of study drugs (e.g., ulcerative 
diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption 
syndrome, small bowel resection);
10. Known hyper-coagulability risks other than malignancy (e.g., 
Factor V Leiden syndrome);
11. Thromboembolic event (e.g. including transient ischemic attacks, 
cerebrovascular accidents, deep vein thrombosis or pulmonary 
emboli) except catheter-related venous thrombosis ≤ 12 weeks 
prior to starting study treatment. Note: Patients with catheter-
related thromboembolic events are allowed;
12. Any of the following:
a. Nitrosourea or mitomycin-C within 6 weeks prior to start of 
study drug
b. Other chemotherapy, radiation therapy that included > 30% of 
the bone marrow reserve, or biological therapy (e.g., antibodies) 
within 4 weeks prior to start of study drug
c. Continuous or intermittent small-molecule therapeutics or 
investigational agents within 5 half-lives of the agent (or within 
4 weeks prior to start of study drug, when half-life is unknown)
d. Residual Common Terminology Criteria for Adverse Events 
(CTCAE) Grade 2 side effects of any such therapy (residual 
Grade 2 alopecia is permitted);
13. Discontinuation of prior BRAF and/or MEK inhibitor treatment 
due to left ventricular dysfunction, pneumonitis/interstitial lung 
disease, or retinal vein occlusion;
14. Known positive serology for human immunodeficiency virus 
(HIV) infection, active hepatitis B and/or active hepatitis C 
infection;
15. History of Gilbert’s syndrome;
16. Other severe, acute, or chronic medical or psychiatric condition or 
laboratory abnormality that may increase the risk associated with 
study participation or study drug administration or that may 
interfere with the interpretation of study results and, in the 
judgement of the Investigator, would make the patient 
inappropriate for the study;


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17. Pregnant or nursing (lactating) women, where pregnancy is 
defined as the state of a female after conception and until 
termination of gestation, confirmed by a positive β-hCG laboratory 
test (> 5 mIU/mL).
ARM 1 ONLY:
1. Positive urine cotinine test at screening;
2. Use, within 2 weeks prior to the start of encorafenib/binimetinib 
treatment on Day 1 and through DDI phase (Day 28), of any 
substrates, inhibitors or inducers of CYP3A4, CYP2C9, CYP1A2, 
or CYP2C19 and any substrates or inhibitors CYP2D6.
ARM 2 ONLY:
1. Use, within 2 weeks prior to the start of encorafenib/binimetinib 
treatment on Day 1 and through DDI phase (Day 28), of any 
substrates, inhibitors or inducers of CYP2B6 or any substrates or 
inhibitors of BCRP, OATP1B1 or OATP1B3.
ARM 3 ONLY:
1. History of psychosis, depression or mania;
2. History of angioedema;
3. History of mitral valve prolapse;
4. History of left ventricular hypertrophy;
5. Use, within 2 weeks prior to the start of encorafenib/binimetinib 
treatment on Day 1 and through DDI phase (Day 28), of any 
substrates, inhibitors or inducers of CYP3A4.
Statistical 
Considerations
Sample Size Determination
For Arm 1, sample size was specified based on the substrate in the 
CYP probe cocktail with the highest reported within patient variability 
in AUC (Ryu 2007). The coefficient of variation of the difference
between 2 AUClast values for the same patient for omeprazole is 
approximately 38%. Assuming a 2-sided significance level of 0.05 and 
a power of 0.8, approximately 20 patients would need to be evaluable 
to detect a difference of 25% in mean AUClast . Additionally, these 
values are similar to other cocktail studies run in oncology patients 
(Goh 2010).
For Arm 2 , the coefficient of variation of the ratio between 
2 rosuvastatin AUClast values for the same patient is approximately 
47% (Stopfer 2016). Assuming a 2-sided significance level of 0.05 
and a power of 0.8, approximately 10 patients would need to be 
evaluable to detect a difference of 50% in mean AUClast. Assuming an 
intrasubject variation of 23% for bupropion AUC0-8 (Bosilkovska 


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2014), there is an 80% probability with 10 subjects that a treatment 
difference will be detected if the true effect size is 33%.
For Arm 3, assuming an intrasubject variation of 36.4% for 
encorafenib AUC over the final dosing interval (AUCtau, Clinical 
Study CMEK162X2110), there is an 80% probability with fixed 
sample sizes of 6 and 12 subjects that a treatment difference will be 
detected if the true effect size is 74 and 46%, respectively.
Pharmacokinetic Analysis
Descriptive statistics will be calculated for all analytes by arm and 
day.  
For the primary analysis in Arms 1 and 2, an analysis of variance 
(ANOVA) will be performed on the natural log (ln)-transformed Cmax
and AUClast of midazolam, 1-OH midazolam, caffeine, paraxanthine, 
omeprazole, 5-hydroxy omeprazole, rosuvastatin, bupropion and 
hydroxybupropion and the urine losartan, E-3174, dextromethorphan 
and dextrorphan Ae0-8. For the primary analysis in Arm 3, an ANOVA 
will be performed on the encorafenib ln-transformed Cmax and AUC. 
The ANOVA model will include treatment as fixed effect and patient 
as the random effect. Each ANOVA will include calculation of the 
least squares means (LSM), the difference between treatment LSM, 
and the standard error associated with this difference. 
Ratios of LSM will be calculated using the exponentiation of the 
difference between treatment LSM from the analyses on the 
ln-transformed parameters. In Arms 1 and 2, these ratios will be 
expressed as a percentage of Day 1 (test) relative to Day -7 
(reference), Day 14 (test) relative to Day 1 (reference) and Day 14 
(test) relative to Day -7 (reference). In Arm 3, these ratios will be 
expressed as a percentage of Day 21 (test) relative to Day 14 
(reference).
Consistent with the 2 one-sided test, 90% confidence intervals (CIs)
for the ratios will be derived by exponentiation of the CIs obtained for 
the difference between treatment LSM resulting from the analyses on 
the ln-transformed parameters. In Arms 1 and 2, the CIs will be 
expressed as a percentage of Day 1 (test) relative to Day -7 (reference) 
and Day 14 (test) relative to Day 1 (reference) and Day 14 (test) 
relative to Day -7 (reference). In Arm 3, these ratios will be expressed 
as a percentage of Day 21 (test) relative to Day 14 (reference).
Similarly, an ANOVA will be performed on the ln-transformed 
MRAUC and MRCmax calculated for 1-OH midazolam/midazolam, 
paraxanthine/caffeine, 5-hydroxy omeprazole/omeprazole,


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hydroxybupropion/bupropion and LHY746/encorafenib and MRAe0-8 
for E-3174/losartan and dextrorphan/dextomethorphan. 
 
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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................20
LIST OF FIGURES .................................................................................................................20
LIST OF APPENDICES..........................................................................................................21
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS............................................22
1. INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ..........................47
2. INTRODUCTION ...............................................................................................................48
2.1. BRAF Mutation-Positive Cancer ............................................................................48
2.2. Drug-Drug Interaction Potential..............................................................................48
2.3. Overview of Encorafenib ........................................................................................49
2.3.1. Nonclinical Studies with Encorafenib ........................................................49
2.3.1.1. Nonclinical Pharmacology........................................................49
2.3.1.2. Nonclinical Toxicity and Safety................................................51
2.3.2. Clinical Experience with Encorafenib........................................................52
2.3.2.1. Clinical Pharmacology..............................................................52
2.3.2.2. Clinical Safety...........................................................................53
2.4. Overview of Binimetinib.........................................................................................53
2.4.1. Nonclinical Studies with Binimetinib.........................................................54
2.4.1.1. Nonclinical Pharmacology........................................................54
2.4.1.2. Nonclinical Toxicity and Safety................................................55
2.4.2. Clinical Experience with Binimetinib ........................................................56
2.4.2.1. Clinical Pharmacology..............................................................56
2.4.2.2. Clinical Safety...........................................................................56
2.5. Overview of Encorafenib and Binimetinib Combination .......................................57
2.5.1. Nonclinical Pharmacodynamics .................................................................57
2.5.1.1. Nonclinical Pharmacokinetics...................................................57
2.5.1.2. Nonclinical Toxicity and Safety................................................58
2.5.2. Clinical Experience with Encorafenib and Binimetinib Combination .......58
2.5.2.1. Clinical Pharmacology..............................................................58
2.5.2.2. Safety.........................................................................................58
2.5.2.3. Efficacy .....................................................................................60
2.6. Rationale..................................................................................................................61
2.6.1. Rationale for the Study...............................................................................61


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2.6.2. Rationale for Dose Selection ......................................................................62
3. STUDY OBJECTIVES AND ENDPOINTS.......................................................................64
3.1. Study Objectives .....................................................................................................64
3.1.1. Primary Objectives .....................................................................................64
3.1.2. Secondary Objectives .................................................................................64
3.2. Study Endpoints ......................................................................................................64
3.2.1. Primary Endpoint........................................................................................64
3.2.2. Secondary Endpoints ..................................................................................65
4. STUDY DESIGN.................................................................................................................66
4.1. Study Design Overview ..........................................................................................66
4.1.1. DDI Phase...................................................................................................66
4.1.2. Post-DDI Phase...........................................................................................68
4.2. Doses and Schedule of Administration ...................................................................68
4.2.1. Treatment Regimens...................................................................................68
4.3. Duration of Treatment.............................................................................................71
5. PATIENT POPULATION...................................................................................................72
5.1. Number of Patients..................................................................................................72
5.2. Selection of Patients................................................................................................72
5.2.1. Inclusion Criteria ........................................................................................72
5.2.2. Exclusion Criteria.......................................................................................73
5.3. Lifestyle Guidelines ................................................................................................76
5.3.1. Requirements for Contraception.................................................................76
5.3.2. Ultaviolet Light Exposure...........................................................................77
5.4. Prior and Concomitant Medications........................................................................77
5.4.1. Prior Treatments .........................................................................................77
5.4.2. Concomitant Medications...........................................................................77
5.4.2.1. Prohibited Concomitant Medications........................................77
5.4.2.2. Permitted Concomitant Medication ..........................................78
5.4.2.3. Permitted Concomitant Medication Requiring Caution 
and/or Action.....................................................................................78
6. STUDY TREATMENT.......................................................................................................80
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6.1. Dosing Regimen......................................................................................................80
6.2. Allocation to Treatment ..........................................................................................80
6.3. Study Drug Supply..................................................................................................81
6.3.1. Packaging and Labeling..............................................................................81
6.3.2. Shipping, Storage and Handling.................................................................81
6.3.3. Accountability and Return of Study Drug Supply......................................81
6.4. Study Drug Dispensing and Administration ...........................................................82
6.5. Dose Modifications and Reductions .......................................................................82
6.5.1. Follow-up for Toxicities.............................................................................92
6.5.1.1. Management of Hand Foot Skin Reaction (HFSR) ..................92
6.5.1.2. Follow-up Evaluations for Appearance of 
Keratoacanthoma (KA) and/or Squamous Cell Carcinoma 
(SCC).................................................................................................93
6.5.1.3. Management of Nausea and/or Vomiting .................................93
6.6. Treatment Compliance ............................................................................................93
7. STUDY PROCEDURES AND ASSESSMENTS...............................................................94
7.1. Safety Assessments .................................................................................................94
7.1.1. Adverse Events...........................................................................................94
7.1.2. Medical History ..........................................................................................94
7.1.3. Physical Examination .................................................................................94
7.1.4. Electrocardiogram.......................................................................................94
7.1.5. ECOG Performance Status .........................................................................95
7.1.6. Clinical Laboratory Tests ...........................................................................95
7.1.6.1. Hematology, Clinical Chemistry and Urinalysis.......................96
7.1.7. Ophthalmic Examination............................................................................97
7.1.7.1. Routine Testing .........................................................................97
7.1.7.2. Additional testing ......................................................................97
7.1.8. Dermatologic Examination.........................................................................97
7.1.9. Pregnancy Tests..........................................................................................97
7.2. Pharmacokinetic Assessments.................................................................................98
7.4. Disease Assessments...............................................................................................99
8. SCHEDULE OF PROCEDURES AND ASSESSMENTS...............................................100
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8.1. Prescreening Evaluations ......................................................................................100
8.2. Screening Evaluations...........................................................................................100
8.3. Study Evaluations..................................................................................................101
8.3.1. DDI Phase – Arms 1 and 2 .......................................................................101
8.3.1.1. Day -7 at Hour 0......................................................................101
8.3.1.2. Day -7 at Hours 1 and 3 ..........................................................102
8.3.1.3. Day -7 at Hours 2, 4, 6 and 8 ..................................................102
8.3.1.4. Day 1 and Day 14 at Hour 0....................................................103
8.3.1.5. Day 1 and Day 14 at Hours 1 and 3 ........................................103
8.3.1.6. Day 1 and Day 14 at Hours 2, 4, 6 and 8 ................................104
8.3.2. DDI Phase – Arm 3...................................................................................104
8.3.2.1. Day 1 and 15 at Hour 0 ...........................................................104
8.3.2.2. Day 1 and 15 at Hours 2 and 4................................................105
8.3.2.3. Day 14 and 21 at Hour 0 .........................................................105
8.3.2.4. Day 14 and Day 21 at Hours 1 and 3 ......................................105
8.3.2.5. Day 14 and Day 21 at Hours 2, 4, 6 and 8 ..............................105
8.3.3. Day 28, End of DDI Phase Visit...............................................................106
8.3.4. Post-DDI Phase.........................................................................................106
8.3.4.1. Every 3-4 Weeks .....................................................................106
8.3.4.2. Every 8-12 Weeks ...................................................................107
8.3.5. Day 30 Safety Follow-up Visit (Approximately 30 Days After Last 
dose of Study Drug).......................................................................................107
9. STUDY DISCONTINUATION ........................................................................................114
9.1. Treatment Discontinuation for Individual Patients ...............................................114
9.2. Replacement of Patients........................................................................................115
10. SAFETY MONITORING: DEFINITIONS AND REPORTING....................................116
10.1. Adverse Events and Serious Adverse Events......................................................116
10.1.1. Time Period and Frequency for Collecting AE and SAE 
Information ....................................................................................................116
10.1.1.1. Reporting SAEs to Pfizer Safety...........................................117
10.1.1.2. Recording Nonserious AEs and SAEs on the CRF...............117
10.1.2. Method of Detecting AEs and SAEs ......................................................117
10.1.3. Follow-up of AEs and SAEs...................................................................117


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10.1.4. Regulatory Reporting Requirements for SAEs.......................................118
10.1.5. Exposure During Pregnancy or Breastfeeding, and Occupational 
Exposure ........................................................................................................118
10.1.5.1. Exposure During Pregnancy..................................................118
10.1.5.2. Exposure During Breastfeeding ............................................120
10.1.5.3. Occupational Exposure .........................................................120
10.1.6. Cardiovascular and Death Events...........................................................120
10.1.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs............................................................................120
10.1.8. Adverse Events of Special Interest.........................................................121
10.1.8.1. Lack of Efficacy....................................................................121
10.1.9. Medical Device Deficiencies..................................................................121
10.1.10. Medication Errors .................................................................................121
10.2. Treatment of Overdose........................................................................................121
11. STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE................123
11.1. General Considerations .......................................................................................123
11.1.1. Sample Size ............................................................................................123
11.1.2. Safety Analysis .......................................................................................123
11.1.3. Pharmacokinetic Analysis ......................................................................124
12. DATA RECORDING, RETENTION AND MONITORING .........................................126
12.1. Case Report Forms..............................................................................................126
12.2. Data Monitoring ..................................................................................................126
12.3. Quality Control and Quality Assurance ..............................................................126
13. REGULATORY, ETHICAL AND LEGAL OBLIGATIONS........................................127
13.1. Good Clinical Practice ........................................................................................127
13.2. Ethics Committee Approval................................................................................127
13.3. Regulatory Authority Approval ..........................................................................127
13.4. Other Required Approvals ..................................................................................127
13.5. Informed Consent................................................................................................127
13.6. Patient Confidentiality.........................................................................................128
13.7. Disclosure of Information ...................................................................................128
13.8. Publication of Study Data ...................................................................................128
13.8.1. Data Sharing ...........................................................................................128


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14. ADHERENCE TO THE PROTOCOL............................................................................130
14.1. Amendments to the Protocol...............................................................................130
15. REFERENCES ................................................................................................................131


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LIST OF TABLES
Table 1.
Study CMEK162B2301: Adverse Events, Regardless of 
Relationship to Study Drug(s), by Preferred Term – Overall and 
Maximum Grades 3 and 4 (> 25% in any treatment group, or Grade 
3/4 AEs >5% in any treatment group; Safety Set, Part 1) ........................59
Table 2.
Efficacy Results for CMEK162B2301 Part 1...........................................60
Table 3.
Dose Reduction for Encorafenib ..............................................................83
Table 4.
Dose Reduction for Binimetinib...............................................................83
Table 5.
Encorafenib and Binimetinib – Recommended Dose Modifications 
Associated with Treatment-Related Adverse Events ...............................84
Table 6.
Summary of Clinical Laboratory Tests.....................................................96
Table 7.
Schedule of Events – Arms 1 and 2........................................................108
Table 8.
Schedule of Events – Arm 3...................................................................111
LIST OF FIGURES
Figure 1:
Study Schema ...........................................................................................67


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LIST OF APPENDICES
Appendix 1. Recommended Guidelines for the Management of Encorafenib-Induced 
and/or Binimetinib-Induced Skin Toxicity.............................................135
Appendix 2. Recommended Guidelines for the Management of Encorafenib-Induced 
Hand-Foot Skin Reactions (HFSR) ........................................................138
Appendix 3. Recommended Guidelines for the Management of Binimetinib-Induced 
Diarrhea ..................................................................................................141
Appendix 4. Recommended Guidelines for the Management of Binimetinib-Induced 
Interstitial lung disease ...........................................................................144
Appendix 5. Snellen Equivalence (Visual Acuity Conversion Chart)...................................145
Appendix 6. List of Concomitant Medications......................................................................146
Appendix 7. Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1...........152
Appendix 8. Child-Pugh Classification .................................................................................162
Appendix 9. Eastern Cooperative Oncology Group Performance Status..............................163
Appendix 10. Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting.......................................................................164
Appendix 11. Liver Safety: Suggested Actions and Follow-up Assessments.......................171
Appendix 12. ECG Findings of Potential Concern................................................................173
Appendix 13. Alternative Measures During Public Emergencies .........................................175


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
The following abbreviations and special terms are used in this study protocol. 
Abbreviation or 
special term
Definition
ADME
absorption, distribution, metabolism, and excretion
AE
adverse event
AESI
adverse events of special interest
Ae0-8
changes in the amount eliminated via urine over an 8-hour period
AJCC
American Joint Committee on Cancer
ALT 
alanine aminotransferase 
ANC
absolute neutrophil count
ASCO
American Society of Clinical Oncology
ANOVA
analysis of variance
AST 
aspartate aminotransferase 
ATP
adenosine triphosphate
AUC
area under the curve
AUClast
concentration time curve from time zero to the time of last quantifiable concentration
AUCinf
concentration time curve from time zero extrapolated to infinity
AUC%extrap
percent of concentration time curve extrapolated 
AUCtau
AUC over the final dosing interval (tau)
AV
atrioventricular
BCRP
breast cancer resistance protein
β-HCG
beta-human chorionic gonadotropin
BID
twice daily
BOR
best overall response
BRAF
BRAF proto-oncogene serine-threonine protein kinase
CDK4/6
cyclin-dependent kinase 4/6


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Abbreviation or 
special term
Definition
CI
confidence interval
CK
creatine phosphokinase
CL/F
apparent total body clearance after extravascular administration
CLR
renal clearance
Cmax
maximum concentration
CNS
central nervous system
COVID-19
Coronavirus Disease 2019
CR 
complete response
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
CSR
clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
CT SAE
clinical trial serious adverse event
CumAe
cumulative amount excreted in urine during each collection interval 
Curine
urine concentration
CT
computed tomography, clinical trial
CTFG
Clinical Trial Facilitation Group
CV
curriculum vitae
CYP
cytochrome P450
DCR
disease control rate
DDI
drug-drug interaction
DILI
drug-induced liver injury
DLT
dose-limiting toxicity
DOR
duration of response


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Abbreviation or 
special term
Definition
DUSP6
dual specificity phosphatase 6
EC
ethics committee (includes institutional review board, research ethics board, and 
institutional ethics committee)
EC50
half maximal response concentration
ECG
electrocardiogram
ECHO
echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EDP
exposure during pregnancy
EGFR
epidermal growth factor receptor
ERK
extracellular regulated signal kinase
ESMO
European Society of Medical Oncology
F
oral bioavailability
FDA
U.S. Food and Drug Administration
Fe%
percentage of dose recovered in urine
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
gamma-glutamyltransferase
GLP
Good Laboratory Practice
HA
Health Authorities
HDPE
high-density polyethylene
hERG
human ether-à-go-go related gene
HFSR
hand-foot skin reaction
Hgb
hemoglobin


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Abbreviation or 
special term
Definition
HIV
human immunodeficiency virus
IC50
half maximal inhibitory concentration
ICH
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committees
IGF-1R
type 1 insulin-like growth factor receptor
INR
international normalized ratio
IOP
intraocular pressure
IRB
Institutional Review Board
IV
intravenous
KA
keratoacanthoma
Kel
apparent terminal elimination rate constant
KI
inhibitory constant
Kinact
rate of enzyme inactivation
KRAS
Kirsten rat sarcoma viral oncogene homolog
LFT
liver function test
LH
luteinizing hormone
LLN
lower limit of normal
LSM
least squares means
LVEF
left ventricular ejection fraction
MAP
mitogen-activated protein
MAPK
MAP kinase
MASCC
Multinational Association of Supportive Care
mCRC
metastatic colorectal cancer
MedDRA
Medical Dictionary for Regulatory Activities 


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Abbreviation or 
special term
Definition
MEK
MAP kinase kinase
MR
metabolite ratio
MRI
magnetic resonance imaging
mRNA
messenger ribonucleic acid
MTD
maximum tolerated dose
MUGA
multigated acquisition scan
NCI
National Cancer Ins
NE
not evaluable
NOAEL
no-observable-adverse-effect level
NRAS
neuroblastoma RAS viral (v-ras) oncogene homolog
NSCLC
non-small cell lung cancer
OAT1
organic anion transporting 1 
OAT3
organic anion transporting 3
OATP
organic anion-transporting polypeptide
OATP1B1
organic anion-transporting polypeptide 1B1
OATP1B3
organic anion-transporting polypeptide 1B3
OCT
ocular coherence tomography
OCT2
organic cation transporter 2
ORR
objective response rate
PD
progressive disease
PDE4D
phosphodiesterase 4D
PDF
portable document format
pERK
phosphorylated ERK
PFS
progression-free survival
P-gp
P-glycoprotein


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Abbreviation or 
special term
Definition
PI3K
phosphoinositide 3-kinase
PK
pharmacokinetic(s)
PKC
protein kinase C
PLT
platelets
pMEK
phosphorylated MEK
PO
oral
PORCN
porcupine homolog
PPES
palmar-plantar erythrodysaesthesia syndrome
PR
partial response
PS
performance status
PT
preferred term
PVC
premature ventricular contraction
QD
once daily
QTcF
QT interval corrected for heart rate using the Fridericia formula
RAF
murine leukemia viral oncogene homolog
RAS
guanosine triphosphatase protein
RBC
red blood cell(s)
RECIST
Response Evaluation Criteria in Solid Tumors
RP2D
recommended Phase 2 dose
RPED
retinal pigment epithelial detachment
RVO
retinal vein occlusion
SAE
serious adverse event
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SAP
statistical analysis plan
SCC
squamous cell carcinoma


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Abbreviation or 
special term
Definition
SD
stable disease
SOP
standard operating procedure
SRSD
single reference safety document
SUSAR
suspected unexpected serious adverse reaction
t1/2
terminal elimination half-life
TdP
Torsade de Pointes
TBili
total bilirubin
Tmax
time of the maximum concentration
UDP
uridine diphosphate
UGT1A1
UDP-glucuronosyl transferase 1A1 
ULN
upper limit of normal
US
United States
Vol
quantity of urine excreted during each collection interval
Vss
volume of distribution at steady state
VZ/F
apparent total volume of distribution after extravascular administration
WBC
white blood cell(s)


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Amendment 7: Protocol Version 8.0
Amendment Rationale
The reasons for this amendment are as follows: 

To change enrollment language to reflect that patients may be enrolled to Arm 3 prior 
to the completion of Arm 1 enrollment as described in a Protocol Administrative 
Change Letter dated 14 April 2020. Unlike Arm 1, both Arms 2 and 3 allow smokers 
and this revision will provide an opportunity for these patients to participate in the trial 
once Arm 2 is fully enrolled.

To revise the Adverse Event and Serious Adverse Events Section 10.1 to align with 
Pfizer standard operating procedures with SAE reporting directly to Pfizer Safety.  

To include a guidance document to address alternative measures that may need to be 
considered at particular sites/regions due to the ongoing pandemic (Appendix 13: 
Alternative Measures During Public Emergencies).  

Other changes have been incorporated to align with Pfizer standards.
Changes to the Protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol. Key changes made in the body of the protocol are reflected in the Protocol 
Summary.
Section # and Name
Description of Change
Brief Rationale
Sponsor Signature Page
Principal Investigator 
Agreement Page
Sponsor signature page and Principal 
Investigator Agreement page has 
been removed from the protocol.
Sponsor signature page and Investigator 
Signature page will be separate from the 
protocol to align with Pfizer protocol 
standards.
Synopsis
4.1.1 DDI Phase
6.2 Allocation to 
Treatment
Enrollment language has been 
changed to reflect that patients may 
be enrolled to Arm 3 prior to the 
completion of Arm 1 enrollment.
Unlike Arm 1, both Arms 2 and 3 allow 
smokers and this revision will provide 
an opportunity for these patients to 
participate in the trial once Arm 2 is 
fully enrolled.
5.0 Patient Population
New Reference to Appendix 13
added.
A reference to Appendix 13 was added 
for guidance for patients with active or 
presumed SARS CoV-2 infection.
6.5 Dose Modifications 
and Reductions
New reference to Appendix 13
added.
A reference to Appendix 13 was added 
for guidance for patients with active or 
presumed SARS CoV-2 infection.
7.0 Study Procedures and 
Assessments
New reference to Appendix 13 
added.
A reference to Appendix 13 was added 
for guidance for patients with active or 
presumed SARS CoV-2 infection.
7.3 Pharmacokinetic 
Assessments
Added language that during COVID-
19 pandemic, sites should 
proactively contact and discuss 
challenges with the Pfizer clinician 
and Pfizer clinical pharmacologist.
Guidance added for patients with active 
or presumed SARS CoV-2 infection.


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Section # and Name
Description of Change
Brief Rationale
8.0 Study Assessments
New reference to Appendix 13 
added.
A reference to Appendix 13 was added 
for guidance for patients with active or 
presumed SARS CoV-2 infection.
9.1 Treatment 
Discontinuation for 
Individual Patients
New paragraph added for patients 
who withdraw consent.
New reference to Appendix 12 
added. 
New text on patients who withdraw 
consent has been added to align with 
Pfizer standard operating procedures. 
A reference to Appendix 12 was added 
for guidance for participants with active 
or presumed SARS CoV2 infection.
10.0 Safety Monitoring: 
Definitions and Reporting
Section 10 was replaced with 
language from Pfizer standard 
operating procedures.
Adverse Events and Serious Adverse 
Events revised to align with Pfizer 
standard operating procedures.
13.8.1 Data Sharing
New Section added
Data sharing section added to align with 
Pfizer standard operating procedures.
Appendix 10. Adverse 
Events: Definitions and 
Procedures for Recording, 
Evaluating, Follow-up, 
and Reporting. 
Appendix 11. Liver 
Safety: Suggested Actions 
and Follow-up
Appendix 12. ECG 
Findings of Potential 
Clinical Concern
Appendix 13. Alternative 
Measures During Public 
Emergencies
Added per Pfizer standard operating 
procedures.
Adverse Events and Serious Adverse 
Events Appendix 10, 11, and 12 added 
to align with Pfizer standard operating 
procedures. The Alternative Measures 
During Public Emergencies Appendix
13 was added as guidance to 
be followed during public emergencies, 
including the COVID-19 pandemic.
Entire document
Grammatical changes were made 
throughout document.
For clarification purposes.
IRB/IEC/HA
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. In addition, if the changes herein affect the Informed Consent, sites are 
required to update and submit for approval a revised Informed Consent that takes into
account the changes described in this amended protocol.


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Amendment 6: Protocol Version 7.0
Amendment Rationale
The primary reason for this amendment is to incorporate additional safety guidelines and safety 
monitoring to be consistent with other protocols in the encorafenib and binimetinib 
development programs. 
In addition, as encorafenib is the primary concern for drug interaction, language regarding 
replacement of patients due to dose discontinuation or dose reduction has been modified. Other 
changes have also been implemented in order to add clarification to the protocol and are 
outlined below.
Changes to the Protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol. All changes made in the body of the protocol are reflected in the Protocol 
Summary.

Synopsis
The synopsis was updated to align with body text in the document.

Section 4.1.1
DDI Phase
This section was updated to clarify when a patient would be considered unevaluable for 
PK, to modify patient replacement language and to clarify when a patient could remain 
on study following missed doses due to noncompliance.

Section 5.4.2.1
Prohibited Concomitant Medications
This section was updated to add a statement regarding prohibited anticancer therapies to 
be consistent with other protocols in the encorafenib and binimetinib development 
programs and to add clarification around timing of the caffeine restriction in each Arm.

Section 5.4.2.2
Permitted Concomitant Medication 
Language has been added regarding initiation of thromboprophylaxis.

Section 6.5
Dose Modifications and Reductions 
The section was updated to modify patient replacement language. 

Table 5
Encorafenib and Binimetinib – Recommended Dose Modifications 
Associated with Treatment-Related Adverse Events 
Language has been added for QTcF prolongation events regarding correction for 
electrolyte abnormalities and controlling cardiac risk factors for QT prolongation.

Table 6
Summary of Clinical Laboratory Tests
This table was updated to correct a formatting issue that was truncating the list of tests 
required and to add laboratory tests to be consistent with other protocols in the encorafenib 
and binimetinib development programs.

Section 7.1.9
Pregnancy Tests 


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Additional information has been added regarding timing of urine pregnancy tests and 
instruction on positive results. 
•
Section 7.4
Disease Assessments 
Language had been added for clarification that efficacy assessments are required 
although efficacy is not formally being assessed.
•
 
•
Section 8.3.4
Post-DDI Phase
Language had been added to specify that efficacy assessments are required every 8-12 
weeks in order to assess continued benefit.
•
Section 8.3.4.2
Every 8-12 Weeks
Language had been added to specify that efficacy assessments are required every 8-12 
weeks in order to assess continued benefit.
•
Section 9.2
Replacement of Patients
This section was updated to clarify when a patient would be considered unevaluable for 
PK, to modify patient replacement language and to clarify when a patient could remain 
on study following missed doses due to noncompliance.
•
Section 15.0
References 
The section has been updated to include a reference supporting the initiation of 
thromboprophylaxis.
IRB/IEC/HA
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. In addition, if the changes herein affect the Informed Consent, sites are 
required to update and submit for approval a revised Informed Consent that takes into
account the changes described in this amended protocol.
CCI


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Amendment 5
Amendment Rationale
The primary protocol revision involves decreasing the caffeine dose to 50 mg in the CYP probe 
cocktail in Arm 1 of the study. A review of the PK data from the first 3 patients who 
inadvertently received a lower dose of caffeine (50 mg caffeine administered as 100 mg 
caffeine citrate), showed adequate bioanalytical quantification at the 50 mg dose level to 
support the evaluation of the primary objective. Caffeine is thought to be a sufficient probe of 
CYP1A2 activity even at a 50 mg dose (Bosilkovska et al. 2014; Croft et al. 2012).
Additional changes include modification to the protocol title to more accurately reflect the 
current design of the study and alignment of the text with the Schedule of Events table with 
regard to PK sampling. Minor changes for consistency and clarification were also 
implemented.
Changes to the Protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol. All changes made in the body of the protocol are reflected in the Protocol 
Summary.

Title
The title has been modified to remove the detail regarding number of Arms in the study 
and drugs being co-administered to better align with the current study design.

Synopsis
The synopsis was updated to align with body text in the document.

Section 2.6.2
Rationale for Dose Selection
This section was modified to clarify that the CYP probe cocktail will be administered at 
the dose closest to, or lower than, the doses referenced in the Inje paper (Ryu 2007). This 
was done to avoid using a higher dose than needed and to allow the use of agents that are 
commercially available at the different sites and regions where the study is being 
conducted.

Section 4.2.1
Treatment Regimens
This section was modified to reflect a lower dose of caffeine administered and to remove 
reference to the mg/mL doses for caffeine and midazolam, as this information is detailed 
in the pharmacy manual and in order to reduce confusion.

Section 6.1
Dosing Regimen
This section was modified to reflect a lower dose of caffeine administered and to remove 
reference to the mg/mL doses for caffeine and midazolam, as this information is detailed 
in the pharmacy manual and in order to reduce confusion.

Section 8.3.2.4
Day 14 and Day 21 at Hours 1 and 3
This section was added to maintain consistency with Table 8 Schedule of Events – Arm 
3.


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IRB/IEC/HA
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. In addition, if the changes herein affect the Informed Consent, sites are 
required to update and submit for approval a revised Informed Consent that takes into account 
the changes described in this amended protocol.


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Amendment 4
Amendment Rationale
The primary reason for amendment 4 is to add a drug-drug interaction assessment of a sensitive 
CYP2B6 substrate and a moderate CYP3A4 inducer.
Arms 1 and 2 will now be allowed to enroll in parallel rather than sequentially and the non-
smoking inclusion criteria has been edited to only apply to patients in Arm 1 to aid patient 
recruitment. Also, the losartan dose has been lowerd from 50 mg to 25 mg to minimize 
potential side effects. 
In addition, some exclusion criteria and guidelines for safety monitoring during the post-DDI 
phase have been revised to be consistent with other protocols in the encorafenib and 
binimetinib development programs.
Changes to the Protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol. All changes made in the body of the protocol are reflected in the Protocol 
Summary.

Synopsis
The synopsis was updated to align with body text in the document.

Principal Investigator Agreement
The section was updated to reflect the current version of the GCP Guidance.

Section 2.3.2.1
Clinical Pharmacology
The section was updated to to add the terminal elimination half-life of encorafenib.

Section 2.5.2.2
Safety
The section was updated to remove reference to the patient population in the current 
study being the same as the Phase 3 Study CMEK162B2301.

Section 2.5.2.3
Efficacy
The section was revised to include updated results from the pivotal phase 3 study 
CMEK162B2301.

Section 2.6.1
Rationale for the Study
The section was updated to include information on a CYP2B6 substrate and a moderate 
CYP3A4 inducer and the rationale for the drugs selected (bupropion and modafinil).

Section 2.6.2
Rationale for Dose Selection
The section was updated to include information on the rationale for the doses of 
bupropion and modafinil selected.

Section 3.1
Study Objectives
The section was updated to include information on the primary and secondary objectives 
for the addition of bupropion and modafinil.


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Section 3.2
Study Endpoints
The section was updated to include information on the primary, secondary 
 
 endpoints for the addition of bupropion and modafinil.
•
Section 4.1
Study Design Overview
The section was updated to include detailed information on the addition of bupropion to 
Arm 2 of the study and to add a new arm (Arm 3) to test the addition of modafinil to 
encorafenib/binimetinib administration. Updates were also made to the study schema in 
Figure 1 to reflect these additions. In addition, language regarding replacement of 
patients has been changed to reflect that patients may be replaced, but not required to be.
•
Section 4.1.1
DDI Phase
The section was updated to allow parallel enrollment into Arms 1 and 2 versus sequential 
enrollment.
•
Section 4.2
Doses and Schedule of Administration
The section was updated to include detailed information on the doses and dosing 
instructions for the addition of bupropion to Arm 2 and modafinil in Arm 3. In addition, 
language regarding replacement of patients has been changed to reflect that patients may 
be replaced, but not required to be.
•
Section 4.2.1
Treatment Regimens
The section was updated to lower the losartan tablet strength from 50 mg to 25 mg.
•
Section 4.3
Duration of Treatment
The section was updated to include duration days for Arm 3 of the study. 
•
Section 5.1
Number of Patients
The section was updated to reflect the increased number of patients planned for the study 
due to the addition of Arm 3.
•
Section 5.2.1
Inclusion Criteria
Inclusion criteria 4 was modified to clarify that the presence of BRAF mutation is 
determined by a local test, not an approved test. 
Inclusion criteria 8 was redefined as being required for Arm 1 only. 
•
Section 5.2.2
Exclusion Criteria
Exclusion criteria 3 was modified to clarify the days of encorafenib/binimetinib 
administration and to add CYP2B6 substrates to the list of restricted medications. Criteria 
was modified for clarity and Arm specific bullets for restricted medications were added. 
Exclusion criteria 10 and 11 replaced the prior thromboembolic criteria for consistency 
with other Array sponsored protocols 
Exclusion criteria 13 was modified to clarify that only patients with specific toxicities be 
excluded from participating. 
Exclusion criteria 15 was redefined as being required for Arm 1 only. 
Additional exclusion criteria were added for patients enrolled into Arm 3 of the study due 
to reported adverse events with modafinil administration.
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Exclusion criteria 9b and 9c were added for patients enrolled into Arm 3 of the study due 
to reported adverse events with modafinil administration.

Section 5.4.2.1
Prohibited Concomitant Medications
The section was updated to add CYP2B6 substrates to the list of restricted medications.
Criteria was modified for clarity and Arm-specific bullets for restricted medications were 
added.

Section 5.4.2.3
Prohibited Concomitant Medication Requiring Caution and/or Action
The section was updated to include cross-references to the schedule of events for Arm 3 
(Table 9). This section was also updated to reflect current program guidelines for 
concomitant medications. 

Section 6.0
Study Treatment
Sections 6.1 Dosing Regimen, 6.2 Allocation to Treatment and 6.3 Packaging and 
Labeling were updated to include detailed information on the doses and dosing 
instructions for the addition of bupropion to Arm 2 and modafinil in Arm 3. In addition, 
the table describing packaging and labeling has been removed for consistency with other 
Array sponsored protocols.

Section 6.1
Dosing Regimen
The section was updated to lower the losartan tablet strength from 50 mg to 25 mg.

Section 6.2
Allocation to Treatment
The section was updated to add detail regarding parallel enrollment into Arms 1 and 2 
versus sequential enrollment.

Section 6.5
Dose Modifications and Reductions
The section has been changed to reflect that patients may be replaced, but not required to 
be, reference to QTcF prolongation following binimetinib administration has been 
removed and a section for uveitis has been added to the dose modification table (Table 6).

Section 6.5.1.2
Follow-up Evaluations for Appearance of Keratoacanthoma (KA) 
and/or Squamous Cell Carcinoma (SCC)
The section has been revised to include guidance on follow up dermatological 
examinations to be consistent with other encorafenib protocols.

Section 7.0
Study Procedures and Assessments
Sub-sections throughout have been updated to include cross-references to the schedule of 
events for Arm 3 (Table 9).

Section 7.1.4
Electrocardiogram
The section was updated to clarify that predose ECGs should be performed up to 30 
minutes before any study drug administration, to give examples of abnormal ECGs to be 
repeated, to indicate that ECG tracing should be made available if requested, and to 
clarify that QT interval correction will be done using the Fridericia formula.


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Section 7.1.6
Table 7 Summary of Clinical Laboratory Tests
The table was updated to remove GGT from the panel of chemistry tests required as it is 
a nonspecific measure of liver function.
•
Section 7.1.8
Dermatologic Examinations
The section was updated to maintain consistentency with the recommended guidelines for 
following patients in the encorafenib development program.
•
Section 7.2
Pharmacokinetic Assessments
The section was updated to include the analysis of bupropion and hydroxybupropion and 
to clarify that analytes quantitated are dependent on study arm.
•
 
•
Section 8.0
Schedule of Procedures and Assessments
Sub-sections throughout have been updated to clarify procedures for Arms 1 and 2, to 
add procedures and schedule of events for Arm 3 and include cross-references to the 
schedule of events for Arm 3 (Table 9). Subsection 8.3.4.1 was updated to clarify 
procedures that are recommended to be performed every 3-4 weeks. Subsection 8.3.4.2 
and 8.3.4.3 were added to clarify procedures that are recommended to be performed 
every 8-12 weeks to be consistent with the recommended guidelines for monitoring 
patients in the encorafenib and binimetinib development programs.
•
Section 9.1
Treatment Discontinuation for Individual Patients
The section was updated to remove the recommendation that patients missing 3 or more 
consecutive encorafenib and binimetinib doses should be discontinued.
•
Section 9.2
Replacement of Patients
The section has been changed to reflect that patients may be replaced, but not required to 
be.
•
Section 10.8
Reporting of Serious Adverse Events
The section has been updated to indicate that safety evaluations are recommended to 
occur every 3 to 4 weeks, unless otherwise specified.
•
Section 11.1.1
Sample Size
The section has been updated to include sample size rationale for Arm 2 and Arm 3 and 
to clarify approximately 20 patients would be needed in Arm 1 for concistency in the 
protocol.
•
Section 11.1.2
Safety Analysis
The section has been updated to reflect the study as 3 arms and to indicate that safety 
evaluations are recommended to occur every 3 to 4 weeks, unless otherwise specified.
•
Section 11.1.3
Pharmacokinetic Analysis
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The section has been updated to include details regarding days of analysis, the analysis of 
bupropion and hydroxybupropion, that modafinil may be analyzed and addition of Arm 3
ANOVA information. 

Section 15.0
References
The section has been updated to include references supporting the choice and doses of 
bupropion and modafinil. 
IRB/IEC/HA
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. In addition, if the changes herein affect the Informed Consent, sites are 
required to update and submit for approval a revised Informed Consent that takes into 
account the changes described in this amended protocol.


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Amendment 3
Amendment Rationale
The reason for the current amendment is to permit enrollment of patients who have had prior 
therapy with a BRAF inhibitor (e.g., vemurafenib, dabrafenib, encorafenib and XL281/BMS-
908662) and/or a MEK inhibitor (e.g., trametinib, binimetinib, selumetinib, cobimetinib and 
refametinib), provided the BRAF inhibitor and/or MEK inhibitor was not in the regimen 
immediately prior to study entry.
In addition, minor changes for consistency and clarification were implemented.
Changes to the Protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol. All changes made in the body of the protocol are reflected in the Protocol 
Summary.

Synopsis
The synopsis was updated to align with body text in the document.

Section 2.4.2.3
Efficacy
The above section was updated to include information on patients with BRAF-mutant 
melanoma who had been rechallenged with combination BRAF/MEK inhibitor therapy 
following prior BRAF inhibitor therapy.

Section 4.1
Study Design Overview
The above section was clarified to state that patients in the post-DDI phase will be 
followed per local standard-of-care practice and to specify that, in the post-DDI phase, all
SAEs should be reported to the Sponsor.

Section 4.12 Post-DDI Phase; Section 8.5.1 [Post-DDI Phase] To Occur Every 3-4 
Weeks; Section 8.5.2 [Post-DDI Phase] Day 30 Safety Follow-up Visit; Section 8.5.2 
Table 8 Schedule of Events
The above sections were clarified to specify that, in the post-DDI phase, all SAEs should 
be reported to the Sponsor. 

Section 5.2.1
Inclusion Criteria
The above section was modified as follows:

Inclusion Criterion 6: Patients with unresectable locally advanced or metastatic 
melanoma permitted to have prior BRAF and/or MEK inhibitor therapy, provided it 
was not in the regimen immediately prior to study entry.

Inclusion Criterion 7: Patients with other (non-melanoma) BRAF V600-mutant 
advanced solid tumors permitted to have prior BRAF and/or MEK inhibitor therapy, 
provided it was not in the regimen immediately prior to study entry, and specifies that 
enrollment of patients who progressed on such prior therapy must be discussed with 
the Sponsor.


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
Inclusion Criterion 10:  Reformatted to present items using letters, rather than bullets, 
for consistency with other eligibility criteria.

Section 5.2.2
Exclusion Criteria
The above section was modified as follows:

Exclusion Criterion 12: Prior BRAF/MEK inhibitor therapy was removed as an 
exclusion criterion; discontinuation of such therapy for toxicity was added as an 
exclusion criterion.

Section 10.1 Adverse Event; Section 10.2 Adverse Events Related to Progression of 
Disease; 10.4 Clinical Laboratory Abnormalities; Section 10.6 Assessment of Severity; 
Section 10.7 Assessment of Causality; Section 10.8 Assessment of Seriousness; Section 
10.9 Reporting of Serious and Nonserious Adverse Events; Section 10.10 Reporting of 
Suspected Unexpected Serious Adverse Events; Section 10.11 Pregnancy or Drug 
Exposure During Pregnancy; 10.12 Review of Safety Data
The above sections were updated with current Sponsor language regarding 
documentation of adverse events.

Section 10.3
Adverse Events Related to Subsequent Anti-Cancer Therapy
The above section was deleted.

Section 15
References
The above section was updated to include a new reference.

Appendix 7
Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1
The above appendix was updated to correct numbering of section headings.
IRB/IEC/HA
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. In addition, if the changes herein affect the Informed Consent, sites are 
required to update and submit for approval a revised Informed Consent that takes into 
account the changes described in this amended protocol.


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Amendment 2
Amendment Rationale
The reason for the current amendment is to clarify certain study procedures (e.g. assessment 
of coagulation; urine PK is for Arm 1 only), add more detailed guidance on contraception 
and ultraviolet light exposure and ensure consistency of wording among protocol sections.
In addition, minor changes for consistency and clarification were implemented.
Changes to the Protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol. All changes made in the body of the protocol are reflected in the Protocol 
Summary.

Synopsis
The synopsis was updated to clarify that the order of the CYP probe cocktail ingredients
as listed is the order in which they should be taken. 
The synopsis was also updated for eligibility criteria to clarify content and align with 
body document text.
The synopsis was also updated to clarify when patient replacement is required.

Section 2.5.1
Rationale for the Study
The above section was updated to add the impact of encorafenib on metabolic processes.

Section 3.2
Study Endpoints
The above section was minimally revised to align wording between synopsis and body of 
document.

Section 4.1.1
DDI Phase
The above section was updated to clarify that urine PK assessment is for patients in Arm 
1 only and to clarify when patient replacement is required.

Section 4.2.1
Encorafenib and Binimetinib
The above section was updated to correctly state the formulation of encorafenib as a 
capsule rather than a tablet. In addition, Added that encorafenib and binimetinib can be 
taken with or without food on non-PK days. Added that the order of the CYP probe 
cocktail ingredients is the order in which they should be taken.

Section 4.3
Duration of Treatment
The above section was updated to updated to clarify the timing of Prescreening and 
Screening.

Section 5.2.1
Inclusion Criteria
The above section was updated to separate Inclusion Criterion #6 into 2 separate criteria 
(added new Inclusion Criterion #7) to clarify the prior therapy criteria for patients with 
unresectable locally advanced or metastatic melanoma (e.g., naïve, untreated patients or 
patients who have progressed on or after prior systemic therapy) and for patients with
other (non-melanoma) BRAF V600-mutant advanced solid tumors (e.g., who have 
progressed on standard therapy or for whom there are no available standard therapy).


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
Section 5.2.2
Exclusion Criteria
The above section was updated for Exclusion Criteria #3 and 4 to clarify content and 
align with body document text pertaining to concomitant medications. Exclusion criterion 
#6 was revised to reflect current eligibility criteria for encorafenib and binimetinib 
protocols for retinal vein occlusion (RVO). Exclusion criterion #7b was corrected for left 
ventricular ejection fraction (LVEF) to be < 50%. Corrected wording of Exclusion 
Criterion 9 and replace “encorafenib” with “study drugs” to match wording in synopsis.

Section 5.3.1
Requirements for Contraception
In the above section, clarified that use of contraception is required for all males and 
females of childbearing potential from Screening through 90 days and 30 days, 
respectively, after the last dose of study drug.

Section 5.3.2
Ultraviolet Light Exposure
The above section was added to recommend use of precautionary measures against 
ultraviolet exposure.

Section 5.4.2.1
Prohibited Concomitant Medications
The above section was updated to to clarify content and align with exclusion criteria 
pertaining to concomitant medications.

Section 6.1
Dosing Regimen
The above section was updated to clarify that the order of the CYP probe cocktail 
ingredients is the order in which they should be taken.

Section 6.4
Study Drug Dispensing and Administration
Section was revised to clarify that dosing diaries will be provided at each study visit.

Section 6.5 
Dose Modifications and Reductions, Table 4 Dose Reduction for 
Encorafenib
The above section was updated to clarify when patient replacement is required due to 
dose modifications. The dose reduction table for encorafenib was revised to list the 
lowest dose option to be used with encorafenib.

Section 7.1.6
Clinical Laboratory Tests and Table 7 Summary of Clinical 
Laboratory Tests
Drug and alcohol testing on Day -7 at Hour 0 was added to the table to match the study 
procedures.

Section 7.2
Pharmacokinetic Assessments
The above section was updated to correct that timepoints indicated are 0 hour through 8 
hours, rather than 1 hour through 8 hours, and to add that patient should void as close to 
the 8 hour time point as possible. The text was clarified to state that the urine PK 
assessments are for Arm 1 only.

Sections
8.2 Screening Evaluations, 8.3.1.1 (Day -7 at Hour 0), 8.3.1.4 (Day 1 and Day 
14 at Hour 0) and 8.4 (Day 28, End of DDI Phase Visit)
The above sections were updated to add that coagulation will also be assessed from the 
blood sample collected and Day -7 urinalysis will include drug and alcohol testing.


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
Sections
8.3.1.1 (Day -7 at Hour 0), 8.3.1.2 (Day -7 at Hours 1 and 3), 8.3.1.3 (Day -7 
at Hours 2, 4, 6 and 8), 8.3.1.4 (Day 1 and Day 14 at Hour 0), 8.3.1.5 (Day 1 and 14 at 
Hours 1 and 3) and 8.3.1.6 (Day 1 and Day 14 at Hours 2, 4, 6 and 8)
The above sections were updated to clarify that urine PK collection is for Arm 1 only.

Table 8
Schedule of Events
The above table was updated to add coagulation assessments, clarify that urine PK 
assessment is for patients in Arm 1 only and to correct footnote numbering. Added to 
footnote “L” that drug and alcohol screen are part of the Day -7 urinalysis.

Section 9.1
Treatment Discontinuation of Individual Patients
The above section was updated to clarify that a patient will be discontinued from 
treatment if he/she misses encorafenib or binimetinib dosing for > 28 days in the post-
DDI phase.
The above section was updated to clarify that  an AE dose delay in requiring treatment 
discontinuation includes delay in the post-DDI phase of more than 28 days to restart 
treatment due to an AE.

Section 9.2
Replacement of Patients
The above section was updated to clarify when patient replacement is required.

Section 11.1.1
Sample Size
The above section was updated to align with wording in synopsis (analysis based on 
mean AUClast).

Section 11.1.3
Pharmacokinetic Analysis
The above section was updated to clarify that patients who have sufficient concentration 
data to calculate at least one PK parameter on Day -7, Day 1 and Day 14 will be included 
in the PK analyses and to correct day range used in analyses.

All Appendices
Appendices headers were corrected for the study number.

Appendix 9: ECOG performance status 
The above appendix table was added for ease of use.
IRB/IEC/HA
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. In addition, if the changes herein affect the Informed Consent, sites are 
required to update and submit for approval a revised Informed Consent that takes into 
account the changes described in this amended protocol.


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Amendment 1
Amendment Rationale
The reason for the current amendment is to clarify certain study procedures (e.g. follow-up in 
the DDI phase), add as an inclusion criterion that patients must be non-smokers, add as an 
exclusion criterion consumption of specific products containing citrus juice and add 
additional laboratory parameters for assessment.
In addition, minor changes for consistency and clarification were implemented.
Changes to the Protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions. All 
changes made in the body of the protocol are reflected in the Protocol Summary.

Section 2.2.2.1 Clinical Pharmacology
The above section was updated to include study numbers and add the encorafenib Tmax
data.

Section 2.2.2.2.1 Encorafenib Monotherapy in Patients with Advanced Cancer
The above section was updated to include data on determination of the encorafenib 
single-agent dose of 300 mg QD.

Section 2.3.2.1 Clinical Pharmacology
The above section was updated to include study numbers and add the binimetinib Tmax
data.

Section 2.3.2.2.1 Binimetinib Monotherapy in Patients with Advanced Cancer
In the above section, data from binimetinib studies with combination agents other 
encorafenib were deleted due to lack of relevance to this protocol.

Section 2.4.2.2
Safety
The above section was updated clarify the studies providing safety data. Information on 
AE withdrawal and deaths was deleted and directed to the Investigator’s Brochure for 
further information.

Section 4.1 Study Design Overview; Section 4.1.2  Post-DDI Phase; Section 8.5.1 To 
Occur Every 3-4 Weeks; Section 8.5.2 Day 30 Follow-up Visit; Table 9; Section 10.9 
Reporting of Serious and Nonserious Adverse Events
The above sections were updated clarify the safety follow-up and data collection in the 
post-DDI phase.

Section 4.2.1 Encorafenib and Binimetinib
The above section was updated to clarify that binimetinib and encorafenib are to be taken 
together and to add clarification on consumption of products containing citrus juice.

Section 5.2.1 Inclusion Criteria
The above section was updated to only include non-smoking patients who had not used 
products with nicotine within 3 months of first dose of study drugs.

Section 5.2.2 Exclusion Criteria
The above section was updated to exclude consumption of specific products containing 
citrus juice and to exclude patients with a positive cotinine test.


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
Section 5.3.1 Requirements for Contraception
The above section was updated to clarify that oral, injectable, or implanted contraceptives 
were acceptable only when combined with other highly effective or acceptable methods.

Section 5.4.2.1  Prohibited Concomitant Medications
The above section was updated to prohibit consumption of specific products containing 
citrus juice.

Section 6.5 Dose Modifications and Reductions
The above section was updated to clarify that if encorafenib was to be continued as 
monotherapy, it be at 300 mg QD.

Section 6.5.1 Follow-up for Toxicities
The above section was updated to clarify that all doses and dose changes are to be 
captured on the eCRF.

Section 7.1.6 Clinical Laboratory Tests – Table 8
The above section was updated to add assessment of amylase, LDH, lipase, aPTT, PT or 
INR.

Table 9 – Schedule of Events
The above section was updated to add that BOR was to be assessed at the Day 30 Follow-
up Visit.
IRB/IEC/HA
A copy of this amended protocol will be sent to the IRBs/IECs and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. In addition, if the changes herein affect the Informed Consent, sites are 
required to update and submit for approval a revised Informed Consent that takes into
account the changes described in this amended protocol.


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1. INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE
The Investigator is the person responsible for the conduct of the study at the investigational 
site. A subinvestigator is any member of the clinical study team designated and supervised by 
the Investigator to perform critical study-related procedures and/or to make important study-
related decisions.
Prior to study initiation, the Principal Investigator at each site must provide to Array 
BioPharma Inc. (a wholly owned subsidiary of Pfizer Inc./Sponsor) a signed protocol 
signature page, a fully executed and signed United States (US) Food and Drug 
Administration (FDA) Form 1572, a current curriculum vitae (CV), medical license and a 
financial disclosure form. Financial disclosure forms, current CVs and medical licenses must 
also be provided for all subinvestigators listed on Form 1572 who will be directly involved in 
the treatment or evaluation of patients in this study.
The study will be administered and monitored by employees or representatives of the 
Sponsor and/or a contract research organization (CRO) in accordance with all applicable 
regulations. Clinical research associates (CRAs) will monitor each site on a periodic basis 
and perform verification of source documentation for each patient. Pfizer Safety (and/or the 
CRO, if applicable) will be responsible for ensuring timely reporting of expedited serious 
adverse event (SAE) reports to regulatory authorities and Investigators.


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2. INTRODUCTION
2.1. BRAF Mutation-Positive Cancer
Activating mutations in the gene encoding the serine̢threonine protein kinase BRAF were 
identified in large-scale screens in human cancers (Davies et al 2002). After this first report 
of BRAF mutations was described in 2002, several other BRAF mutation studies in different 
tumors types were reported. It is now well established that 90% of reported BRAF mutations 
result in a substitution of valine by glutamic acid at amino acid 600 (V600E mutation) which 
leads to a 500-fold increase in BRAF activity compared to wild-type BRAF (Wan et al 
2004). More than half of patients with metastatic melanoma have mutations in BRAF, and 
over 95% of these are in BRAF exon 15 at V600 (Davies et al 2002). Somatic mutations of 
BRAF also occur in 8-15% of colorectal cancers, (Rajagopalan et al 2002; Hodis et al 2012;
Krauthammer et al 2012), in 30% of serous borderline ovarian cancers (Singer et al 2003), in 
40-70% of papillary thyroid carcinomas (Brose et al 2002; Cohen et al 2003; Nikiforova et al 
2003; Fukushima et al 2003) and in 7-8% of all solid tumors (Brower 2010), implicating 
activating oncogenic mutations of BRAF as critical promoters of malignancy. 
The most common V600 mutations in metastatic melanoma are V600E and V600K 
accounting for 66-91% and 7-30% of all BRAF V600 mutations, respectively (Cheng et al 
2011; Colombino et al 2012; Jakob et al 2012; Greaves et al 2013). These mutations 
constitutively activate BRAF protein and downstream signal transduction in the 
RAF/MEK/ERK pathway, which signals for cancer cell proliferation and survival.
Melanoma is a cancer that primarily arises from melanocytes, the cells that produce the 
pigment melanin. Both the incidence and mortality rate of melanoma are rapidly increasing 
throughout the world, constituting a significant and growing health burden (Ferlay et al 2015; 
American Cancer Society 2016). The worldwide incidence of melanoma in 2012 was 
estimated at over 232,000 (data source GLOBOCAN 2016 at Cancer Today; 
http//gco.iarc.fr/today/home), and it is estimated that over 76,000 people will be diagnosed 
and that over 12,000 deaths will be attributed to melanoma in 2016 in the US alone (Siegel et 
al 2016; American Cancer Society 2016).
Although the current MEK/BRAF inhibitor combinations have transformed the standard-of-
care treatment for melanoma, they each have liabilities that could limit their effectiveness 
suggesting that additional therapeutic options are needed. Advanced BRAF V600-mutated 
melanoma remains an aggressive disease that portends a poor prognosis and there remains a 
need to develop new treatment regimens to expand the therapeutic options for patients.
Encorafenib (LGX818) and binimetinib (also known as MEK162 or ARRY-438162) are 
being developed to inhibit the growth of tumors with activating mutations of the 
RAS/RAF/MEK/ERK pathway.
2.2. Drug-Drug Interaction Potential
Metabolic routes of elimination, including those occurring through the cytochrome P450 
(CYP) family of enzymes and uridine diphosphate (UDP)-glucuronosyl transferases (UGTs), 
and uptake and efflux transporters can be inhibited and/or induced by concomitant drug 
treatment. Changes arising from these drug-drug interactions can be significant, and 
contribute to increases or decreases in the blood and tissue concentrations of the parent drug 


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or active metabolite. Increased concentrations of a parent drug or its active metabolite can 
alter the safety and efficacy profile of a drug. It is, therefore, important to determine if 
metabolic drug-drug interactions are likely to significantly affect the elimination of a drug.
The FDA guidance for Drug Interaction studies recommends evaluating the extent of enzyme 
and transporter inhibition and/or induction by conducting a study with probes sensitive to 
changes in activity of the corresponding enzyme or transporter (Food and Drug 
Administration. Guidance for Industry 2012). The main purpose of this study is thus to 
evaluate the potential effect of encorafenib in combination with binimetinib on enzymes and 
transporters of interest in vivo (see Section 2.6.1).
2.3. Overview of Encorafenib
Encorafenib is a novel oral small-molecule kinase inhibitor with potent and selective 
inhibitory activity against mutant BRAF kinase, a member of the murine leukemia viral 
oncogene homolog (RAF)/ mitogen-activated protein (MAP) kinase kinase (MEK)/
extracellular regulated signal kinase (ERK)/ MAP kinase (MAPK) pathway, which plays a 
prominent role in controlling several key cellular functions including growth, proliferation, 
and survival.
Encorafenib is currently being investigated as a single-agent and in combination with other 
agents including inhibitors of the MEK, phosphoinositide 3-kinase (PI3K), epidermal growth 
factor receptor (EGFR), cyclin-dependent kinase 4/6 (CDK4/6), porcupine homolog 
(PORCN) and cMET proteins in patients with selected advanced or metastatic BRAF-
mutated solid tumors, such as melanoma, colorectal, lung and thyroid cancers.
2.3.1. Nonclinical Studies with Encorafenib
2.3.1.1. Nonclinical Pharmacology
2.3.1.1.1. Target Inhibition
Encorafenib is a highly selective adenosine triphosphate (ATP) competitive small-molecule 
RAF kinase inhibitor which suppresses the RAF/MEK/ERK pathway in tumor cells 
expressing BRAFV600E. For example, the half maximal response concentration (EC50) for 
suppression of phosphorylated MEK (pMEK) and phosphorylated ERK (pERK) in A375 
human melanoma cells are 2 nM and 3 nM, respectively. Suppression of the RAF/MEK/ERK 
pathway causes cell cycle arrest which leads to inhibition of cell proliferation with an 
EC50 = 4 nM. Similar to other selective small molecule RAF kinase inhibitors, encorafenib 
inhibits CRAF, BRAF, as well as BRAFV600E in cell-free assays; however, this class of 
inhibitor does not inhibit RAF/MEK/ERK signaling in cells expressing wild-type BRAF. 
Given both the high degree of selectivity of encorafenib for the RAF kinases in biochemical 
assays (only 2/75 non-RAF kinases inhibited at concentrations < 1 μM), and the failure of 
encorafenib to inhibit wild type RAF kinases in cells, encorafenib has no antiproliferative 
activity in tumor cell lines that express wild-type BRAF.
The metabolite NVP-LYH746 (also known as M42.5A) was assessed for its off-target 
activity on 56 G protein coupled receptors, transporters, ion channels, nuclear receptors and 
enzymes since this metabolite represented 15.5% of total radioactivity in plasma in the 


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human absorption, distribution, metabolism, and excretion (ADME) study. The results 
showed activities of > 50% inhibition at 10 µM were found on kinase insert domain receptor 
(half maximal inhibitory concentration [IC50] = 1.8 µM, n = 1) and phosphodiesterase 4D 
(PDE4D) (IC50 = 4.2 µM, n = 2), showing significantly less potency than encorafenib.
The narrow kinase profile and potent antiproliferative activity of encorafenib translates into a 
very wide therapeutic index in vivo. In mouse and rat xenograft models of human melanoma 
expressing BRAFV600E, encorafenib induces tumor regression at doses as low as 5 mg/kg 
and 1 mg/kg, respectively (~360 ng*hr/mL free drug plasma exposure). Tumor regression 
was associated with continuous and strong (> 75%) suppression of pMEK, pERK, and 
downstream transcriptional targets dual specificity phosphatase 6 (DUSP6) and SPRY4. By 
contrast, encorafenib was tolerated in the 1 month Good Laboratory Practice (GLP) 
toxicology study at doses up to 100 mg/kg in males and females (5140 ng*hr/mL in cyno and 
23400 ng*hr/mL in rats free drug exposure). Taken together, these data suggest that 
encorafenib has a wide therapeutic index (> 11 fold) and that regression of BRAFV600E 
human melanoma tumor xenografts is associated with a strong and sustained inhibition of the 
RAF/MEK/ERK pathway.
2.3.1.1.2. Nonclinical Absorption, Distribution, Metabolism, Excretion and 
Pharmacokinetics
The oral bioavailability (F) of encorafenib was ~40 to ~50% in the mouse, rat, and dog. In 
the monkey ADME study, F was low (22%). Encorafenib showed low plasma clearance in 
the rat and mouse and a moderate to high plasma clearance in the monkey and dog. The 
estimated volume of distribution at steady state (Vss) was low in the rodents and moderate in 
the dog and monkey. In the monkey 13-week toxicity study, encorafenib increased 
proportionally with dose and no accumulation upon multiple dosing. 
Encorafenib is a substrate of P glycoprotein (P-gp) with a high apparent passive permeability. 
Binding to human plasma proteins was ~86%.
Distribution into rat tissues was rapid. There was no distribution to the central nervous 
system (CNS; brain and spinal cord) and no retention in the melanin-rich tissues.
For all species investigated, monohydroxylation, N-dealkylation, and subsequent 
glucuronidation represented the major metabolic pathways. Glucuronidation, both direct and 
indirect, occurred more readily in human than in other species. Encorafenib is metabolized 
by cytochrome P450 (CYP) 3A4, CYP2C19, and CYP2D6. CYP3A4 was predicted to be the 
major enzyme contributing to total oxidative clearance of encorafenib in human liver 
microsomes (~83.3%), followed by CYP2C19 and CYP2D6 (~16.0% and 0.71%, 
respectively).
The predominant route of excretion of 14C-encorafenib in monkeys was via fecal excretion 
while the urinary excretion was a minor route of elimination. Encorafenib is predominantly 
excreted as metabolites.
In vitro experiments indicate that encorafenib is a relatively potent reversible inhibitor of 
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(UGT1A1), CYP2B6, CYP2C9, and CYP3A4/5, and also a time-dependent inhibitor of 
CYP3A4. Encorafenib induced CYP1A2, CYP2B6, CYP2C9, and CYP3A4 in human 
primary hepatocytes. Finally, encorafenib was found to be a weak inhibitor of breast cancer 
resistance protein (BCRP), and a potent inhibitor of renal transporters organic cation 
transporter (OCT) 2, organic anion transporter (OAT) 1, OAT3 and hepatic transporters 
OCT1, organic anion transporting polypeptide (OATP) 1B1 and OATP1B3.
2.3.1.2. Nonclinical Toxicity and Safety
Preclinical safety pharmacology data do not indicate a clinical risk for QTc prolongation, or 
adverse effects on the CNS or respiratory system. Administration of encorafenib to male 
albino rats as a single oral dose of 100 mg/kg produced no drug related effects on the CNS or 
respiratory system. In Good Laboratory Practice (GLP) 4- and 13 week oral (gavage) toxicity 
studies in monkeys and a GLP monkey telemetry study, encorafenib had no effect on 
electrocardiographic morphology, rhythm, or PR, QRS, QT, and QTc duration. Using cloned 
human ether-à-go-go related gene (hERG) potassium channels expressed in mammalian 
cells, the IC50 for hERG inhibition by encorafenib was determined to be 73.4 µM indicating 
an unlikely effect of encorafenib on QTc prolongation. Encorafenib was evaluated for safety 
in rats and cynomolgus monkeys in studies for up to 13 weeks in duration. Overall, 
encorafenib was well tolerated. There were findings believed to be associated with the 
pharmacologic activity of a BRAF kinase inhibitor activation of the RAF/MEK/ERK 
pathway. These included hyperplasia and hyperkeratosis in the skin (plantar surface of feet) 
and nonglandular stomach in rats. Additional toxicity was observed in the 4- and 13-week 
GLP rat study in the testes/seminiferous tubules and epididymides that included an absence 
of the later stages of spermatid maturation. This finding did not appear to be reversible in 
affected tubules in the 4-week rat study, but the 13-week rat study showed evidence of 
recovery. There was significant mortality/morbidity in rats (mostly females) at the highest 
dose (400 mg/kg/day) in the 4-week rat study. In these early death rats, significant lesions 
were seen in the kidneys, liver, stomach, esophagus, bone marrow, spleen, thymus, lymph 
nodes, pancreas, adrenal glands, and parathyroid glands. However in the 4 female rats that 
survived the recovery, there were no histopathologic findings indicating these toxicities were 
reversible. 
The formulation used in the 4-week GLP monkey study, 56:29:15% (w:w:w) 
PEG400:Cremophor EL:oleic acid, has given the best exposure but causes significant 
diarrhea in all groups, including the vehicle control animals. The high dose (100 mg/kg/day) 
was associated with increased severity of diarrhea and slight body weight loss. 
In the 13-week monkey study with a solid dispersion formulation, at doses up to 60 
mg/kg/day, the only test article-related finding was abnormal retina (with blister like lesions 
over the macular region) in 2 high-dose animals. This finding showed evidence of recovery 
in one of the affected animals. Histopathology examination of the affected eyes suggested 
that the findings were similar to retinopathy associated with MEK inhibitor.
The GLP Ames and chromosomal aberration assays as well as a rat micronucleus study 
indicate that encorafenib is not genotoxic. Encorafenib showed a potential for phototoxicity 
in a screen 3T3 NRU in vitro assay. Additionally, encorafenib did not show a sensitizing 


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potential in the murine LLNA TIER I assay, although revealed a weak irritating potential. 
However, it tested negative in the primary skin irritation assay in rabbits.
Embryo-fetal development studies show evidence of delayed skeletal development secondary 
to decreased fetal body weight at maternally toxic doses in rabbits and in rats decreased 
ossification that is considered to be secondary to decreased fetal body weight as a result of 
moderately decreased maternal body weights.
Detailed information regarding nonclinical studies of encorafenib is presented in the 
Investigator’s Brochure.
2.3.2. Clinical Experience with Encorafenib
2.3.2.1. Clinical Pharmacology
The human ADME study in healthy subjects (CLGX818A2101) showed that encorafenib is 
at least 86% absorbed based on recovered radioactivity and has a preferential distribution to 
plasma as compared to blood. The predominant biotransformation reaction of encorafenib 
was N-dealkylation (other major metabolic pathways involved hydroxylation, carbamate 
hydrolysis, indirect glucuronidation and glucose conjugate formation.). The most abundant 
circulating component was encorafenib, ranging from 17.9% to 36.4% of the radioactivity in 
plasma. Encorafenib was mainly eliminated via metabolism, with low levels of unchanged 
encorafenib detected in urine and feces. The dose was equally recovered in urine and feces 
(47.2% in each matrix) and the renal clearance was estimated to be 1.8%. The terminal 
elimination half-life of encorafenib as observed in patients is approximately 3.5 hours (Study 
CMEK162X2110).
Preliminary results from a food-effect clinical study (ARRAY-818-102) have indicated that 
the influence of food on the PK of encorafenib is mild and not clinically relevant; therefore, 
encorafenib can be taken without regard to food. Preliminary results from Study ARRAY-
162-105, an ongoing drug interaction study in healthy subjects, indicate that the extent of 
encorafenib exposure is not altered in the presence of the proton-pump inhibitor rabeprazole.
Encorafenib as a single-agent in patients with locally advanced or metastatic BRAF-mutant 
melanoma in the dose-escalation phase of Study CLGX818X2101 showed that the Day 15 
exposures were consistently decreased by 30 to 60% compared to those at Day 1, probably 
due to induction of CYP enzymes. Area under the plasma concentration time curve (AUC)
and maximum observed plasma concentration (Cmax) ratios at steady state (Day 15) relative 
to Day 1 did not appear to change with dose. The dose-expansion phase in patients with 
locally advanced or metastatic BRAF-mutant melanoma or metastatic colorectal cancer 
(mCRC) showed exposure of encorafenib in terms of Cmax and AUC over the final dosing 
interval (tau) (AUCtau) was within the range observed at the 300-mg dose level for the dose-
escalation phase. Encorafenib Tmax was consistent across dose levels and days at 2 hours. 
The results of the dose-proportionality assessment in patients with locally advanced or 
metastatic BRAF-mutant melanoma suggest that encorafenib exposure was approximately 
dose proportional over the dose range studied.


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In combination studies, when administered with binimetinib, pharmacokinetic (PK)
parameters of encorafenib were similar to those observed in the single-agent study. 
2.3.2.2. Clinical Safety
As of the data cutoff date of 11 May 2016, a total of 1495 healthy subjects and patients with
advanced cancer had received at least one dose of encorafenib, either as a single agent, in 
combination with targeted agents, or in the case of one patient, both monotherapy and 
combination therapy, in 13 completed or ongoing human studies in which safety parameters 
either were or are currently being assessed. These patients constitute the encorafenib safety 
population, which includes 91 healthy subjects and 1404 patients with advanced cancer. 
Based on the experience from these ongoing studies, encorafenib has demonstrated an 
acceptable and manageable safety profile.
2.3.2.2.1. Encorafenib Monotherapy in Patients with Advanced Cancer
As of the data cutoff date of 11 May 2016, 414 patients with advanced cancer have received 
at least one dose of encorafenib monotherapy in 4 clinical studies. The safety and tolerability 
of encorafenib was first evaluated in Study CLGX818X2101, a Phase 1 open-label, multi-
center, dose-escalation and expansion study in adult patients with BRAF V600-mutant 
locally advanced or metastatic melanoma or metastatic colorectal cancer (mCRC) (expansion 
part only). Doses up to 700 mg QD were assessed in the dose escalation portion of the study 
and the maximum tolerated dose (MTD) was determined to be 450 mg QD. Of the 34 
patients enrolled at the MTD in the dose expansion, 9 patients were considered to have a 
dose-limiting toxicity (DLT) during the first cycle. Eighteen (52.9%) patients at the MTD 
required at least 1 dose reduction. As a result of the DLTs and number of patients requiring 
dose reductions, the 300-mg dose level was declared as the recommended Phase 2 dose 
(RP2D).
Across the monotherapy studies, the most common adverse events (AEs) (≥20% of patients), 
regardless of grade and dose, were dermatological (palmar-plantar erythrodysaesthesia 
syndrome [PPES], hyperkeratosis, keratosis pilaris, pruritus, alopecia, dry skin, erythema, 
melanocytic naevus, xerosis, rash), gastrointestinal (nausea, vomiting, decreased appetite), 
musculoskeletal (arthralgia, myalgia, pain in extremity), fatigue, asthenia, insomnia and 
headache.
Refer to the Investigator’s Brochure for more detailed information on encorafenib.
2.4. Overview of Binimetinib
Binimetinib is an orally bioavailable, selective and potent MEK 1 and MEK 2 inhibitor.
As a MEK inhibitor, this compound has the potential to benefit patients with advanced 
cancers by inhibiting the RAS/RAF/MEK/ ERK pathway. Binimetinib has previously been 
examined in the treatment of rheumatoid arthritis based on the role of the 
RAS/RAF/MEK/ERK pathway in inflammatory processes.
Binimetinib is currently being investigated as a single agent and in combination with a 
variety of additional compounds, including paclitaxel and inhibitors of PI3K, RAF, EGFR, 
protein kinase C (PKC), CDK4/6 and type 1 insulin-like growth factor receptor (IGF-1R) in 


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patients with selected advanced or metastatic solid tumors, including, among other tumors, 
melanoma, biliary, colorectal and ovarian cancers. The clinical development program of 
binimetinib encompasses patients with selected advanced or metastatic solid tumors, 
including neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS)- and BRAF-mutant 
melanoma, BRAF- and Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutant non-
small cell lung cancer (NSCLC), high-grade platinum-resistant ovarian cancer, low-grade 
serous ovarian cancer, biliary, colorectal and pancreatic cancers.
2.4.1. Nonclinical Studies with Binimetinib
2.4.1.1. Nonclinical Pharmacology
2.4.1.1.1. Target Inhibition
Binimetinib is an ATP-uncompetitive inhibitor of MEK1/2. In cell-free systems, binimetinib 
inhibits MEK1/2 with a IC50 of 12 nM. In vitro, binimetinib potently inhibits 
MEK-dependent phosphorylation of ERK in human BRAF-mutant melanoma cell lines, 
including A375, IGR-1, IGR-39, Colo-800, MDA-MB-435S, RPMI-7951, UACC-62, and 
WM-115, as well as NRAS-mutant melanoma lines, such as IPC-298, Hs944.T, MEL-JUSO, 
SK-MEL-2 and SK-MEL-30. In vivo, binimetinib treatment results in dose- and time-
dependent inhibition of phosphorylation of ERK in the HT-29 human colorectal cancer 
(CRC) xenograft. Similarly, levels of both pERK and DUSP6 messenger ribonucleic acid 
(mRNA) (a target gene of pERK) are reduced in the A375 melanoma xenograft. Lastly, in ex 
vivo experiments, binimetinib reduces pERK levels in human whole blood cells.
2.4.1.1.2. Nonclinical Absorption, Distribution, Metabolism, Excretion and 
Pharmacokinetics
The F in rat and monkey ADME studies was moderate (48%) and similar to the fraction 
absorbed (based on radioactivity excreted), suggesting a minimal first pass effect. 
Binimetinib showed a low total systemic plasma clearance and volume of distribution at 
steady state after intravenous (IV) administration, and mean plasma terminal half-life (t1/2) 
has ranged from 2 to 9 hours in preclinical species.
In vitro experiments indicate that binimetinib has moderate to high membrane permeability 
and is a substrate of P-gp and BCRP.
Binimetinib is highly bound to plasma proteins (humans: 97.2%).
Binimetinib is more distributed in plasma than blood. The blood-to-plasma concentration 
ratios of binimetinib have ranged from 0.652 to 0.994 in the species tested. In humans, the 
blood-to-plasma ratio was 0.718.
14C-binimetinib-derived radioactivity was absorbed and widely distributed to tissues in both 
pigmented rats and albino rats following a single oral (PO) dose.
With multiple routes of metabolism, binimetinib was metabolized primarily by 
glucuronidation pathways (mainly via UGT1A1, 1A3 and 1A9) and to a lesser extent by 
oxidation pathways (mainly via CYP1A2 and CYP2C19). UGT1A1 was shown to be the 
major contributor (90%) to the formation of the direct glucuronide.


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Following IV dosing in the rat, fecal and urinary excretion accounted for 46% and 45% of
total radioactivity, respectively. Approximately 15% and 16% of binimetinib was excreted 
unchanged in urine and feces, respectively. The total recovery of radioactivity in the excreta 
of monkeys was 99% and 85% following PO and IV dosing, respectively. The most abundant 
drug-related components in monkey excreta included binimetinib, the 2 glucuronides and the 
amide.
In vitro, binimetinib reversibly inhibits CYP2B6 and is a weak reversible inhibitor of 
CYP1A2 and CYP2C9. Binimetinib is not considered a time-dependent inhibitor of 
CYP1A2, CYP2C9, CYP2D6 or CYP3A4/5. Binimetinib has also induced CYP3A, but this 
induction was not confirmed in a human drug-drug interaction (DDI) study.
2.4.1.2. Nonclinical Toxicity and Safety
Binimetinib and its active metabolite, AR00426032, showed no significant hERG channel 
inhibition (IC50 of each > 30µM). In telemeterized monkeys, no effects were observed on 
electrocardiogram (ECG) wave-forms or cardiac intervals including QTc at doses as high at 
10 mg/kg where exposure exceeded that attained clinically at the MTD of 60 mg twice daily 
(BID).
Repeat-dose toxicological studies indicated that binimetinib was tolerated at doses up to 
30 mg/kg for 28 days or 10 mg/kg for 6 months in rats and up to 3 mg/kg for 28 days or 
2 mg/kg for 9 months in monkeys. The most prominent in vivo findings were dose-related, 
reversible hair loss and/or scabbing in rats and loose or watery stools in monkeys.
Administration of binimetinib to rats was associated with microscopic findings of soft tissue 
mineralization, skin effects and minimal to mild clinical pathology changes. Gastric mucosal 
lesions were associated with single-dose binimetinib administration to rats at 100 mg/kg. In 
cynomolgus monkeys, administration of binimetinib was associated with soft stools, 
moderate clinical pathology changes in some animals and reversible histopathologic changes 
in the gastrointestinal tract.
No evidence of genotoxicity was observed from the 2 in vitro assays (bacterial reverse 
mutation or mouse lymphoma) or the in vivo assay (mouse erythrocyte micronucleus).
Embryo-fetal development studies showed evidence of teratogenicity in rabbits (ventricular 
septal defects and outflow tract defects) and in rats decreased ossification that was
considered to be secondary to decreased fetal body weight at maternally toxic doses.
Daily oral administration of binimetinib to juvenile Sprague-Dawley rats on postnatal Day 10 
through 40 was not tolerated at doses ≥ 10 mg/kg/day. The MTD in juvenile rats was 3 
mg/kg and the no-observable-adverse-effect level (NOAEL) was 1 mg/kg/day.
Detailed information regarding nonclinical studies of binimetinib is presented in the 
Investigator’s Brochure.


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2.4.2. Clinical Experience with Binimetinib
2.4.2.1. Clinical Pharmacology
The PK of binimetinib are characterized by moderate to high variability, accumulation of 
approximately 1.5-fold, and steady state concentrations reached within 15 days. Binimetinib 
Tmax tends to range from 1.5 to 2 hours. Binimetinib has been shown to be approximately 
dose proportional (Study ARRAY-162-111). The human ADME study (CMEK162A2102) 
indicated that approximately 50% of binimetinib dose was absorbed. The primary metabolic 
pathways include glucuronidation (up to 61.2% via UGT1A1), N-dealkylation, amide 
hydrolysis (up to 17.8% via CYP1A1 and CYP2C19). The excretion route was 31.7% of 
unchanged binimetinib in feces and 18.4% in urine. Estimated renal clearance of unchanged 
binimetinib was 6.3% of total dose. The impact of UGT1A1 inhibitors or inducers has not 
been clinically assessed. 
Food-effect clinical studies have indicated that the influence of food on the PK of binimetinib 
is mild and not clinically relevant; therefore, binimetinib can be taken with food (ARRAY-
162-104 and CMEK162A2103). Results from a drug interaction study with binimetinib and 
midazolam suggested that continuous intake of binimetinib produced no relevant CYP3A4 
induction (CMEK162A2105). Binimetinib solubility in vitro has been shown to be pH 
dependent. Preliminary results from an ongoing drug interaction study in healthy subjects 
indicate that the extent of binimetinib exposure is not altered in the presence of the proton-
pump inhibitor rabeprazole (ARRAY-162-105). In vitro studies also demonstrated that 
binimetinib is a P-gp and BCRP substrate, but the effects of inhibitors of these substrates on 
the PK of binimetinib in vivo are unknown.
Preliminary results from an ongoing hepatic impairment study (CMEK162A2104) indicate 
that the exposure of binimetinib in healthy subjects and those with mild hepatic impairment 
is comparable, while a potential increase in exposure is observed in subjects with moderately 
impaired hepatic function. Exposure in subjects with severe hepatic impairment has not yet 
been determined.
2.4.2.2. Clinical Safety
As of 20 January 2016, a total of 2555 healthy subjects and patients had received at least
one dose of binimetinib and are therefore eligible for inclusion in the overall safety 
population of binimetinib, which comprises 220 healthy subjects, 164 patients with 
rheumatoid arthritis, 12 patients with hepatic dysfunction and 2159 patients with advanced 
cancer.
2.4.2.2.1. Binimetinib Monotherapy in Patients with Advanced Cancer
Binimetinib has been administered as a single agent to 884 patients with cancer across 7 
studies.
The recommended single-agent dose of binimetinib is 45 mg BID, which has been evaluated 
in two Phase 1 studies conducted in patients with advanced solid tumors, advanced or 
metastatic biliary cancer and KRAS- or BRAF-mutant mCRC (Study ARRAY-162-111) and 
in Japanese patients with advanced solid tumors (Study CMEK162X1101); in two Phase 2 


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studies conducted in BRAFV600 or NRAS-mutant melanoma patients (Study 
CMEK162X2201) and in advanced solid tumors (Study CMEK162AUS11); in one Phase 2 
study conducted in Chinese patients with advanced KRAS/BRAF/NRAS-mutant NSCLC 
(Study CINC280X2205); and in two Phase 3 studies in patients with NRAS-mutant 
melanoma (Study CMEK162A2301) and low grade serous carcinomas of the ovary, fallopian 
tube or primary peritoneum (Study ARRAY-162-311).
Across the monotherapy studies, the most frequently reported AEs considered related to 
single-agent binimetinib, regardless of grade and binimetinib dose, have been dermatologic 
events (rash, dermatitis acneiform), gastrointestinal events (nausea, vomiting, diarrhea), 
edema peripheral, fatigue and increased CK. 
Detailed information regarding clinical studies of binimetinib is presented in the 
Investigator’s Brochure.
2.5. Overview of Encorafenib and Binimetinib Combination
2.5.1. Nonclinical Pharmacodynamics
Binimetinib has been combined with several different inhibitors of the MAPK pathway in 
cell line models derived from a variety of lineages and genetic backgrounds. Combining 
binimetinib with encorafenib resulted in the overall synergistic inhibition of proliferation in 
panels of both melanoma- and CRC-derived cancer models. In this case, combination activity 
was predominantly observed in models with activating mutations in the BRAF gene. In vitro, 
this combination either additively or synergistically inhibited the proliferation of a set of 16 
BRAF mutant melanoma-derived cell line models. In vivo, this combination significantly 
increased the conditional survival of mice implanted with a BRAF-mutant primary human 
melanoma xenograft. Although most single agent and all combination treatments effectively 
inhibited tumor growth, increased survival resulted from reductions in the overall rates (and 
in some cases complete prevention) of the emergence of resistant tumors in the combination 
relative to the single agent treatment groups.
2.5.1.1. Nonclinical Pharmacokinetics
2.5.1.1.1. Binimetinib as a Perpetrator on Encorafenib Pharmacokinetics
The biotransformation of encorafenib was mainly through oxidation (see Section 2.3.1.1.2). 
Encorafenib is metabolized by CYP3A4, CYP2C19 and CYP2D6. The primary CYP 
responsible for this metabolism is CYP3A4 (approximately 83%).
Encorafenib is relatively potent reversible inhibitor of CYP3A4 and also a time-dependent 
inhibitor of CYP3A4 (inhibitory constant [KI] = 20.5 μM and rate of enzyme inactivation 
[Kinact] = 0.0527/min). Furthermore, encorafenib was identified to potentially induce 
CYP3A4 based on an in vitro PXR reporter gene assay at high concentrations (≥10 -50 μM). 
Exploratory PK in Study CLGX818X2101 (single agent) and Study CMEK162X2110 
(combination with binimetinib) showed that Day 15 exposure of encorafenib was 
consistently lower than that on Day 1 within subjects, indicating auto-induction. Based on in 
vitro data, binimetinib is not expected to reversibly inhibit CYP3A4, CYP2D6 or CYP2C19. 
In addition, it did not show time-dependent inhibition of CYP450 enzymes. 


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2.5.1.1.2. Encorafenib as a Perpetrator on Binimetinib Pharmacokinetics
Nonclinical in vitro data indicate that main pathways of metabolism for binimetinib include 
glucuronidation by UGT1A1, UGT1A3 and UGT1A9 and to a lesser extent oxidation by 
CYP1A2 and CYP2C19. UGT1A1 was the primary enzyme to mediate the formation of the 
direct glucuronide M10.9 (see Section 2.4.1.1.2).
Encorafenib is weak (IC50 ≥ 20 μM) reversible inhibitor of CYP1A2, CYP2C8, CYP2C19 
and CYP2D6. Encorafenib is also a UGT1A1 inhibitor with in vitro IC50 ranging from 4 to 7 
μM. Encorafenib could affect the PK of binimetinib due to inhibition of UGT1A1 but no 
significant DDI was observed up to the highest dose tested in Study CMEK162X2110. 
2.5.1.2. Nonclinical Toxicity and Safety
When combining MEK and RAF kinase inhibitors, the potential for overlapping toxicities 
needs to be considered. For binimetinib, the predominant toxicities consisted of various skin 
lesions, including exudates, erosions, inflammation and scabbing and soft tissue 
mineralization of numerous internal organ (seen in rat) and degeneration of the intestinal 
epithelium resulting in enteritis (seen in monkeys). For encorafenib, the primary toxicities 
were skin lesions, including dry, scaly and thickened skin on the plantar surface of the feet, 
which histologically presented as slight to marked hyperkeratosis, squamous cell hyperplasia 
and inflammatory cell infiltration, bone marrow hypocellularity, hyperkeratosis and 
hyperplasia of the non-glandular stomach. Given that MEK and RAF are in the same 
pathway, it appears likely that gastrointestinal intolerance/toxicity, skin rash and neutropenia 
may be dose limiting in the clinical setting when these agents are combined. Although 
retinopathy has not been seen with either compound alone in the preclinical studies, given the 
retinopathy seen clinically with binimetinib, careful monitoring of ophthalmic effects will be 
extremely important in the clinical setting.
2.5.2. Clinical Experience with Encorafenib and Binimetinib Combination
2.5.2.1. Clinical Pharmacology
When administered with encorafenib, exposure to binimetinib as described by Cmax and AUC 
was within the ranges of values observed in the single-agent studies even though some 
variability was moderate. There was no trend towards higher or lower Cmax or AUCs with 
increasing doses of encorafenib over the entire encorafenib dose range (50 to 800 mg), even 
though these parameters tended to decrease when increasing the dose of encorafenib to 400 
mg. This trend was not observed for encorafenib doses from 450 to 800 mg. The ratio of 
AUC at steady-state compared with after the first administration was consistent with that 
observed in single-agent studies, although it seemed to decrease with increasing encorafenib 
doses. As for AUC, this was attributed to variability. Exposure to the active metabolite 
AR00426032 was low (~16% or less) compared to that of the parent drug as observed in 
single-agent studies. The PK parameters of encorafenib co-administered with binimetinib 
were similar to those observed in the single-agent Study CLGX818X2101.
2.5.2.2. Safety
The primary source of safety data on the combination of encorafenib co-administered with 
binimetinib is from Study CMEK162B2301. This is a 2-part, ongoing Phase 3, randomized


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open-label study of combination encorafenib plus binimetinib treatment versus vemurafenib
in patients with locally advanced or metastatic BRAFV600 melanoma. Patients have been 
treated with the combination encorafenib plus binimetinib in 2 additional studies, Study 
CMEK162X2110 (Phase 1b/2 dose escalation study) and Study CLGX818X2109 (Phase 2 
study of the combination encorafenib plus binimetinib followed by addition of targeted 
agents). Details on Studies CMEK162X2110 and CLGX818X2109 are presented in the 
Investigator’s Brochure.
A total of 192 patients from Part 1 of Study CMEK162B2301 had been treated with the 
combination of encorafenib plus binimetinib and were evaluable for inclusion in the 
preliminary safety analyses at the time of data cutoff of 19 May 2016. Preliminary data were 
presented at the 2016 Annual Meeting of the Society for Melanoma Research and are 
summarized in Table 1.
Table 1.
Study CMEK162B2301: Adverse Events, Regardless of Relationship to Study
Drug(s), by Preferred Term – Overall and Maximum Grades 3 and 4 (> 25% in 
any treatment group, or Grade 3/4 AEs >5% in any treatment group; Safety 
Set, Part 1)
Encorafenib 450 mg + 
Binimetinib 45 mg 
N =192
Encorafenib 300 mg   
N = 192
Vemurafenib
N = 186
Preferred Term
All Grades 
%
Grade 3/4
%
All Grades 
%
Grade 3/4
%
All Grades 
%
Grade 3/4
%
Total
98
58
99
66
99
63
Nausea
41
2
39
4
34
2
Diarrhea
36
3
14
2
34
2
Vomiting
30
2
27
5
15
1
Fatigue
29
2
25
1
31
2
Arthralgia
26
1
44
9
45
6
Blood CK increased
23
7
1
0
2
0
Headache
22
2
27
3
19
1
Pyrexia
18
4
15
1
28
0
GGT increased
15
9
11
5
11
3
Alopecia
14 
0
56
0
37
0
Hyperkeratosis
14
1
38
4
29
0
Dry skin
14
0
30
0
23
0
Myalgia
14
0
28
10
18
1
Rash 
14
1
21
2
29
3
Hypertension
11
6
6
3
11
3
Palmoplantar keratoderma
9
0
26
2
16
1
Palmar-plantar    
erythrodysaesthesia 
syndrome
7
0
51
14
14
1
Abbreviations: AE = adverse event; GGT = gamma-glutamyltransferase; PT = preferred term
Preferred terms are presented by descending order based on frequency in the all patients all-grades column. A patient with 
multiple occurrences of an AE under a PT is counted only once for that PT. A patient with multiple AEs is counted only once in 
the total row.


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2.5.2.3. Efficacy
In study CMEK162B2301 the primary objective was met as the combination of encorafenib 
and binimetinib significantly improved progression free survival (PFS) compared with 
vemurafenib. In addition, overall survival (OS) and confirmed overall response rates (ORR) 
were also improved in patients treated with the combination binimetinib compared to
vemurafenib (Table 2). 
Table 2.
Efficacy Results for CMEK162B2301 Part 1
BRAFTOVI
with binimetinib
N = 192
Vemurafenib
N = 191
Progression-Free Survival
Median PFS in months (95% CI)
14.9 (11.0, 18.5)
7.3 (5.6, 8.2)
HR (95% CI)a
0.54 (0.41, 0.71)
P-valueb
<0.0001
Overall Survival
Median OS in months (95% CI)
33.6 (22.4, 39.2)
16.9 (14.0, 24.5)
HR (95% CI)a
0.61 (0.47, 0.79)
Confirmed Overall Response Rate by Central Assessment
ORR (95% CI)
63% (56%, 70%)
40% (33%, 48%)
CR
8%
6%
PR
55%
35%
Duration of Response
Median DoR in months (95% CI)
16.6 (12.2, 20.4)
12.3 (6.9, 16.9)
CI = Confidence interval; CR = Complete Response; HR = hazard ratio; NE = Not estimable; PFS = progression-free 
survival; PR = Partial response.
a Estimated with Cox proportional hazard model adjusted by the following stratification factors: American Joint 
Committee on Cancer (AJCC) Stage (IIIB, IIIC, IVM1a or IVM1b, versus IVM1c) and Eastern Cooperative Oncology 
Group (ECOG) performance status (0 versus 1).  
b Log-rank test adjusted by the same stratification factors.
Although the safety and efficacy of BRAF and MEK inhibitors have been established in 
patients with BRAF-mutant melanoma without prior exposure to these agents, there is clinical 
evidence that the combination of binimetinib and encorafenib is also active in patients who 
have received prior BRAF inhibitors. In an ongoing Phase 1b/2 study of encorafenib in 
combination with binimetinib (Study CMEK162X2110), in a cohort of 26 patients with 
BRAF-mutant melanoma who had received prior BRAF inhibitor treatment, confirmed 
responses were reported in 11 (42.3%) patients, including 1 complete response (CR). The 
disease control rate (CR + partial response [PR] + stable disease [SD]) was 73.1% in this 


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cohort. The duration of response and progression-free survival (PFS) in this cohort were both 
3.8 months. 
The data with binimetinib and encorafenib are consistent with recent retrospective analyses 
suggesting that BRAF-mutant tumors may be re-sensitized to targeted therapy following a 
drug holiday or after administration of a non-BRAF inhibitor therapy. Valpione and 
colleagues identified 116 patients with BRAF-mutant melanoma who were re-challenged 
with a range of BRAF and MEK inhibitors, including binimetinib and encorafenib, after a 
median 7.7 months following cessation of an initial BRAF inhibitor-containing regimen. A 
total of 31 (37%) patients who had progressed on prior BRAF inhibitor-containing therapy 
experienced a response (including 1 patient with a CR) when re-treated with targeted therapy 
(Valpione et al 2017). Collectively, these data suggest that in a portion of patients with 
BRAF-mutant melanoma, re-treatment with a BRAF/MEK inhibitor combination may offer
clinical benefit.
2.6. Rationale 
2.6.1. Rationale for the Study
Preclinical and clinical data suggest that the combination of a BRAF inhibitor and a MEK 
inhibitor may be more effective than BRAF inhibitor monotherapy in patients with BRAF
mutant cancer. By simultaneous, dual, vertical pathway inhibition of the RAF/MEK/ERK 
signaling pathway, the combination of encorafenib and binimetinib may possibly improve the 
duration of response and delay the emergence of resistance to single-agent treatment in 
patients with BRAF V600-mutant unresectable or metastatic melanoma or other advanced 
solid tumors. 
This study is being conducted in patients with BRAF-mutant advanced solid tumors rather 
than in healthy volunteers due to its repeat-dose administration design and the risk of 
carcinogenicity (secondary neoplasm) with selective BRAF inhibitors (Zimmer et al 2012).
Data from in vitro studies indicated that encorafenib is mainly metabolized by CYP3A4, 
followed by CYP2C19 and CYP2D6, thus making encorafenib susceptible to DDI when 
coadministered with CYP inhibitors or inducers (for further details see Section 2.3.1.1.2). 
Encorafenib is a relatively potent reversible inhibitor of UGT1A1, CYP2B6, CYP2C9, and 
CYP3A4/5, and also a time-dependent inhibitor of CYP3A4. Encorafenib induced CYP1A2, 
CYP2B6, CYP2C9 and CYP3A4 in human primary hepatocytes. Encorafenib was found to 
be a weak inhibitor of BCRP, and a potent inhibitor of renal transporters OCT2, OAT1, 
OAT3 and hepatic transporters OCT1, OATP1B1 and OATP1B3.
The main pathways of metabolism for binimetinib include glucuronidation by UGT1A1, 
UGT1A3 and UGT1A9 and to a lesser extent oxidation by CYP1A2 and CYP2C19 (for 
further details see Section 2.4.1.1.2). In vitro, binimetinib reversibly inhibits CYP2B6 and is 
a weak reversible inhibitor of CYP1A2 and CYP2C9. Binimetinib is not considered a time-
dependent inhibitor of CYP1A2, CYP2C9, CYP2D6 or CYP3A4/5. Binimetinib is a 
substrate of P-gp and BCRP. 


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No significant PK DDIs between encorafenib and binimetinib have been observed in clinical 
studies in oncology patients. However, the potential for DDIs of this combination with other 
agents has not been evaluated and this study is designed to contribute to that information by 
evaluating a probe cocktail containing key CYP isozymes of interest (CYP3A4, CYP2C19, 
CYP2D6, CYP1A2, CYP2C9), a OATP/BCRP substrate, a CYP2B6 substrate and a 
moderate CYP3A4 inducer. However, given the nonclinical data, it is unlikely that 
binimetinib would have relevant contribution to any clinical DDI observed.
In Arm 1 of this study, the effect of encorafenib in combination with binimetinib on the 
single oral dose PK of specific CYP isozymes substrates will be assessed. The “Inje” probe 
cocktail was selected as it includes losartan (CYP2C9), midazolam (CYP3A4), caffeine 
(CYP1A2), omeprazole (CYP2C19), and dextromethorphan (CYP2D6), which are all CYP 
substrates of interest to coadministration with encorafenib (Ryu 2007).
In Arm 2 of this study, the effect of encorafenib in combination with binimetinib on the 
single oral dose PK of an OATP/ BCRP substrate and a CYP2B6 substrate will be assessed.
Rosuvastatin was chosen as the OATP/ BCRP substrate of interest as it is not known to 
inhibit or induce any CYPs relevant to encorafenib metabolism (Causevic-Ramosevac 2013;
Neuvonen 2006). Bupropion was chosen as the CYP2B6 substrate of interest as it is 
considered a sensitive substrate (Food and Drug Administration, Drug Development and 
Drug Interactions: Table of Substrates, Inhibitors and Inducers) and no interaction with 
rosuvastatin is expected (bupropion hydrochloride prescribing information; rosuvastatin 
calcium prescribing information).
In Arm 3 of the study, the effect of repeat doses of a moderate CYP3A4 inducer on the repeat 
dose PK of CYP3A4 substrate encorafenib will be assessed. Modafinil was chosen as the 
CYP3A4 inducer as it is considered a moderate inducer (Food and Drug Administration,
Guidance for Industry 2012). The effect of modafinil (200 mg for 7 days followed by 400 mg 
for 21 days) on CYP3A4 substrate triazolam PK was moderate, with a 59% decrease on 
mean AUCinf (Robertson et al. 2002). Based on the similarity of the observed DDI with oral 
CYP3A4 substrate midazolam from a cocktail study (Rowland et al. 2018) with modafinil 
(200 mg modafinil for 7 days with single 1 mg midazolam dose as probe, AUC ratio of 0.66), 
and from a DDI study (Darwish et al. 2008) of armodafinil (R-modafinil, 250 mg for 32 days 
with single 5 mg midazolam dose as probe, AUC ratio of 0.66), 7 days is a sufficient period 
of coadministration for induction. Modafinil has been shown to be well tolerated with the 
only AE observed in >15% of patients is headache (Roth et al. 2007).
The study will be conducted in 3 arms to mitigate any unknown interaction between the 
substrates and inducer.
2.6.2. Rationale for Dose Selection
Dosing for encorafenib (450 mg once daily [QD]) in combination with binimetinib (45 mg 
BID) in this study is consistent with the dosing the regimen used in the registrational study, 
CMEK162B2301 and therefore most appropriate to assess possible DDIs. In previous 
studies, these doses have been shown to be clinically active with an acceptable safety profile 
in patients with BRAF-mutated locally advanced unresectable or metastatic melanoma. 
Notably, based on preliminary data, BRAF inhibitor target toxicities such as hand foot skin 


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reaction, hyperkeratosis, arthralgia, myalgia, and fatigue that are frequently observed with 
encorafenib single agent, were reduced by the combination with binimetinib.
The CYP probe cocktail drugs will be administered at the dose closest to, or lower than, the
doses referenced in the Inje cocktail paper (Ryu 2007). Rosuvastatin will be administered at 
the initial recommended starting dose of 10 mg. Bupropion will be administered at the lowest 
commercially available dose. For modafinil PK, steady state is achieved after approximately 
2-4 days of dosing (modafinil prescribing information). Modafinil will be administered at 
400 mg for 7 days to ensure sufficient time for CYP3A4 induction (Rowland 2018), while 
minimizing the time for which patients may have reduced exposures to encorafenib. 


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3. STUDY OBJECTIVES AND ENDPOINTS
3.1. Study Objectives
All objectives pertain to the DDI phase of the study only.
3.1.1. Primary Objectives
•
To evaluate the effect of single and multiple oral doses of encorafenib in combination 
with binimetinib on the single oral dose PK of the CYP enzyme probe substrates, 
losartan (CYP2C9), midazolam (CYP3A4), caffeine (CYP1A2), omeprazole 
(CYP2C19), and dextromethorphan (CYP2D6) and selected metabolites, in patients 
with BRAF V600-mutant unresectable or metastatic melanoma or other advanced 
solid tumors.
•
To evaluate the effect of single and multiple oral doses of encorafenib in combination 
with binimetinib on the single oral dose PK of rosuvastatin, an OATP /BCRP 
substrate, and on the single oral dose PK of bupropion (a CYP2B6 substrate) and 
hydroxybupropion, in patients with BRAF V600-mutant unresectable or metastatic 
melanoma or other advanced solid tumors.
•
To evaluate the effect of multiple doses of modafinil, a moderate CYP3A4 inducer,
on the multiple oral dose PK of encorafenib and its metabolite, LHY746, in patients 
with BRAF V600-mutant unresectable or metastatic melanoma or other advanced 
solid tumors.
3.1.2. Secondary Objectives
•
To assess the single and multiple dose PK of encorafenib, LHY746 and binimetinib 
(and its metabolite, AR00426032) after coadministration with a single oral dose of 
the CYP probe cocktail, rosuvastatin and bupropion.
•
To assess the safety and tolerability of single and multiple oral doses of encorafenib 
in combination with binimetinib when administered with a single oral dose of the 
CYP probe cocktail, rosuvastatin and bupropion during the DDI portion of the study.
•
To assess safety and tolerability of multiple oral doses of encorafenib in combination 
with binimetinib when administered with multiple doses of modafinil during the DDI 
portion of the study.
 
 
3.2. Study Endpoints
3.2.1. Primary Endpoint
•
Changes in plasma maximum concentration (Cmax) and area under the concentration 
time curve from time zero to the time of last quantifiable concentration (AUClast): 
midazolam, 1-OH midazolam, caffeine, paraxanthine, omeprazole, 5-hydroxy 
omeprazole, rosuvastatin, bupropion and hydroxybupropion.
CCI


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•
Changes in the amount eliminated via urine over an 8-hour period (Ae0-8): losartan 
and its metabolite (E-3174), dextromethorphan and dextrorphan 
•
Changes in plasma encorafenib and LHY746 Cmax and area under the concentration 
time curve over the dosing interval (AUC) in Arm 3.
3.2.2. Secondary Endpoints
•
Metabolite ratios (MRAUC and MRCmax) for 1-OH midazolam/midazolam, 
paraxanthine/caffeine, 5-hydroxy omeprazole/omeprazole, 
hydroxybupropion/bupropion and LHY746/encorafenib and MRAe0-8 for 
E-3174/losartan and dextrorphan/dextomethorphan.
•
Pharmacokinetic parameters (e.g., time to reach Cmax [Tmax], AUC from time zero 
extrapolated to infinity [AUCinf], percent of AUC extrapolated [AUC%extrap], apparent 
terminal elimination rate constant [Kel], apparent T1/2, apparent total body clearance 
after extravascular administration [CL/F] and apparent total volume of distribution 
after extravascular administration [Vz/F]) where calculable, for midazolam, 1-OH 
midazolam, caffeine, paraxanthine, omeprazole, 5-hydroxyomeprazole, rosuvastatin, 
bupropion and hydroxybupropion.
•
Pharmacokinetic parameters (e.g., urine concentration [Curine], quantity of urine 
excreted during each collection interval [Vol], cumulative amount excreted in urine 
during each collection interval [CumAe], and percentage of dose recovered in urine 
[Fe %]) for losartan, E-3174, dextromethorphan and dextrorphan.
•
Pharmacokinetic parameters (e.g., Cmax, AUClast, Tmax, AUCinf, AUC%extrap, Kel, T1/2, 
CL/F, and Vz/F) for encorafenib, LHY746, binimetinib and AR00426032 where 
calculable.
•
Safety will be evaluated by monitoring AEs, physical examinations, ophthalmic 
examinations, vital sign measurements, 12-lead ECGs, echocardiogram 
(ECHO)/multigated acquisition scan (MUGA), and clinical laboratory tests.
 
CCI


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4. STUDY DESIGN
4.1. Study Design Overview
This is an open-label, 3-arm, fixed-sequence study to evaluate the effect of single and 
multiple oral doses of encorafenib in combination with binimetinib on the single oral dose 
PK of CYP enzyme probe substrates using a probe cocktail, on an OATP/BCRP substrate 
using rosuvastatin and on a CYP2B6 substrate using bupropion. In addition, this study will 
evaluate the effect of multiple doses of modafinil, a moderate CYP3A4 inducer, on the 
multiple oral dose PK of encorafenib.
The study will have 2 treatment phases, a DDI phase followed by a post-DDI phase. During
the DDI phase patients will receive the CYP probe drug cocktail (Arm 1), the OATP/BCRP 
probe substrate, rosuvastatin and CYP2B6 substrate, bupropion (Arm 2), or the CYP3A4 
inducer, modafinil (Arm 3) and encorafenib in combination with binimetinib.
During the post-DDI phase patients may continue to receive treatment with encorafenib in 
combination with binimetinib until treatment discontinuation criteria are met (see 
Section 9.1). The combination of encorafenib 450 mg QD and binimetinib 45 mg BID has 
been evaluated in over 300 patients with BRAF V600 mutant melanoma in previous studies 
including 192 patients in the pivotal Phase 3 trial, CMEK162B2301. Since the safety and 
efficacy of the combination has already been extensively studied in previous trials, in the 
post-DDI phase of the current trial, patients will be followed as per local standard-of-care 
practice for patients with BRAF V600-mutant unresectable or metastatic melanoma or other 
advanced solid tumors and only limited data will be collected (see Section 8.3.4). The 
follow-up in the post-DDI phase will include a review of concomitant medications and 
assessment of compliance with administration of encorafenib and binimetinib. There will 
also be review of AEs with recording of all Grade 3 or 4 AEs and all SAEs (SAEs, follow-up 
of SAEs to continue as described in Section 10.1.5). Other safety evaluations may be 
conducted if clinically indicated.
4.1.1. DDI Phase 
Enrollment to Arms 1 and 2 will occur in parallel. Patients will be assigned to the appropriate 
treatment arm by the Sponsor study team based on eligibility. Enrollment to Arm 3 will begin 
once Arm 2 enrollment is complete. The study schema for each Arm are presented in 
Figure 1.


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Figure 1:
Study Schema
Arm 1 (CYP Probe Cocktail)
Arm 2 (Rosuvastatin and Bupropion)
Arm 3 (Modafinil)
In Arm 1, patients will receive a single oral dose of the CYP probe cocktail on Day -7. 
Encorafenib, administered 450 mg QD and binimetinib, administered 45 mg BID will be 
initiated on Day 1. Patients will then receive a single oral dose of the CYP probe cocktail 
Day 1 and Day 14 within 5 minutes after the encorafenib/binimetinib administration. Blood 
and urine PK sampling will be conducted from 0 to 8 hours on Day -7, Day 1 and Day 14.
In Arm 2, patients will receive a single oral dose of rosuvastatin and bupropion on Day -7. 
Encorafenib, administered 450 mg QD and binimetinib, administered 45 mg BID will be 


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initiated on Day 1. Patients will then receive a single oral dose of rosuvastatin and bupropion 
on Day 1 and Day 14 within 5 minutes after the encorafenib/binimetinib administration. 
Blood PK sampling will be conducted from 0 to 8 hours on Day -7, Day 1 and Day 14.
In Arm 3, patients will inititate continuous treatment with encorafenib 450 mg QD and 
binimetinib 45 mg BID on Day 1. Patients will then receive continuous treatment of 
modafinil on Day 15 through Day 21. Blood PK sampling will be conducted from 0 to 8 
hours on Day 14 and Day 21.
Patients who discontinue or require a dose reduction of study drug(s), in particular 
encorafenib, prior to completion of the last PK sampling on Day 14 in Arms 1 and 2 or on
Day 21 in Arm 3 may be considered unevaluable for PK analyses and may be replaced. If a 
patient misses 3 or more consecutive doses of encorafenib in any arm or 3 or more 
consecutive doses of modafinil in Arm 3 prior to completion of the last PK sampling on Day 
14 in Arms 1 and 2 or on Day 21 in Arm 3 due to noncompliance, the patient may remain on
treatment but may be replaced if limited data are available from the patient. In addition, 
patients who miss any dose of study drugs on any of the PK days, or who vomit within 4 
hours after dosing on any of the PK days, may be replaced but may remain on treatment.   
4.1.2. Post-DDI Phase
During the post-DDI phase patients may continue to receive treatment with the 
encorafenib/binimetinib combination until one of the treatment discontinuation reasons 
described in Section 9.1 occur (e.g., until disease progression, unacceptable toxicity,
withdrawal of consent, pregnancy, significant protocol deviation, lost to follow up, 
Investigator decision, death, or study termination by Sponsor). Patients should be followed 
by the Investigator per standard clinical practice and all Grade 3-4 AEs and all SAEs should 
be reported to the Sponsor (see Section 8.3.4). If a patient chooses to not continue in the post-
DDI phase, the Day 30 Safety Follow-up Visit assessments will be performed.
If a patient in the post-DDI phase permanently discontinues treatment with binimetinib, they 
may continue treatment with encorafenib as monotherapy at its RP2D the dose of 300 mg 
QD. However, due to the limited efficacy of binimetinib alone in the study population, if a 
patient permanently discontinues treatment with encorafenib, they must discontinue 
treatment with binimetinib and complete the Day 30 Safety Follow-up Visit.
4.2. Doses and Schedule of Administration
4.2.1. Treatment Regimens
Encorafenib/binimetinib (continuous daily dosing starting on Day 1 for all arms):

450 mg (6 x 75 mg) encorafenib oral capsule QD

45 mg (3 x 15 mg) binimetinib oral tablet BID
Encorafenib and binimetinib are to be taken together 5 minutes before the CYP probe 
cocktail (Arm 1), rosuvastatin and bupropion (Arm 2) or modafinil (Arm 3) on days when all 
study drugs are administered together.


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Patients will be supplied with a sufficient number of tablets and/or capsules for the number 
of doses to be taken prior to the next scheduled visit. In addition, patients will be provided a 
dosing diary and should document in this diary each prescribed dose, and whether it was 
taken or not.
Patients should be instructed to take encorafenib and binimetinib with ~250 mL of 
noncarbonated water at room temperature daily at approximately the same time every day.
Patients should be instructed to swallow the capsules/tablets whole and not to chew or crush 
them. The prescribed dose for encorafenib should be taken once daily in the morning at 
approximately the same time every day. The prescribed doses for binimetinib should be taken 
twice daily, approximately 12 ± 2 hours apart.
Consumption of grapefruit, pomegranates, star fruits, Seville oranges or products containing 
the juice of each starting from Day -14 through the DDI phase (Day 28) is prohibited, due to 
potential CYP3A4 interaction with the study drugs (see Section 5.4.2.1). Orange juice is 
allowed.
On all PK days during the DDI phase of the study, patients should not eat anything within 
2 hours prior to the morning dose(s) of study drug intake and refrain from eating for 1 hour 
following encorafenib and binimetinib intake. During the remainder of the study, the 
afternoon/evening doses of binimetinib may be taken with or without a meal but the same 
method should be used consistently throughout the study. Encorafenib and binimetinib may 
be taken with or without food on non-PK days.
On visit days when the patient is scheduled to be at the clinic, patients will take encorafenib 
and binimetinib in the clinic under the supervision of the Investigator or designee in the 
morning. On the evening of the visit day patients will take binimetinib at home. On all other 
days patients will take encorafenib and binimetinib at home.Doses of encorafenib that are 
omitted for AEs or any other reason can be taken up to 12 hours prior to the next dose. Doses 
of binimetinib that are omitted for AEs or any other reason should not be made up. If a 
patient misses 3 or more consecutive doses of encorafenib and binimetinib in any arm or 3 or 
more doses of modafinil in Arm 3 during the DDI phase due to noncompliance, the patient 
may remain on treatment but may be replaced if limited data are available from the patient
(see Section 9.2). In addition, patients who miss a dose of study drugs on any of the PK days 
and patients who vomit within 4 hours after dosing on any of the PK days may be replaced
but may remain on treatment. If a patient vomits at any time after dosing, the dose of study 
drug should not be re-administered.
Complete dosing instructions will be provided to patients and will include the minimum 
times between doses and instructions for missed doses. The Investigator or responsible site 
personnel should instruct the patient to take the study drugs as per protocol (promote 
compliance). All dosages prescribed and dispensed to the patient and all dose changes and all 
missed doses during the study must be recorded on the Dosage Administration Record 
electronic case report form (eCRF). Drug accountability must be performed on a regular 
basis. Patients will be instructed to return unused study drugs to the site at each evaluation 
visit. The site personnel will ensure that the appropriate dose of each study drug is 


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administered at each visit and will provide the patient with the correct amount of drugs for 
subsequent dosing.
CYP Probe Cocktail (once on Day -7, Day 1 and Day 14 for Arm 1 only) taken in the 
following order:

25 mg losartan oral tablet

30 mg dextromethorphan oral capsule

50 mg caffeine as oral liquid

20 mg omeprazole oral capsule

2 mg midazolam as oral syrup
The CYP probe cocktail will be administered in the clinic. The CYP probe cocktail is to be 
taken approximately 5 minutes after administration of encorafenib and binimetinib on days 
when all study drugs are administered. The total time for administration of all study drugs 
should be within 10 minutes.
The actual dose time for each drug will be recorded. Time 0 will be the time that the first 
drug is taken. None of the oral drugs with solid dose forms should be chewed. Each oral 
administration should be confirmed by checking the oral cavity of the patient. A glass with 
250 mL of water (room temperature) should be available to take the oral doses. Any 
remaining water after finishing all dosing should be consumed if possible.
Rosuvastatin and bupropion (Day -7, Day 1 and Day 14 for Arm 2 only):

10 mg rosuvastatin oral tablet

75 mg bupropion immediate release (IR) oral tablet
Rosuvastatin and bupropion doses will be administered in the clinic and are to be taken
approximately 5 minutes after administration of encorafenib and binimetinib on days when 
all study drugs are administered. The total time for administration of all study drugs should 
be within 10 minutes.
The actual dose time for each drug will be recorded. Time 0 will be the time that the first 
drug is taken. These solid dose forms should not be chewed. Each oral administration should 
be confirmed by checking the oral cavity of the patient. A glass with 250 mL of water (room 
temperature) should be available to take the oral doses. Any remaining water after finishing 
all dosing should be consumed if possible.
Modafinil (continuous daily dosing starting on Day 15 through Day 21 for Arm 3 only):

400 mg modafinil as oral tablet(s) QD


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Patients will be supplied with a sufficient number of tablets for the number of doses to be 
taken prior to the next scheduled visit. In addition, patients will be provided a dosing diary 
and should document in this diary each prescribed dose, and whether it was taken or not.
Patients should be instructed to take encorafenib and binimetinib with ~250 mL of 
noncarbonated water at room temperature daily at approximately the same time every day. 
Patients should be instructed to swallow the tablets whole and not to chew or crush them. 
The prescribed dose for modafinil should be taken once daily in the morning at 
approximately the same time every day. Modafinil may be taken with or without food on 
non-PK days.
On visit days when the patient is scheduled to be at the clinic, patients will take modafinil in 
the clinic under the supervision of the Investigator or designee in the morning. On all other 
days patients will take modafinil at home.
Complete dosing instructions will be provided to patients and will include the minimum 
times between doses and instructions for missed doses. The Investigator or responsible site 
personnel should instruct the patient to take the study drugs as per protocol (promote 
compliance). All dosages prescribed and dispensed to the patient and all dose changes and all 
missed doses during the study must be recorded on the corresponding electronic case report 
form (eCRF). Drug accountability must be performed on a regular basis. Patients will be 
instructed to return unused study drugs to the site at each evaluation visit. The site personnel 
will ensure that the appropriate dose of each study drug is administered at each visit and will 
provide the patient with the correct amount of drugs for subsequent dosing.
4.3. Duration of Treatment
Prescreening:
Prescreening evaluations must be performed between Day -57 and Day -36 in Arms 1 and 2 
and between Day -50 and Day -29 in Arm 3.
Screening:
Screening of patients will occur within 28 days prior to the first study drug dose on Day -7 
(Day -35 to Day -8, inclusive) in Arms 1 and 2 and prior to the first study drug dose on Day 1 
(Day -28 to Day -1, inclusive) in Arm 3.
DDI Phase:
The duration of the DDI phase will be 35 days in Arms 1 and 2 and will include clinic visits 
on Day -7, Day 1, Day 14, and Day 28. The duration of the DDI phase will be 28 days in 
Arm 3 and will include clinic visits on Day 1, Day 14, Day 15, Day 21 and Day 28.
Post-DDI Phase: 
Patients will be followed by the Investigator following standard clinical practice and may 
continue to receive study treatment as long as none of the treatment discontinuation criteria
are met (Section 9.1).


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5. PATIENT POPULATION
During the COVID-19 pandemic, please refer to Appendix 13 for additional eligibility 
considerations.
5.1. Number of Patients
Up to approximately 42 patients with unresectable or metastatic BRAF V600-mutant cancer 
are planned for enrollment; 20 patients in Arm 1,10 patients in Arm 2 and up to 12 patients in 
Arm 3.  
5.2. Selection of Patients
Questions regarding patient eligibility should be addressed to the Sponsor prior to 
enrollment. Patients must fulfill all of the following inclusion criteria and none of the 
exclusion criteria to be eligible for admission to the study.
5.2.1. Inclusion Criteria
Patients must meet all of the following criteria to be eligible for enrollment in the study.
1. Signed written informed consent;
2. Male or female patient, age ≥ 18 years;
3. Histologically confirmed diagnosis of locally advanced, unresectable or metastatic 
cutaneous melanoma or unknown primary melanoma American Joint Committee on 
Cancer (AJCC) Stage IIIB, IIIC or IV, or other BRAF V600-mutant advanced solid 
tumors;
4. Presence of BRAF V600E and/or V600K mutation in tumor tissue prior to enrollment, 
as determined using a local test;
5. Evidence of measurable or non-measurable lesions as detected by radiological or 
photographic methods according to guidelines based on Response Evaluation Criteria 
in Solid Tumors (RECIST) v1.1 (Appendix 7);
6. Patient with unresectable locally advanced or metastatic melanoma who has received 
no prior treatment or progressed on or after other prior systemic therapy
Note: Prior therapy with a BRAF inhibitor (e.g., vemurafenib, dabrafenib, encorafenib 
and XL281/BMS-908662) and/or a MEK inhibitor (e.g., trametinib, binimetinib, 
selumetinib, cobimetinib and refametinib) is permitted except in the regimen 
immediately prior to study entry. Progression during prior BRAF/MEK inhibitor 
treatment is not required;
7. Patient with other (non-melanoma) BRAF V600E and/or V600K -mutant advanced 
solid tumors who has progressed on standard therapy or for whom there are no available 
standard therapies
Note: Prior therapy with a BRAF inhibitor and/or a MEK inhibitor is permitted except 
in the regimen immediately prior to study entry. Progression during prior BRAF/MEK 
inhibitor treatment is not required; if it occurred, the patient’s circumstances 
(e.g., ≥1 year since prior BRAF and/or MEK inhibitor, equivocal progression, 


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refractory to available therapies) must be discussed with the Sponsor prior to 
enrollment;
8. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1;
9. Adequate bone marrow, organ function and laboratory parameters:
a.
Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
b. Hemoglobin (Hgb) ≥ 9 g/dL without transfusions
c.
Platelets (PLT) ≥ 100 x 109/L without transfusions
d. Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≤ 2.5 
× upper limit of normal (ULN); patient with liver metastases ≤5 ×ULN
e.
Total bilirubin ≤ 2 × ULN
f.
Creatinine ≤ 1.5 mg/dL, or calculated creatinine clearance (determined as per
Cockcroft-Gault) ≥50 mL/min;
10. Able to take oral medications;
11. Patient is deemed by the Investigator to have the initiative and means to be compliant 
with the protocol (treatment and follow-up);
12. Negative serum beta-human chorionic gonadotropin (β-HCG) test (female patient of 
childbearing potential only) performed within 72 hours prior to first dose and consent 
to ongoing urine pregnancy testing during the course of the study;
13. Male patients and female patients of childbearing potential must agree to use an 
acceptable method of contraception as defined in the study protocol (Section 5.3.1).
ARM 1 ONLY:
1. Non-smoker who has not used nicotine containing products for at least 3 months prior 
to the first dose. 
5.2.2. Exclusion Criteria
Patients meeting any of the following criteria are ineligible for enrollment in the study.
1. Symptomatic brain metastasis. Patients previously treated or untreated for these 
conditions who are asymptomatic in the absence of corticosteroid and anti-epileptic 
therapy are allowed. Brain metastases must be stable, with imaging (e.g., magnetic 
resonance imaging [MRI] or computed tomography [CT] demonstrating no current 
evidence of progressive brain metastases at screening);
2. History of reaction to any of the study medications in the arm the patient is enrolled
in this trial;
3. Use, within 2 weeks prior to the start of encorafenib/binimetinib treatment on Day 1
and through DDI phase (Day 28), of any herbal medications/supplements or any 
medications or foods that are moderate or strong inhibitors or inducers of CYP 
3A4/5;


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4. Consumption of grapefruit, pomegranates, star fruits, Seville oranges or products 
containing the juice of each starting starting from Day -14 and through DDI phase
(Day 28), due to potential CYP3A4 interaction with the study drugs (see 
Section 5.4.2.1). Orange juice is allowed;
5. Symptomatic or untreated leptomeningeal disease;
6. History or current evidence of retinal vein occlusion (RVO) or current risk factors for 
RVO (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity 
or hypercoagulability syndromes);
7. Clinically significant cardiac disease including any of the following: 
a.
Congestive heart failure requiring treatment (New York Heart Association 
Grade ≥ 2)
b. Left ventricular ejection fraction (LVEF) < 50% as determined by MUGA or 
ECHO
c.
Uncontrolled hypertension defined as persistent systolic blood pressure 
≥150 mmHg or diastolic blood pressure ≥ 100 mmHg despite current therapy
d. History or presence of clinically significant ventricular arrhythmias or atrial 
fibrillation
e.
Clinically significant resting bradycardia
f.
Unstable angina pectoris ≤ 3 months prior to start of study drug
g. Acute myocardial infarction ≤ 3 months prior to start of study drug
h. QT interval corrected for heart rate using the Fridericia formula (QTcF) 
> 480 msec at screening;
8. Impaired hepatic function as defined by Child-Pugh class B or C (Appendix 8);
9. Impaired gastrointestinal function or disease which may significantly alter the 
absorption of study drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, 
diarrhea, malabsorption syndrome, small bowel resection);
10. Known hyper-coagulability risks other than malignancy (e.g., Factor V Leiden 
syndrome);
11. Thromboembolic event (e.g. including transient ischemic attacks, cerebrovascular 
accidents, deep vein thrombosis or pulmonary emboli) except catheter-related venous 
thrombosis ≤ 12 weeks prior to starting study treatment. Note: Patients with catheter-
related thromboembolic events are allowed.;
12. Any of the following:
a.
Nitrosourea or mitomycin-C within 6 weeks prior to start of study drug
b. Other chemotherapy, radiation therapy that included > 30% of the bone 
marrow reserve, or biological therapy (e.g., antibodies) within 4 weeks prior 
to start of study drug
c.
Continuous or intermittent small-molecule therapeutics or investigational 
agents within 5 half-lives of the agent (or within 4 weeks prior to start of 
study drug, when half-life is unknown)


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d. Residual Common Terminology Criteria for Adverse Events (CTCAE) Grade 
2 side effects of any such therapy (residual Grade 2 alopecia is permitted);
13. Discontinuation of prior BRAF and/or MEK inhibitor treatment due to left ventricular 
dysfunction, pneumonitis/interstitial lung disease, or retinal vein occlusion;
14. Known positive serology for human immunodeficiency virus (HIV) infection, active 
hepatitis B and/or active hepatitis C infection;
15. History of Gilbert’s syndrome;
16. Other severe, acute, or chronic medical or psychiatric condition or laboratory 
abnormality that may increase the risk associated with study participation or study 
drug administration or that may interfere with the interpretation of study results and, 
in the judgement of the Investigator, would make the patient inappropriate for the 
study;
17. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a
female after conception and until termination of gestation, confirmed by a positive β-
hCG laboratory test (> 5 mIU/mL).
ARM 1 ONLY:
1. Positive urine cotinine test at screening;
2. Use, within 2 weeks prior to the start of encorafenib/binimetinib treatment on Day 1 
and through DDI phase (Day 28), of any substrates, inhibitors or inducers of 
CYP3A4, CYP2C9, CYP1A2 or CYP2C19 and any substrates or inhibitors of 
CYP2D6
ARM 2 ONLY:
1. Use, within 2 weeks prior to the start of encorafenib/binimetinib treatment on Day 1 
and through DDI phase (Day 28), of any substrates, inhibitors or inducers of CYP2B6 
or any substrates or inhibitors of BCRP, OATP1B1 or OATP1B3.
ARM 3 ONLY:
1. History of psychosis, depression or mania;
2. History of angioedema;
3. History of mitral valve prolapse;
4. History of left ventricular hypertrophy;
5. Use, within 2 weeks prior to the start of encorafenib/binimetinib treatment on Day 1 
and through DDI phase (Day 28), of any substrates, inhibitors or inducers of 
CYP3A4.


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5.3. Lifestyle Guidelines
5.3.1. Requirements for Contraception
Females of non-childbearing potential (study patients or partners of study patients) are not 
required to use contraception. To be considered of non-childbearing potential, a female 
patient must meet at least one of the following criteria:

Postmenopausal (defined as without menses for at least 12 consecutive months before 
screening) AND at least 55 years old

Postmenopausal (defined as without menses for at least 12 consecutive months before 
screening) AND a follicle-stimulating hormone (FSH) value > 30 IU/L at the 
Screening Visit

Hysterectomy OR bilateral oophorectomy

Tubal ligation at least 5 years prior to the Screening Visit with no subsequent 
pregnancies.
Contraception must be used starting at screening for males and females of childbearing 
potential. Use must continue for 90 days after the last dose of study drug for males and 30 
days after the last dose of study drug for females. The following methods of contraception 
have been determined to be effective and acceptable per Clinical Trial Facilitation Group 
(CTFG) guidance and are mandated under this protocol for use by the patient and his/her 
partner:

Complete abstinence from sexual intercourse when this is in line with the preferred 
and usual lifestyle of the patient

Double barrier methods
o
Condom with spermicide in conjunction with use of an intrauterine device
o
Condom with spermicide in conjunction with use of a diaphragm

Birth control patch or vaginal ring

Oral, injectable, or implanted contraceptives only when combined with other highly 
effective or acceptable methods
o
This is required due to the potential of encorafenib to induce CYP3A4 which 
may reduce the effectiveness of hormonal contraception methods, hormonal 
agents (including but not limited to birth control patch, vaginal ring, oral, 
injectable, or implanted contraceptives)

Surgical sterilization (bilateral oopherectomy with or without hysterectomy, tubal 
ligation or vasectomy) at least 6 weeks prior to taking study treatment. In the case of 


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oophorectomy alone, only when the reproductive status of the woman has been 
confirmed by follow-up levels of FSH.
5.3.2. Ultaviolet Light Exposure
Photosensitivity was reported infrequently in patients treated with encorafenib (2.9% - 5.6% 
in single-agent Study CLGX818X2101 Expansion Phase). However, it is recommended that 
patients use precautionary measures against ultraviolet exposure from the first day of study 
drug treatment through the last day of study drug treatment. It is recommented that patients 
avoid extended exposure to ultraviolet light and when out of doors, to wear occlusive 
clothing, sunscreen, and sunglasses.
5.4. Prior and Concomitant Medications
5.4.1. Prior Treatments
All prior cancer treatments are to be recorded in the eCRF. Other prior treatments (i.e., other 
than cancer treatments) taken within 4 weeks of screening should also be recorded.
5.4.2. Concomitant Medications
During the DDI phase of the study, all medications (other than study drugs) and significant 
non-drug therapies (including physical therapy, herbal/natural medications and blood 
transfusions) administered during the study must be listed on the Concomitant Medications 
or the Surgical and Medical Procedures eCRF.
5.4.2.1. Prohibited Concomitant Medications
Please refer to Appendix 6 for a list of prohibited medications.
Anticancer therapies (including chemo- or biologic-therapy or radiation therapy, covering 
>30% of the red bone marrow reserve, and surgery) are prohibited while the patients are 
receiving study treatment. If such therapeutic measures are required for a patient then the
patient must be discontinued from study treatment.
For all Arms of the study, from Day 1 and through the DDI phase (Day 28) of the study, the 
use of any herbal medications/supplements or any medications or foods that are moderate or
strong inhibitors or inducers of CYP 3A4/5. Other prohibited medications specific to each 
study arm are specified below: 

Arm 1: Use, within 2 weeks prior to the start of encorafenib/binimetinib treatment on 
Day 1 and through DDI phase (Day 28), of any substrates, inhibitors or inducers of 
CYP3A4, CYP2C9, CYP1A2 or CYP2C19 and any substrates or inhibitors of 
CYP2D6.

Arm 2: Use, within 2 weeks prior to the start of encorafenib/binimetinib treatment on 
Day 1 and through DDI phase (Day 28), of any substrates, inhibitors or inducers of 
CYP2B6 or any substrates or inhibitors of BCRP or OATP.


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
Arm 3: Use, within 2 weeks prior to the start of encorafenib/binimetinib treatment on 
Day 1 and through DDI phase (Day 28), of any substrates, inhibitors or inducers of 
CYP3A4.
Consumption of grapefruit, pomegranates, star fruits, Seville oranges or products containing 
the juice of each starting from Day -14 through the DDI phase (Day 28) is prohibited, due to 
potential CYP3A4 interaction with the study drugs. Orange juice is allowed.
During the DDI phase of the study, drinks and food containing caffeine must be excluded 48 
hours before PK assessments and the day of PK assessments (i.e., Days -9 to -7, -2 to 1, 12 to
14 for Arms 1 and 2 and Days 12 to 14 and Days 19 to 21 for Arm 3).
5.4.2.2. Permitted Concomitant Medication
The patient must notify the investigational site about any new medications he/she takes after 
the start of the study drug. Patients taking concomitant medications chronically should 
maintain the same dose and dose schedule throughout the study if medically feasible.
On the days PK blood sampling is performed, the patient should continue their consistent use 
of other concomitant medication. However, if a concomitant medication is used 
intermittently during the study, this medication should be avoided on these days, if medically 
feasible.
Apixaban when used for thromboprophylaxis has been shown to result in a significantly 
lower rate of venous thromboembolism than placebo in ambulatory cancer patients with 
intermediate-to-high risk based on a Khorana score ≥2 who were starting chemotherapy. 
During the treatment period, major bleeding occurred in 2.1% of the patients treated with 
apixaban (versus 1.1% of patients who received placebo) with higher rates of gastrointestinal 
bleeding, hematuria, and gynecological bleeding. Patients with gastrointestinal or 
gynecological cancers had the highest rates of bleeding. There was no significant difference 
in overall survival between the apixaban-treated and placebo-treated patients in the study 
(Carrier 2019). The Investigator should assess the potential benefit/risk to the patient and 
determine whether it is in the patient’s best interest to initiate thromboprophylaxis
5.4.2.3. Permitted Concomitant Medication Requiring Caution and/or Action
Please refer to Appendix 6 for a list of permitted medications to be used with caution.
During the post-DDI phase of the study, the following guidance on permitted concomitant 
therapy will apply:
Encorafenib is a reversible inhibitor of CYP2B6, CYP2C9, CYP3A4 and UGT1A1. It is also 
a time dependent inhibitor of CYP3A4. Permitted medications to be used with caution in this 
study include those that are sensitive substrates of CYP2B6, CYP2C9, CYP3A4, and 
UGT1A1 or those substrates that have a narrow therapeutic index (NTI). 
There is a potential for encorafenib to induce CYP3A4 at concentrations >10-50 µM, which 
may reduce the effectiveness of hormonal contraception methods. Therefore, the use of at 
least one form of non-hormonal contraception will be needed during the participation in this 


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study. Caution should be used in patients receiving concomitant treatment with other drugs 
that are substrates of CYP3A4 as the efficacy of these drugs could be reduced when 
administered with encorafenib.
Encorafenib has been identified to be primarily metabolized by CYP3A4 and to a lesser 
extent by CYP2C19 in vitro. The use of strong inhibitors of CYP3A4 are prohibited
throughout the study. Concomitant use of moderate CYP3A4 inhibitors after the DDI phase 
of the study should be avoided. If use of a moderate CYP3A4 inhibitor is unavoidable, short-
term use (30 days) following discussion with the Sponsor may be permitted with an 
accompanying dose reduction to one-half of the encorafenib dose prior to use of the moderate 
CYP3A4 inhibitor. After the inhibitor has been discontinued for 3 to 5 elimination half-lives, 
resume the encorafenib dose that was taken prior to initiating the CYP3A4 inhibitor.
Moderate inhibitors of CYP3A4 should be taken with caution when co-administered with 
encorafenib. Patients should be closely monitored for the occurrence of AEs. Regular 
assessments will be performed as described in Table 7 and Table 8. If a patient develops 
toxicity, encorafenib dose may be adjusted as outlined in the dose modification Table 5.
In vitro data showed that both encorafenib and binimetinib are substrates of P-gp. 
Binimetinib is also a substrate of BCRP. Thus, the use of drugs that are known to inhibit or 
induce P-gp and BCRP should be used with caution. Encorafenib is a BCRP inhibitor. It is 
also a potent inhibitor of the renal transporters OAT1, OAT3 and OCT2 and the hepatic 
transporters OATP1B1 and OATP1B3. Therefore the co-administration of drugs that are 
known to be sensitive or NTI substrate of BCRP, OAT1, OAT3, OCT2, OATP1B1 and 
OATP1B3 should be used with caution.
Drugs with a conditional, possible, or known risk to induce Torsade de Pointes (TdP) should 
be used with caution. Patients receiving such medications must be carefully monitored for 
potentiating of toxicity due to any individual concomitant medication, and may require dose 
titration of the drug substance. Investigators should use caution when prescribing 
co-medications, as clinical experience with these compounds in patients with cancer is often 
limited. Investigators should contact the Sponsor when they are unsure whether a drug should 
be prescribed to a patient in the clinical trial.
Please refer to Appendix 6 for a list of permitted medications to be used with caution.


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6. STUDY TREATMENT
The term “study drug” is defined as all components of the CYP probe cocktail, rosuvastatin, 
bupropion, modafinil, encorafenib or binimetinib.
6.1. Dosing Regimen
Treatments are described as follows (see Section 4.2):
CYP Probe Cocktail (once on Day -7, Day 1 and Day 14 for Arm 1 only) taken in the 
following order:
25 mg losartan oral tablet
30 mg dextromethorphan oral capsule
50 mg caffeine as oral liquid
20 mg omeprazole oral capsule
2 mg midazolam as oral syrup
Rosuvastatin and bupropion (once on Day -7, Day 1 and Day 14 for Arm 2 only):
10 mg rosuvastatin oral tablet
75 mg bupropion immediate release (IR) oral tablet
Modafinil (continuous daily dosing starting on Day 15 through Day 21 for Arm 3 only):
400 mg modafinil as oral tablet(s) QD
Binimetinib/encorafenib (continuous daily starting on Day 1 for all Arms):
450 mg (6 x 75 mg) encorafenib oral capsules QD
45 mg (3 x 15 mg) binimetinib oral tablet BID
6.2. Allocation to Treatment
Enrollment to Arms 1 and 2 will occur in parallel. Patients will be assigned to the appropriate 
treatment arm by the Sponsor study team based on eligibility. For example, a smoking 
patient would not be allowed to enroll in Arm 1. As there are multiple centers participating, 
the site must contact the study manager, or delegate, and receive the dosing assignment for 
each patient. Enrollment to Arm 3 will begin once Arm 2 enrollment is complete.
Twenty patients will be enrolled into Arm 1. Patients will receive a single oral dose of the 
CYP probe cocktail (losartan, dextromethorphan, caffeine, omeprazole, and midazolam) on 
Day -7. Encorafenib QD and binimetinib BID will be initiated on Day 1. Patients will then 
receive a single oral dose of the CYP probe cocktail on Day 1 and Day 14 within 5 minutes 
of the encorafenib/binimetinib administration.
Ten patients will be enrolled in Arm 2. Patients will receive a single oral dose of rosuvastatin
and bupropion on Day -7. Encorafenib QD and binimetinib BID will be initiated on Day 1. 
Patients will then receive a single oral dose of rosuvastatin and bupropion on Day 1 and Day 
14 within 5 minutes after the encorafenib/binimetinib administration.  


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Once enrollment to Arms 1 and 2 is completed, the next 6 to 12 patients will be enrolled in 
Arm 3. Patients will inititate continuous treatment with encorafenib QD and binimetinib BID 
on Day 1. Patients will then begin receiving continuous treatment of modafinil QD on Day 
15 through Day 21.
6.3. Study Drug Supply
6.3.1. Packaging and Labeling
Encorafenib and binimetinib will be supplied centrally. Agents in the CYP probe cocktail,
rosuvastatin, bupropion and modafinil will be supplied centrally. 
Encorafenib and binimetinib will be packaged in high-density polyethylene (HDPE)
containers, induction sealed and include child-resistant closures. For both encorafenib and 
binimetinib, each bottle will be labelled, at a minimum, with a lot number, contents (number 
of tablets), dosage strength, storage conditions, and the name and address of the Sponsor.
Medication labels for encorafenib and binimetinib will be in the local language and comply 
with the legal requirements of each country. The patient number should be hand-written by 
the Investigator or its staff at the drug delivery time.
The CYP probe cocktail, rosuvastatin, bupropion, and modafinil will be sourced separately
for United States and Canada/European sites. All labels will be in the local language and 
comply with the legal requirements for each country.
6.3.2. Shipping, Storage and Handling
Labeled, packaged study drugs will be shipped to each site by the Sponsor or designee 
following receipt of the necessary regulatory documents. The Investigator or an approved 
representative (e.g., registered pharmacist) will ensure that all study drugs are stored as 
outlined in the Investigational Product (IP) Manual and in accordance with applicable 
regulatory requirements. The drug storage area at the site must be secure, with access limited 
to authorized personnel.
Stability studies to support drug storage conditions for encorafenib and binimetinib have 
been conducted by the Sponsor or an affiliate. The Sponsor will continue to monitor the 
stability of encorafenib and binimetinib and will alert the site if a lot is nearing the end of its 
anticipated shelf life.
Detailed instructions for storage and handling of study drugs will be provided in the IP
Manual.
6.3.3. Accountability and Return of Study Drug Supply
The Investigator or an approved representative (e.g., pharmacist) must maintain accurate 
records of dates and quantities of study drug received, to whom study drug is dispensed 
(patient-by-patient accounting), and accounts of any study drug accidentally or deliberately 
destroyed. The Investigator must retain all unused or expired study drug supplies until the 
study monitor has confirmed the accountability data. If a site’s policy prohibits holding study 
drug supplies for monitor review, then a copy of the standard operating procedure (SOP) for 
processing drug returns must be provided to the Sponsor.


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To ensure adequate records, all study drug will be accounted for on a drug accountability 
inventory form as instructed by the Sponsor. Refer to the IP Manual for details on how to 
process all unused or expired study supplies.
6.4. Study Drug Dispensing and Administration
The Investigator or responsible site personnel must instruct the patient or caregiver to take 
the study drugs as per protocol. Study drugs will be dispensed to the patient by authorized 
site personnel only. All dosages prescribed to the patient and all dose changes during the 
study must be recorded on the Dosage Administration Record eCRF.
Patients will receive a diary to document self-administered dosing of study drugs to include 
the dose of study drugs taken, the date of dosing (and times if applicable), and if any doses 
were missed and the reason for the missed dose. Diaries will be provided on a regular basis. 
Patients will be instructed to return unused study drugs and the patient diary to the site at 
each visit.
Patients should not take extra doses of study drugs to compensate for doses missed for AEs 
or any other reason. If a patient vomits at any time after dosing, the dose of study drugs
should not be re-administered.
The pharmacist or study nurse will ensure that the appropriate dose is dispensed and will 
provide the patient with at least the appropriate number of tablets for the number of doses to 
be taken prior to the next scheduled visit. The site personnel will train the patient and/or the 
patient’s caregiver on dosing procedures for the study drugs.
Agents comprising the CYP probe cocktail and rosuvastatin will be centrally provided, based 
on local regulations and requirements. Complete dispensing instructions, dosing instructions
(including the timing of administration), will be provided in the Pharmacy Manual.
6.5. Dose Modifications and Reductions
For patients who do not tolerate encorafenib and/or binimetinib initial dosing schedule, dose 
adjustment is permitted in order to allow the patient to continue on study drug (see Table 3
for encorafenib and Table 4 for binimetinib). If patients require a dose reduction, in particular 
for encorafenib, during the DDI phase, the patient may be replaced (see Section 9.2).
A dose reduction below 75 mg QD for encorafenib and below 15 mg BID for binimetinib is 
not allowed. If a patient misses 3 or more consecutive doses of encorafenib and binimetinib 
in any arm or 3 or more doses of modafinil in Arm 3 during the DDI phase due to 
noncompliance, the patient may remain on treatment but may be replaced if limited data are
available from the patient. Dose interruptions of more than 28 consecutive days in the post-
DDI phase are not allowed unless approved by the study Medical Monitor.


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Table 3.
Dose Reduction for Encorafenib
Dose Level
Encorafenib Dose and Schedule
0
450 mg QD
-1
300 mg QD
-2
225 mg QD
-3
150 mg QD
-4
75 mg QDa
Abbreviation: QD = once daily
a Dose reduction below 75 mg is not allowed
Table 4.
Dose Reduction for Binimetinib
Dose Level
Binimetinib Dose and Schedule
0
45 mg BID
-1
30 mg BID
-2
15 mg BIDa
Abbreviation: BID = twice daily
a Dose reduction below 15 mg is not allowed
Doses of encorafenib that are omitted for AEs or any other reason can be taken up to 12 
hours prior to the next dose. Doses of binimetinib that are omitted for AEs or any other 
reason should not be made up. For both encorafenib and binimetinib, when the toxicity that 
resulted in a dose reduction improves to Grade 1 or less, the dose should be re-escalated at 
the Investigator’s discretion provided there are no other concomitant toxicities. 
If encorafenib is dose reduced due to prolonged QTcF > 500 msec, no dose re-escalation is 
allowed. If binimetinib is dose reduced due to left ventricular dysfunction, no dose re-
escalation is allowed. Dose reduction/interruption/discontinuation decisions should be based 
on the CTCAE grade of the toxicity and the guidelines provided below (Table 5). In general, 
doses should not be reduced or interrupted for Grade 1 toxicities, but treatment to control 
symptoms should be provided as appropriate. All AEs should be followed weekly or as 
clinically appropriate until stabilization or resolution. 
If a patient discontinues treatment with binimetinib, the patient may continue treatment with 
encorafenib at the R2PD single-agent dose of 300 mg QD. However, due to the limited 
efficacy of binimetinib alone in the study population, if a patient discontinues treatment with 
encorafenib, they must discontinue treatment with binimetinib and complete the Day 30 
Safety Follow-up Visit. 
Please refer to Table 5 for dose adjustment recommendations for encorafenib and/or 
binimetinib induced toxicities. Please refer to Appendix 2 for additional supportive care 
guidelines for the management of encorafenib induced HFSR. Furthermore, please refer to 


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Appendix 1 and Appendix 3 for additional supportive care guidelines for the management of 
encorafenib and binimetinib induced skin toxicity and diarrhea respectively.
Please see Appendix 13 for alternative study measures to be followed during public 
emergencies, including the COVID-19 pandemic.
Table 5.
Encorafenib and Binimetinib – Recommended Dose Modifications 
Associated with Treatment-Related Adverse Events
Worst toxicity
CTCAE, v.4.03 
Grade 
(unless otherwise 
specifieda)
Dose Modification for Encorafenib and for Binimetinib 
Eye Disorders - Retinal Events (including serous detachment of the retina)
Note: Results and images of ocular coherence tomography (OCT) must be made available upon 
request.
Any visual acuity impairment at screening should be documented and should be considered as 
baseline.
Grade 1
Maintain dose levels of encorafenib and binimetinib and repeat ophthalmic 
monitoring including visual acuity assessment and OCT within 10 days

If patient remains asymptomatic (Grade 1), maintain dose level of 
encorafenib and binimetinib and continue the schedule of visual assessments 
established per protocol

If patient becomes symptomatic (blurred vision, photophobia, etc.) or visual 
acuity assessment shows Grade 2, follow Grade 2 dose guidelines below
Grade 2
Interrupt dosing of encorafenib and binimetinib and repeat ophthalmic monitoring 
including visual acuity assessment and OCT within 10 days

If resolved to baseline or Grade ≤ 1, resume treatment at current dose level 
of encorafenib and binimetinib and continue the schedule of visual 
assessments established per protocol

If not resolved to baseline or Grade ≤ 1, resume treatment at 1 reduced dose 
levelb of encorafenib and binimetinib and continue the schedule of visual 
assessments established per protocol

If posterior uveitis lasts > 6 weeks, permanently discontinue binimetinib and 
encorafenib.
Grade 3
Interrupt dosing of encorafenib and binimetinib and repeat ophthalmic monitoring 
including visual acuity assessment and OCT within 10 days:

If posterior uveitis resolves to baseline or Grade ≤ 1 in < 6 weeks, resume 
treatment at 1 reduced dose levelb of encorafenib and binimetinib and 
continue the schedule of visual assessments established per protocol 

If posterior uveitis does not resolve to baseline or Grade ≤ 1 in < 6 weeks, 
permanently discontinue binimetinib and encorafenib

If resolved to baseline or Grade ≤ 2, resume treatment at 1 reduced dose 
levelb of encorafenib and binimetinib and continue the schedule of visual 
assessments established per protocol 

If not resolved to baseline or Grade ≤ 2, continue the interruption and repeat 
the ophthalmic assessment in 10 days.


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Table 5.
Encorafenib and Binimetinib – Recommended Dose Modifications 
Associated with Treatment-Related Adverse Events
Worst toxicity
CTCAE, v.4.03 
Grade 
(unless otherwise 
specifieda)
Dose Modification for Encorafenib and for Binimetinib 
o
If resolved to baseline or Grade ≤ 2, resume treatment at 1 reduced 
dose levelb of encorafenib and binimetinib and continue the schedule of 
visual assessments established per protocol
o
If remains Grade 3, permanently discontinue encorafenib and 
binimetinib
Grade 4
Permanently discontinue encorafenib and binimetinib and immediately follow-up 
with ophthalmic monitoringc
Eye Disorders - Posterior Uveitisc
Note: Results and images of ocular coherence tomography (OCT) must be made available upon 
request.
Any visual acuity impairment at screening should be documented and should be considered as 
baseline.
Grade 1
Maintain dose levels of encorafenib and binimetinib and repeat ophthalmic monitoring 
including visual acuity assessment and OCT within 10 days.

If subject remains asymptomatic (Grade 1), maintain dose level of encorafenib 
and binimetinib and continue the schedule of visual assessments established 
per protocol.
If subject becomes symptomatic (blurred vision, photophobia, etc.) or visual acuity 
assessment shows Grade 2, follow Grade 2 dose guidelines below.
Grade 2
Interrupt dosing of encorafenib and binimetinib and repeat ophthalmic monitoring 
including visual acuity assessment and OCT within 10 days.

If resolved to baseline or Grade ≤ 1, resume treatment at current dose level of 
encorafenib and binimetinib and continue the schedule of visual assessments 
established per protocol.

If not resolved to baseline or Grade ≤ 1, resume treatment at 1 reduced dose 
levelb of encorafenib and current dose of binimetinib and continue the 
schedule of visual assessments established per protocol.
If posterior uveitis lasts > 6 weeks, permanently discontinue binimetinib and 
encorafenib.
Grade 3 
Interrupt dosing of encorafenib and binimetinib and repeat ophthalmic monitoring 
including visual acuity assessment and OCT within 10 days:

If resolved to baseline or Grade ≤ 2, resume treatment at 1 reduced dose levelb
of encorafenib and current dose of binimetinib and continue the schedule of 
visual assessments established per protocol.

If not resolved to baseline or Grade ≤ 2, continue the interruption and repeat 
the ophthalmic assessment in 10 days.
If remains Grade 3, permanently discontinue encorafenib and binimetinib.
Grade 4
Permanently discontinue binimetinib and immediate follow-up with ophthalmic 
monitoringc.
Eye Disorder - RVOc


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Table 5.
Encorafenib and Binimetinib – Recommended Dose Modifications 
Associated with Treatment-Related Adverse Events
Worst toxicity
CTCAE, v.4.03 
Grade 
(unless otherwise 
specifieda)
Dose Modification for Encorafenib and for Binimetinib 
Note: Results and images of ophthalmic examinations should be made available upon request. This 
includes scans/images of fluorescein angiography should a patient be assessed using this technique.
RVO of any grade
Permanently discontinue encorafenib and binimetinib and immediately follow-up 
with ophthalmic monitoringc
Other Eye Disorders (i.e., Non-retinal and Non-uveitis Events)
Grade 1 – 2
Maintain dose level of encorafenib and binimetinib and increase frequency of 
ophthalmic monitoring to at least every 14 days until stabilization or resolution
Grade 3
Interrupt dosing of encorafenib and binimetinib and refer patient to ophthalmologist 
within 7 daysc:

If resolved to Grade ≤ 1 in ≤ 21 days, resume treatment at 1 reduced dose 
levelb of encorafenib and binimetinib

If not resolved to Grade ≤ 1 in ≤ 21 days, permanently discontinue 
encorafenib and binimetinib and close follow-up with ophthalmic 
monitoring until stabilization or resolutionc
Grade 4
Permanently discontinue encorafenib and binimetinib and immediate follow-up with
ophthalmic monitoring until stabilization or resolutionc
Liver-related Adverse Events
Grade 1 
AST or ALT 
> ULN to 3 × ULN
Maintain dose level of encorafenib and binimetinib 
Grade 2
AST or ALT 
> 3 to 5.0 × ULN or 
3 × baseline valued
AND 
blood bilirubing
≤ 2.0 × ULN
Maintain dose level of encorafenib and interrupt dosing of binimetinib until resolved 
to Grade ≤ 1 (or Grade ≤ 2 in case of liver metastasis), then:

If resolved in ≤ 14 days, maintain dose level of encorafenib and binimetinib

If not resolved in ≤ 14 days, interrupt dose of encorafenib (in addition to 
prior binimetinib) until resolved to Grade ≤ 1 (or Grade ≤ 2 in case of liver 
metastasis), then resume treatment at current dose level of encorafenib and 1 
reduced dose levelb of binimetinib
If additional occurrence: 

Interrupt dosing of encorafenib and binimetinib until resolved to Grade ≤ 1 
(or Grade ≤ 2 in case of liver metastasis), then resume treatment at 1 reduced 
dose levelb of encorafenib and binimetinib
Treatment with encorafenib and binimetinib may be resumed sequentially at the 
Investigator’s discretion, with encorafenib being resumed alone for one week before 
resuming binimetinib treatment
AST or ALT 
> 3.0 to 5.0 × ULN 
AND 
blood bilirubing
> 2.0 × ULN
Interrupt dosing of encorafenib and binimetinib until resolved to Grade ≤ 1, then:

If resolved in ≤ 7 days, resume treatment at 1 reduced dose levelb of 
encorafenib and binimetinib

If not resolved in ≤ 7 days, permanently discontinue encorafenib and 
binimetinib


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Table 5.
Encorafenib and Binimetinib – Recommended Dose Modifications 
Associated with Treatment-Related Adverse Events
Worst toxicity
CTCAE, v.4.03 
Grade 
(unless otherwise 
specifieda)
Dose Modification for Encorafenib and for Binimetinib 
Treatment with encorafenib and binimetinib may be resumed sequentially at the 
Investigator’s discretion, with encorafenib being resumed alone for one week before 
resuming binimetinib treatment
Grade 3
AST or ALT 
> 5.0 to 8.0 × ULN) 
AND 
blood bilirubing
≤ 2.0 × ULN
Interrupt dosing of encorafenib and binimetinib until resolved to Grade ≤ 1 (or Grade 
≤ 2 in case of liver metastasis), then:

If resolved in ≤ 14 days, resume treatment at current dose level of 
encorafenib and binimetinib

If not resolved in ≤ 14 days, resume treatment at 1 reduced dose levelb of 
encorafenib and binimetinib
Treatment with encorafenib and binimetinib may be resumed sequentially at the 
Investigator’s discretion, with encorafenib being resumed alone for one week before 
resuming binimetinib treatment
If additional occurrence:

Interrupt dosing of encorafenib and binimetinib until resolved to Grade ≤ 1 
(or Grade ≤ 2 in case of liver metastasis), then resume treatment at 1 reduced 
dose levelb of encorafenib and binimetinib
AST or ALT 
>8 × ULN 
AND blood 
bilirubing
≤2.0 × ULN
Permanently discontinue encorafenib and binimetinib
AST or ALT 
> 5.0 × ULN
AND
blood bilirubing
> 2.0 × ULN
Permanently discontinue encorafenib and binimetinib
Grade 4 
AST or ALT 
> 20.0 × ULN
Permanently discontinue encorafenib and binimetinib
Cardiac Disorders - Left Ventricular Systolic Dysfunctiona (Dose Adjustment for Binimetinib ONLY)
Asymptomatic
absolute decrease 
of > 10% in LVEF 
compared to 
baseline and the 
LVEF is below the 
institution’s lower 
limit of normal 
(LLN) (e.g., a 
decrease of 60% to 
48% is an absolute 
decrease of 12%)
Interrupt dosing of binimetinib and repeat evaluation of LVEF within 2 weeks

If the LVEF recovers (defined as LVEF ≥ 50% or ≥ LLN and absolute 
decrease 
≤ 10% compared to baseline) ≤ 21 days, resume treatment at 1 reduced dose 
levelb of binimetinib after approval of the Sponsor Medical Monitor. 
Monitor LVEF 2 weeks after resuming binimetinib, every 4 weeks for 12 
weeks and subsequently as per protocol

If the LVEF does not recover in ≤ 21 days, permanently discontinue 
binimetinib. Closely monitor LVEF until resolution or for up to 16 weeks


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Table 5.
Encorafenib and Binimetinib – Recommended Dose Modifications 
Associated with Treatment-Related Adverse Events
Worst toxicity
CTCAE, v.4.03 
Grade 
(unless otherwise 
specifieda)
Dose Modification for Encorafenib and for Binimetinib 
Grade 3 – 4
Permanently discontinue binimetinib. Closely monitor LVEF until resolution or up to 
16 weeks
Note: Copies of ECHO and/or MUGA scans could be requested for patients to be 
available to the Sponsor for patients with absolute decrease of >10% in LVEF 
compared to baseline and LVEF < 50% or LLN
CK Elevation 
Grade 1-2
Maintain dose of encorafenib and binimetinib. Ensure patient is adequately hydrated. 
Closely monitor CK and serum creatinine

If total CK ≥ 3 × ULN, measure CK isoenzymes and myoglobin in blood or 
urine
Grade 3
> 5.0 - 10.0 x ULN 
without
renal impairment 
(i.e., serum 
creatinine < 1.5 × 
ULN or 
1.5 × baseline)
If asymptomatic, maintain dosing of encorafenib and binimetinib. Ensure patient is 
adequately hydrated. Monitor and measure isoenzymes and myoglobin in blood or 
urine and serum creatinine
If symptomatic (muscle pain/spasms/muscle weakness), maintain dosing of 
encorafenib and interrupt dosing of binimetinib until resolved to CTCAE Grade ≤ 1 
and monitor closely, then:

If resolved in ≤ 21 days, maintain dose of encorafenib and resume treatment 
at 1 reduced dose levelb of binimetinib

If not resolved in ≤ 21 days, maintain dose of encorafenib and permanently 
discontinue binimetinib
Grade 4 
without
renal impairment 
(i.e., serum 
creatinine < 1.5 × 
ULN or 
1.5 × baseline)
If asymptomatic, maintain dose of encorafenib and interrupt dosing of binimetinib. 
Ensure patient is adequately hydrated. Monitor and measure isoenzymes and 
myoglobin in blood or urine and serum creatinine

If resolved in ≤ 21 days, maintain dose of encorafenib and resume treatment 
at 1 reduced dose levelb of binimetinib

If not resolved in ≤ 21 days, maintain dose of encorafenib and permanently 
discontinue binimetinib
If symptomatic (muscle pain/spasms/muscle weakness), maintain dose of encorafenib 
and permanently discontinue binimetinib
Grade 3 or 4 
with
renal impairment
(i.e., serum 
creatinine ≥ 1.5 × 
ULN or 
1.5 × baseline)
Interrupt dosing of encorafenib and binimetinib until resolved to CTCAE Grade < 1 
or baseline level. Ensure patient is adequately hydrated. Monitor closely and measure 
isoenzymes and myoglobin in blood or urine and serum creatinine, then:

If resolved in ≤ 21 days, consider resuming treatment at 1 reduced dose 
levelb of encorafenib and binimetinib

If not resolved in ≤ 21 days, permanently discontinue encorafenib and 
binimetinib
2nd occurrence:

Permanently discontinue encorafenib and binimetinib
Cardiac Investigation – Prolongation of the QT Interval QTcF Value


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Table 5.
Encorafenib and Binimetinib – Recommended Dose Modifications 
Associated with Treatment-Related Adverse Events
Worst toxicity
CTCAE, v.4.03 
Grade 
(unless otherwise 
specifieda)
Dose Modification for Encorafenib and for Binimetinib 
QTcF > 500 ms 
during treatment 
and change from 
pre-treatment value 
remains ≤ 60 ms
Electrolyte abnormalities, including magnesium, should be corrected and cardiac risk 
factors for QT prolongation (e.g., congestive heart failure, bradyarrhythmias) should 
be controlled. 
1st occurrence: 

Temporarily interrupt dosing of encorafenib until QTcF < 500 ms. Then 
resume treatment at 1 reduced dose levelb of encorafenib 
2nd occurrence:

Temporarily interrupt dosing of encorafenib treatment until QTcF < 500 ms. 
Then resume treatment at 1 reduced dose levelb of encorafenib 
3rd occurrence: 

Permanently discontinue encorafenib and binimetinib
QTcF increase 
during treatment is 
both > 500 ms and > 
60 ms change from 
pre-treatment values 
Electrolyte abnormalities, including magnesium, should be corrected and cardiac risk 
factors for QT prolongation (e.g., congestive heart failure, bradyarrhythmias) should 
be controlled. 
Permanently discontinue encorafenib and binimetinib
Rash (see Appendix 1)
Grade 1
Maintain dose level of encorafenib and binimetinib
Initiate Initial Rash Treatment Regimen if it was not already started and rash should 
be closely monitored
Grade 2 
1st occurrence: 

Maintain dose level of encorafenib and binimetinib

Initiate Initial Rash Treatment Regimen if it was not already started and rash 
should be closely monitored

Reassess within ≤ 14 days. If rash worsens or does not improve, interrupt 
dosing of encorafenib and binimetinib until resolved to Grade ≤1. Then 
resume treatment at current dose level of encorafenib and binimetinib. For 
dermatitis acneiform, treatment with encorafenib may be maintained if, in 
the judgment of the Investigator, the rash is considered to be unrelated to 
encorafenib. If treatment with encorafenib was maintained and no 
improvement within 8 days, interrupt dosing of encorafenib
2nd occurrence:

Reassess within ≤ 14 days. If rash worsens or does not improve, interrupt 
dosing of encorafenib and binimetinib until resolved to Grade ≤1. Then 
resume treatment at current dose level of encorafenib and 1 reduced dose 
levelb of binimetinib. For dermatitis acneiform rash, treatment with 
encorafenib may be maintained if, in the judgment of the Investigator, the 
rash is considered to be unrelated to encorafenib. If treatment with 
encorafenib was maintained and no improvement within 8 days, interrupt 
dosing of encorafenib


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Table 5.
Encorafenib and Binimetinib – Recommended Dose Modifications 
Associated with Treatment-Related Adverse Events
Worst toxicity
CTCAE, v.4.03 
Grade 
(unless otherwise 
specifieda)
Dose Modification for Encorafenib and for Binimetinib 
Grade 3
1st occurrence: 

Interrupt dosing of encorafenib and binimetinib until resolved to Grade ≤1. 
Reassess weekly. Then resume treatment at current dose level of encorafenib 
and binimetinib.

Consider referral to dermatologist and manage rash per dermatologist’s 
recommendation.
2nd occurrence: 

Interrupt dosing of encorafenib and binimetinib until resolved to Grade ≤ 1. 
Then resume treatment at 1 reduced dose levelb of encorafenib and 
binimetinib.
Resume treatment with encorafenib at the same dose level if, in the judgment 
of the Investigator, the rash is considered to be unrelated to encorafenib

Consider referral to dermatologist and manage rash per dermatologist’s 
recommendation
Grade 4
Permanently discontinue encorafenib and binimetinibf
Hand-foot Skin Reaction (HFSR)/Palmar-plantar Erythrodysesthesia Syndromee (Dose Adjustment 
for Encorafenib ONLY) (see Appendix 2)
Grade 1
Maintain dose of encorafenib. Promptly institute supportive measures, such as topical 
therapy, for symptomatic relief. Give instruction on life-style modifications. 
Grade 2 
1st occurrence: 

Maintain dose of encorafenib and HFSR should be closely monitored. 
Promptly institute supportive measures, such as topical therapy, for 
symptomatic relief. Give instruction on life-style modifications.

If no improvement ≤ 14 days, interrupt dosing of encorafenib until resolved 
to Grade ≤ 1. Resume treatment with encorafenib at current dose level. 
Continue supportive measures, such as topical therapy, for symptomatic 
relief. Give instruction on life-style modifications.
Additional occurrence: 

Treatment with encorafenib may be maintained or interrupted based upon the 
Investigator’s discretion. Continue supportive measures, such as topical 
therapy, for symptomatic relief. Give instruction on life-style modifications.

If interrupted dosing of encorafenib per Investigator’s judgment, interrupt 
until resolved to Grade ≤ 1. Resume treatment with encorafenib at the same 
dose level or 1 reduced dose levelb based upon the Investigator’s discretion.
Grade 3
1st or additional occurrence: 

Interrupt dosing of encorafenib until resolved to Grade ≤ 1. Promptly initiate 
supportive measures, such as topical therapy, for symptomatic relief. Give 
instruction on life-style modifications. Reassess the patient weekly.
Then resume treatment at one reduced dose levelb of encorafenib

Consider referral to dermatologist and manage HFSR per dermatologist’s 
recommendation
> 3nd occurrence:


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Table 5.
Encorafenib and Binimetinib – Recommended Dose Modifications 
Associated with Treatment-Related Adverse Events
Worst toxicity
CTCAE, v.4.03 
Grade 
(unless otherwise 
specifieda)
Dose Modification for Encorafenib and for Binimetinib 

Interrupt dosing of encorafenib until resolved to Grade ≤ 1, decision to 
resume treatment with encorafenib at one reduced dose levelb or permanently 
discontinue encorafenib should be based upon the Investigator’s discretion.
Squamous Cell Carcinoma (SCC), Keratoacanthoma (KA) and any Other Suspicious Skin Lesion 
(Dose Adjustment for Encorafenib ONLY)
Grade ≤ 3
Maintain dose of encorafenib (dose interruptions or modifications are not required). 
Treatment of SCC, KA, and any other suspicious skin lesion (eg. new primary 
melanoma) should occur based upon institutional practice. 
Diarrhea (see Appendix 3)
Uncomplicated 
Grade 1-2
Maintain dose of encorafenib. Consider temporary interruption of binimetinib until 
resolved to Grade ≤ 1. Then resume treatment at current dose level of binimetinib
Complicated
Grade 1-2
Consider temporary interruption of encorafenib until resolved to Grade ≤ 1. Then 
resume treatment at current dose level of encorafenib
Interrupt dosing of binimetinib until resolved to Grade ≤ 1. Then resume treatment at 
1 reduced dose levelb of binimetinib
Grade 3-4
Interrupt dosing of encorafenib and binimetinib until resolved to Grade ≤ 1. Then 
resume treatment at current dose level of encorafenib if, in the judgment of the 
Investigator, the toxicity is considered to be unrelated to encorafenib, or at one 
reduced dose levelb. Resume treatment at 1 reduced dose level of binimetinib
Nausea/Vomiting
Grade 1-2
Maintain dose level of encorafenib and binimetinib. Promptly institute antiemetic 
measure. 
Grade 3
Interrupt dosing of encorafenib and binimetinib until resolved to Grade ≤ 1. Then 
resume treatment at 1 reduced dose levelb of encorafenib. Resume treatment with 
binimetinib at the current dose if, in the judgment of the Investigator, the toxicity is 
considered to be unrelated to binimetinib, or at 1 reduced dose levelb.
Note: Interrupt dosing of encorafenib and binimetinib for ≥ Grade 3 vomiting or 
Grade 3 nausea only if the vomiting or nausea cannot be controlled with optimal 
antiemetics (as per local practice)
Grade 4
Permanently discontinue encorafenib and binimetinibf
Interstitial Lung Disease/Pneumonitis (see Appendix 4)
Grade 1
Maintain dose level of encorafenib and binimetinib.
Grade 2
Maintain dose of encorafenib. Withhold binimetinib for up to 3 weeks.
If improved to Grade 0 or 1, resume treatment at 1 reduced dose level of binimetinib.
If not resolved within 3 weeks, permanently discontinue binimetinib.
Grade 3-4
Permanently discontinue binimetinib.
All Other Adverse Events (Suspected To Be Related To Encorafenib and/or Binimetinib)
Grade 1-2
If the event is a persistent Grade 2 AE not responsive to a specific therapy, consider 
interruption or reduction of encorafenib and binimetinib, as applicable


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Table 5.
Encorafenib and Binimetinib – Recommended Dose Modifications 
Associated with Treatment-Related Adverse Events
Worst toxicity
CTCAE, v.4.03 
Grade 
(unless otherwise 
specifieda)
Dose Modification for Encorafenib and for Binimetinib 
Grade 3
Interrupt dosing of encorafenib and binimetinib until resolved to Grade ≤1 or to 
pretreatment/baseline level. If the event resolves ≤ 21 days, then study drug may be 
resumed at 1 reduced dose levelb based upon the Investigator’s discretion.
Grade 4
Permanently discontinue encorafenib and binimetinibf
a Not according to NCI CTCAE
b Dose reduction below 75 mg QD for encorafenib, and below 15 mg BID for binimetinib is not allowed.
c Ophthalmic monitoring mandated for retinal events, posterior uveitis, RVO: further evaluation with specialized retinal 
imaging (e.g. ocular coherence tomography, fluorescein angiography). Any diagnosis of retinal events must be 
supported by presence or absence of symptoms, visual acuity assessment and findings in OCT.
d For patients enrolled with liver metastases and baseline LFT elevations.
e Disorder characterized by redness, marked discomfort, swelling, and tingling in the palms of the hands or the
soles of the feet.
f A patient with a Grade 4 AE may resume treatment at the lower dose level if the AE recovers to Grade ≤ 1 within 28 
days of discontinuing drug in the post-DDI phase and, if in the opinion of the Investigator and Sponsor Medical 
Monitor, the event is not life-threatening and the patient can be managed and monitored for recurrence of AE. Any 
patients requiring a treatment interruption of duration > 28 days must discontinue study drug permanently.
g Refers to total bilirubin.
6.5.1. Follow-up for Toxicities
Patients whose treatment is interrupted or permanently discontinued due to an AE or 
clinically significant laboratory value, must be followed up at least once a week (or more 
frequently if required by institutional practices, or if clinically indicated) for 4 weeks, and 
subsequently at approximately 4-week intervals, until resolution or stabilization of the event, 
whichever comes first.
Appropriate clinical experts such as an ophthalmologist, cardiologist or dermatologist should 
be consulted as deemed necessary. Further guidelines and recommendations for the 
management of specific study drug induced toxicities are provided in Table 5. All dosages 
prescribed to the patient and all dose changes during the study must be recorded on the 
Dosage Administration Record eCRF.
6.5.1.1. Management of Hand Foot Skin Reaction (HFSR)
Because HFSR has been reported for encorafenib, it is recommended that patients are 
educated prior to starting study treatment to avoid activities that can cause friction on hands 
and feet. In addition, supportive measures for prevention and/or management of HFSR 
should be instituted. Clinical judgment and experience of the treating physician should guide 
the management plan of each patient.
Dose reduction/interruption/discontinuation decisions for HFSR should be based on the 
CTCAE grade of the toxicity and the guidelines provided in Table 5.


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Additional recommended guidance is provided for the prevention, management and support 
of HFSR in Appendix 2. A visit at a podiatrist may also be recommended at the discretion of 
the Investigator.
6.5.1.2. Follow-up Evaluations for Appearance of Keratoacanthoma (KA) and/or 
Squamous Cell Carcinoma (SCC)
The skin of patients should be examined regularly to monitor for the possible development of 
KA and/or SCC, as these have been reported to occur under selective BRAF inhibitor 
treatment (Flaherty et al 2010; Kefford et al 2010; Robert et al 2011). Patients should be 
instructed to inform their physicians upon the occurrence of any skin changes. In case of 
occurrence of KA and/or SCC, patients’ treatment will follow institutional standards. Results 
of biopsies will be collected. A dermatological exam is recommended to be performed every 
8 weeks for up to 6 months following discontinuation of encorafenib.
6.5.1.3. Management of Nausea and/or Vomiting
Because nausea and vomiting have been reported for encorafenib and binimetinib, it is 
recommended that patients are educated on the possibility of occurrence of these side effects 
prior to starting study treatment. Patient education as well as proper management of nausea 
and/or vomiting at the first sign is important. Ondansetron is recommended for management 
during the DDI phase, however, clinical judgment and experience of the treating physician 
should guide the management plan of each patient. 
In the post-DDI phase, patients experiencing nausea and/or vomiting CTCAE ≥1 may
receive antiemetics at the discretion of the treating physician (as per local guideline). It is 
recommended that patients be provided a prescription for antiemetics, and are instructed on 
the use of antiemetics on the first day of study drug treatment. Prophylactic antiemetics such 
as dexamethasone 8 mg, prochlorperazine, or metoclopramide may be administered to 
patients on an "as needed" basis.
Dose interruption/reduction decisions for nausea and/or vomiting should be based on the 
CTCAE grade of the toxicity and the guidelines provided in Table 5.
As a guidance for recommendations on supportive measures for the prevention and/or 
management of nausea and/or vomiting, the published recommendation from American 
Society of Clinical Oncology (ASCO), the European Society of Medical Oncology (ESMO) 
and Multinational Association of Supportive Care (MASCC) can be used (Basch et al 2011; 
Roila et al 2010).
6.6. Treatment Compliance
Compliance will be evaluated at each visit by a review of patient diary entries, an accounting 
of returned drug product, and patient interviews during the DDI Phase of the study.


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7. STUDY PROCEDURES AND ASSESSMENTS
The procedures and assessments that will be conducted during this study are described in this 
section in narrative form, described by study visit in Section 8 and summarized in Table 7
and Table 8.
Written informed consent must be granted by each patient prior to the initiation of any study 
procedure or assessment (other than those considered standard of care).
Please see Appendix 13 for alternative study measures to be followed during public 
emergencies, including the COVID-19 pandemic.
7.1. Safety Assessments
7.1.1. Adverse Events
Adverse events will be assessed by direct observation and patient interviews. Patients should 
be questioned using non-leading questions. Assessment and reporting of AEs is described in 
detail in Section 10.
7.1.2. Medical History
Significant (at the Investigator’s discretion) past and present medical history will be 
recorded. Medical history will include alcohol and nicotine use for the 3 months before 
screening. Any ongoing condition observed prior to the initiation of study treatment will be 
recorded.
7.1.3. Physical Examination
Full physical examinations will be performed by trained medical personnel at the time points 
specified in Table 7 and Table 8.
Vital signs (blood pressure, pulse and temperature) will be measured per institutional standards 
as part of the physical examination. Height will be measured only at screening. All physical 
examinations occurring on dosing days must be performed prior to study drug administration. 
Significant findings in the Investigator’s opinion that are present prior to the start of study drug 
must be included in the Relevant Medical History/Current Medical Conditions page on the 
patient’s eCRF. Significant findings made after signing the study informed consent which meet 
the definition of an AE must be recorded on the Adverse Event eCRF.
7.1.4. Electrocardiogram
Triplicate 12-lead ECGs will be performed at the time points specified in Table 7 and 
Table 8. At each measurement, 3 serial ECGs will be obtained within approximately 5 to 
10 minutes total time. Triplicate 12-lead ECGs will be performed at predose (up to 30 
minutes before any study drug administration) and for all protocol specified post-baseline 
assessments. Postdose ECGs are to be performed at all protocol specified post-baseline 
assessments (± 30 minutes). Triplicate 12-lead ECGs are to be performed during the post-
DDI phase if clinically indicated.


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The mean of the triplicate ECG measurements performed at baseline will serve as each 
patient’s baseline value for all postdose comparisons. When ECGs and PK sampling are 
performed at the same nominal time point, the ECGs will be performed first.
An abnormal ECG (e.g., QTc of > 500 ms or with a change in QTc from baseline of ≥60 ms) 
may be repeated if it cannot be interpreted by the Investigator. ECG tracings should be made 
available if requested by the Sponsor for central assessment by an independent reviewer.
QT interval values will be corrected for heart rate using the Fridericia formula (QTcF).
7.1.5. ECOG Performance Status
Assessment of ECOG PS will be conducted at the time points specified in Table 7 and 
Table 8.
7.1.6. Clinical Laboratory Tests
Blood and urine samples for the laboratory tests listed in Table 6 will be collected as outlined 
in Section 8 and at the time points specified in Table 7 and Table 8.


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Table 6.
Summary of Clinical Laboratory Tests
Hematology
Chemistry
Urinalysis
Coagulation
Others
Hemoglobin
Hematocrit
RBC
Platelets
WBC
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
Albumin
Alkaline phosphatase
ALT
Amylase
AST
Bicarbonate (CO2)
Total bilirubin
Direct bilirubin (if 
total bilirubin values 
are abnormal)
BUN
Calcium
Chloride
CK (If total CK ≥3 X 
ULN, then measure 
isoenzymes, serum 
creatinine and 
myoglobin in blood 
or urine weekly.)
Creatinine
Glucose
LDH
Lipase
Magnesium
Inorganic phosphate
Potassium
Total protein
Sodium
Uric acid
Appearance
Color
Specific gravity
pH
Protein
Glucose
Ketones
Blood
Nitrite
Leukocyte esterase
If urinalysis is 
abnormal, then 
microscopy:
WBC
RBC
Bacteria
Epithelial cells
Casts
PT or INR
aPTT
At screening only:
Hepatitis B surface 
antigen
Hepatitis B surface 
antigen antibody
Hepatitis C core 
antibody
HIV, as applicable per 
local regulations
Urine cotinine test
(Arm 1 only)
If applicable:
Serum pregnancy test
Urine pregnancy test
FSH 
Urine drug and alcohol 
testing
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; CK = 
creatine kinase; FSH = follicle-stimulating hormone; LDH = lactate dehydrogenase; RBC = red blood cells;  WBC = white 
blood cells
7.1.6.1. Hematology, Clinical Chemistry and Urinalysis
Site-specific handling instructions for hematology, clinical chemistry and urinalysis samples 
should be followed. Screening results will be assessed by the Investigator to determine 
patient eligibility. Day -7 (Arms 1 and 2) and Day 1 (Arm 3) results will be assessed by the 
Investigator prior to first dose of study treatment. Additional clinical laboratory tests may be 
obtained at any time during the study at the Investigator’s discretion. Clinically significant 
findings should be followed to resolution or stabilization.


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Blood and urine sample collections on clinic days must be performed prior to study treatment 
administration. Laboratory test results required to make decisions regarding potential dose 
modifications during the post-DDI phase (as specified in Section 6.5) should be reviewed 
prior to study treatment administration.
7.1.7. Ophthalmic Examination
7.1.7.1. Routine Testing
Full ophthalmic examination including slit lamp examination, best recorded visual acuity for 
distance testing, intraocular pressure (IOP) and dilated funduscopy with attention to retinal 
abnormalities, especially retinal pigment epithelial detachment (RPED), retinal detachment 
(serous or rhegmatogenous), and retinal vein occlusion (RVO), will be performed at the time 
points listed in Table 7 and Table 8 during on-study treatment phase and at EOT. Ophthalmic 
examinations are to be performed during the post-DDI phase if clinically indicated.
7.1.7.2. Additional testing
Patients with clinical suspicion of retinal abnormalities (i.e. photopsia, metamorphopsia, 
impairment of visual acuity, etc.) RVO, must complete at least one of the following 
additional assessments:

For retinal abnormalities: optical coherence tomography of the macula (spectral 
domain is preferred)

For vascular abnormalities: fluorescein angiography of the central 30 degrees.
Any diagnosis of a retinal event (e.g.: macular edema, detachment) should have its 
evolution/resolution substantiated by OCT.
Images of the ophthalmic exams, especially OCT and/or fluorescein angiography should be 
sent to the investigative site along with the results of the exam and be maintained in the 
patient’s source document file. These images may be requested to be sent to the Sponsor or 
designee.
7.1.8. Dermatologic Examination
The possible appearance of SCC, KA or other suspicious skin lesion will be monitored. 
Dermatologic evaluations will be performed as a part of the physical examinations at the 
timepoints specified Table 7 and Table 8. Patients should be instructed to inform their 
physician upon the occurrence of any skin changes. Dermatologist examination and/or 
dermatologic biopsy will be performed only if clinically indicated. In the occurrence of these 
lesions, the lesions should be removed and the patient must be treated as per institutional 
practice. Biopsy results will be collected.
7.1.9. Pregnancy Tests
All females of childbearing potential are required to undergo serum pregnancy assessments at 
screening and serum or urine pregnancy assessments during the study at the time points 
specified in Table 7 and Table 8. Any positive test will result in immediate cessation of study 
drug administration.


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Urine pregnancy tests will be performed locally as outlined in the SoA, as medically 
indicated (e.g., in case of loss of menstrual cycle, when pregnancy is suspected), or per 
country-specific requirement (note that country-required urine pregnancy testing will be 
outlined and communicated to investigational sites under separate cover). All blood and urine 
collections for pregnancy tests occurring on dosing days must be performed prior to study 
drug administration, with a negative test result required prior to administration of study 
treatment. 
If a urine pregnancy test is positive, the results will be confirmed with a serum pregnancy 
test. If the serum pregnancy test is negative after a urine test was positive, the Investigator 
will assess the potential benefit/risk to the patient and determine whether it is in the patient’s 
best interest to resume study treatment and continue participation in the study. Any female 
patient who becomes pregnant while participating in the study will be instructed to 
immediately discontinue study treatment. If pregnancy is confirmed by a serum pregnancy 
test, see Section 10 for reporting requirements.
Females of nonchildbearing potential do not require pregnancy tests. This includes women 
who have undergone hysterectomy, bilateral oophorectomy, bilateral tubal ligation or who 
are over the age of 55 and amenorrheic. Women of age 55 and under and who are 
amenorrheic should have FSH measurement within the postmenopausal range for the 
institution to be considered of nonchildbearing potential.
All blood and urine collections for pregnancy tests occurring on dosing days must be 
performed prior to study drug administration.
7.2. Pharmacokinetic Assessments
A 6-mL venous blood sample (Arms 1 and 2) or a 4-mL venous blood sample (Arm 3) for 
measurement of plasma concentrations of encorafenib (and its metabolite, LHY746), 
binimetinib (and its metabolite, AR00426032), midazolam, 1-OH midazolam, caffeine, 
paraxanthine, omeprazole, 5-hydroxy omeprazole, rosuvastatin, bupropion and/or
hydroxybupropion will be drawn at each time point specified in Table 7 and Table 8.
Analytes for quantitation will depend on the study arm. Complete instructions for sample 
collection, processing, handling and shipment will be provided in the Laboratory Manual.
All PK samples up to and including the 8-hour time point must be obtained within 
15 minutes of the designated collection time.  Predose PK samples must be obtained prior to, 
but within 30 minutes of, administration of any study drug or probe substrate.
All urine during the 0 to 8 hour interval is to be collected from patients in Arm 1 for 
measurement of urine concentrations of losartan, E-3174, dextromethorphan and 
dextrorphan. Patients should attempt to void as close to the 8 hour time point as possible. The 
urine from timepoints 0 hour through 8 hours will be pooled and refrigerated during the 
collection interval.
At the end of each interval, total urine volume will be measured using a cylindrical graduate 
and recorded.


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Refer to the Laboratory Manual for further details regarding urine sample processing.
If vomiting occurs within 4 hours following study drug administration on the day of PK 
blood sampling, the time (using the 24-hour clock) of vomiting should be recorded on the 
transmittal forms that accompany the sample and that dose of study drug should not be re-
administered.
During the COVID-19 pandemic, please proactively discuss any PK collection issue with the 
Pfizer clinician and clinical pharmacologist.
 
 
 
 
 
7.4. Disease Assessments
Tumor assessments will include imaging (e.g., CT, MRI) and caliper measurements, as 
applicable, and will be performed at screening. Tumor response will be evaluated locally by 
the Investigator according to RECIST, v1.1 (Appendix 7).
Although this study does not formally assess efficacy, efficacy assessment are required every 
8-12 weeks in order for the Investigator to assess continued benefit. 
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8. SCHEDULE OF PROCEDURES AND ASSESSMENTS
Before recruitment of patients into the study, written ethic committee (EC) approval of the 
protocol, informed consent, and any additional patient information must be obtained.
During screening, a unique number will be assigned to each patient who provides written 
informed consent. Once a patient is in screening or is enrolled in the study, that patient will 
be identified only by the assigned patient number.
The Investigator or designee is responsible for verifying that the patient is eligible before 
enrolling the patient. 
At the site, the Investigator will maintain a log for all screened patients (including patients 
who fail screening after providing written informed consent) and all enrolled patients.
Please see Appendix 13 for alternative study measures to be followed during public 
emergencies, including the COVID-19 pandemic.
The procedures and assessments that will be conducted during this study are described in this 
section by study visit and summarized in Table 7 and Table 8.
8.1. Prescreening Evaluations
Prescreening evaluations must be performed between Day -57 and Day -36 in Arms 1 and 2 
and between Day -50 and Day -29 in Arm 3. These include:

Mutation prescreen consent

Tumor sample
8.2. Screening Evaluations
All screening procedures must be performed within 28 days prior to the first dose of study 
drug on Day -7 (Day -35 to Day -8, inclusive) in Arms 1 and 2 and prior to the first study 
drug dose on Day 1 (Day -28 to Day -1, inclusive) in Arm 3. These include:

Confirm BRAF mutation status

Administration of written informed consent (must be obtained prior to 
performance of any study-specific tests or evaluations that are not considered 
standard of care)

Disease assessments based on RECIST v1.1 (imaging and /or caliper measurements; 
can be up to Day -49 but must be confirmed by Day -7; if a patient has had an 
imaging assessment up to 6 weeks prior to Day -7 [Day -49 to Day -7], repeat 
assessment is not required)

Demographics

Medical history, including alcohol and nicotine use for the 3 months before screening


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•
Verification of eligibility criteria
•
Prior treatments, including all cancer treatments, and any other prior treatments (i.e., 
other than cancer treatments) taken within 4 weeks before screening
•
ECOG PS
•
Full physical exam, including body weight and height
•
Vital signs, including blood pressure, pulse, and temperature
•
Triplicate 12-lead ECG within approximately 5 to 10 minutes total time
•
ECHO/MUGA
•
Ophthalmic examination
•
Blood samples for the following tests:
o
Serum pregnancy test (females of childbearing potential only)
o
Serum FSH, as applicable to confirm menopausal status 
o
Clinical chemistry, coagulation and hematology
o
 
•
Urine sample for the following tests:
o
Urinalysis
o
Urine cotinine (Arm 1 only)
•
Review of concomitant medications
•
Review of AEs
8.3. Study Evaluations
8.3.1. DDI Phase – Arms 1 and 2
8.3.1.1. Day -7 at Hour 0
•
Verification of eligibility criteria
•
Weight
•
Vital signs, including blood pressure, pulse, and temperature 
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
Triplicate 12-lead ECG within approximately 5 to 10 minutes total time (repeat if 
QTcF > 480 msec)

Blood samples for the following tests:
o
Pharmacokinetics
o
Clinical chemistry, coagulation and hematology
o
Serum (or urine) pregnancy test (females of childbearing potential only)

Urine sample for the following tests:
o
Pharmacokinetics – Arm 1 only (pre-dose sample will not be pooled with 
subsequent post-dose samples)
o
Urinalysis
o
Urine (or serum) pregnancy test (females of childbearing potential only)
o
Drug and alcohol testing

Review of concomitant medications

Review of AEs

Administration/dispensing of CYP probe cocktail (Arm 1 only)

Administration/dispensing of rosuvastatin (Arm 2 only)
8.3.1.2. Day -7 at Hours 1 and 3

Urine sample for PK – Arm 1 only (sample to be included in a pooled urine sample of 
all urine collected from time 0 [postdose] to 8 hours post-dose)

Blood sample for PK

Review of AEs
8.3.1.3. Day -7 at Hours 2, 4, 6 and 8

Vital signs, including blood pressure, pulse, and temperature 

Triplicate 12-lead ECG within approximately 5 to 10 minutes total time

Urine sample for PK – Arm 1 only (sample to be included in a pooled urine sample of 
all urine collected from time 0 [postdose] to 8 hours post-dose)

Blood sample for PK


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
Review of AEs
8.3.1.4. Day 1 and Day 14 at Hour 0

Weight

Vital signs, including blood pressure, pulse, and temperature 

Triplicate 12-lead ECG within approximately 5 to 10 minutes total time

Blood samples for the following tests:
o
Pharmacokinetics
o
Clinical chemistry, coagulation and hematology
o
Serum (or urine) pregnancy test (females of childbearing potential only)

Urine samples for the following:
o
Pharmacokinetics – Arm 1 only (pre-dose sample will not be pooled with 
subsequent post-dose samples)
o
Urinalysis
o
Urine (or serum) pregnancy test (females of childbearing potential only)

Review of concomitant medications

Review of AEs

Administration/dispensing of encorafenib and binimetinib

Administration/dispensing of CYP probe cocktail (Arm 1 only)

Administration/dispensing of rosuvastatin and bupropion (Arm 2 only)

Assess compliance with administration of encorafenib and binimetinib on Day 14
8.3.1.5. Day 1 and Day 14 at Hours 1 and 3

Urine sample for PK – Arm 1 only (sample to be included in a pooled urine sample of 
all urine collected from time 0 [postdose] to 8 hours postdose)

Blood sample for PK

Review of AEs


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8.3.1.6. Day 1 and Day 14 at Hours 2, 4, 6 and 8

Vital signs, including blood pressure, pulse, and temperature 

Triplicate 12-lead ECG within approximately 5 to 10 minutes total time

Urine sample for PK – Arm 1 only (sample to be included in a pooled urine sample of 
all urine collected from time 0 [postdose] to 8 hours postdose)

Blood sample for PK

Review of AEs
8.3.2. DDI Phase – Arm 3 
8.3.2.1. Day 1 and 15 at Hour 0 

Verification of eligibility criteria (Day 1 only)

Weight (Day 1 only)

Blood samples for the following tests (Day 1 only):
o
Clinical chemistry, coagulation and hematology
o
Serum (or urine) pregnancy test (females of childbearing potential only)

Urine sample for the following tests (Day 1 only):
o
Urinalysis
o
Urine (or serum) pregnancy test (females of childbearing potential only)
o
Drug and alcohol testing

Review of concomitant medications (Day 1 only)

Vital signs, including blood pressure, pulse, and temperature 

Triplicate 12-lead ECG within approximately 5 to 10 minutes total time (repeat if 
QTcF > 480 msec)

Review of AEs

Administration/dispensing of encorafenib and binimetinib

Administration/dispensing of modafinil (Day 15 only)


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8.3.2.2. Day 1 and 15 at Hours 2 and 4

Vital signs, including blood pressure, pulse, and temperature 

Triplicate 12-lead ECG within approximately 5 to 10 minutes total time

Review of AEs
8.3.2.3. Day 14 and 21 at Hour 0

Weight

Vital signs, including blood pressure, pulse, and temperature 

Triplicate 12-lead ECG within approximately 5 to 10 minutes total time  

Blood samples for the following tests:
o
Pharmacokinetics
o
Clinical chemistry, coagulation and hematology
o
Serum (or urine) pregnancy test (females of childbearing potential only)

Urine samples for the following:
o
Urinalysis
o
Urine (or serum) pregnancy test (females of childbearing potential only)

Review of concomitant medications

Review of AEs

Administration/dispensing of encorafenib and binimetinib

Administration of modafinil (Day 21 only)

Assess compliance with administration of modafinil, encorafenib and binimetinib
8.3.2.4. Day 14 and Day 21 at Hours 1 and 3

Blood sample for PK

Review of AEs
8.3.2.5. Day 14 and Day 21 at Hours 2, 4, 6 and 8

Vital signs, including blood pressure, pulse, and temperature 


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
Triplicate 12-lead ECG within approximately 5 to 10 minutes total time

Blood sample for PK

Review of AEs
8.3.3. Day 28, End of DDI Phase Visit

Full physical exam, including body weight 

Vital signs, including blood pressure, pulse, and temperature

Triplicate 12-lead ECG within approximately 5 to 10 minutes total time

ECHO/MUGA

Ophthalmic examination

Blood samples for the following tests:
o
Serum pregnancy test (females of childbearing potential only)
o
Clinical chemistry, coagulation and hematology

Urine sample for urinalysis

Review of concomitant medications

Review of AEs

Assess compliance with administration of encorafenib and binimetinib
8.3.4. Post-DDI Phase
It is recommended patients be evaluated according to standard practice.  The following are 
provided as suggested time points for evaluation. In addition, efficacy assessment must be 
performed every 8-12 weeks in order to assess continued benefit. 
8.3.4.1. Every 3-4 Weeks

Review of concomitant medications

Review of AEs with reporting of all Grade 3 or 4 AEs and all SAEs (follow-up of 
SAEs to continue as described in Section 10.1.3)

Physical examination, hematology and chemistry laboratory testing

If clinically indicated: triplicate 12-lead ECG within approximately 5 to 10 minutes 
total time


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
Assess compliance with administration of encorafenib and binimetinib
8.3.4.2. Every 8-12 Weeks

Efficacy assessment in order to assess continued benefit

ECHO/MUGA (more frequent if clinically indicated)

Ophthalmic examination (and as clinically indicated if visual symptoms are reported)

Dermatologic examination every 8 weeks to be continued up to 6 months after 
discontinuing encorafenib
8.3.5. Day 30 Safety Follow-up Visit (Approximately 30 Days After Last dose of Study 
Drug)

Review of concomitant medications

Review of AEs with reporitng of all Grade 3 or 4 AEs and all SAEs (follow-up of 
SAEs to continue as described in Section 10.1.3)


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Table 7.
Schedule of Events – Arms 1 and 2
Study Procedures
Prescreen
Screen
DDI Phase
Post DDI Phase
Days →
-57 to -36
-35 to -8
Day -7, Day 1 and Day 14
Day 28 / End 
of DDI 
Phase 
Treatmenta
Every 3-4 
weeksb
Day 30 
Safety 
Follow-up 
Visitc
Hours →
0
1
2
3
4
6
8
Mutation Prescreen Consentd
X
Tumor Sampled
X
Confirm BRAF Mutation Statusd
X
Informed Consent
X
 
Disease Assessments (imaging and 
/or caliper measurements)e
X
Inclusion/Exclusion Criteriaf
X
X
Demographics
X
Medical Historyg
X
Prior Treatmentsh
X
Full Physical Examination
X
X
Xi
RECIST v1.1
X
ECOG PS
X
Height
X
Weight
X
X
X
Vital Signsj
X
X
X
X
X
X
X
Triplicate 12-Lead ECGk
X
X
X
X
X
X
X
X
ECHO/MUGAl
X
X
X
Ophthalmic Examination m
X
X
X
Hematology
X
X
X
X
Clinical Chemistry
X
X
X
X
Coagulation
X
X
X
Urinalysisn
X
X
X
Pregnancy Testo
X
X
X
Serum FSHo
X
AE Monitoringb
X
X
X
X
X
X
X
X
X
X
X
CCI


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Table 7.
Schedule of Events – Arms 1 and 2
Study Procedures
Prescreen
Screen
DDI Phase
Post DDI Phase
Days →
-57 to -36
-35 to -8
Day -7, Day 1 and Day 14
Day 28 / End 
of DDI 
Phase 
Treatmenta
Every 3-4 
weeksb
Day 30 
Safety 
Follow-up 
Visitc
Hours →
0
1
2
3
4
6
8
Concomitant Medication
Monitoring
X
X
X
X
X
Probe Cocktail Administration
(Arm 1)
X
Rosuvastatin and Bupropion
Administration (Arm 2)
X
Encorafenib QD/ Binimetinib BID 
Administrationp
X
Urine for PKq,r
X
X
X
X
X
X
X
Blood for PKs
X
X
X
X
X
X
X
Confinement in the CRUt
X
X
X
X
X
X
X
Encorafenib /  Binimetinib –
Dispense and /or Assess 
Compliances
X
X
X
Determine BOR per Investigator 
and date of progression
X
AE = adverse event; BOR = best overall response; CT = computed tomography; ECG = electrocardiogram; ECOG PS = Eastern Conference Oncology Group Performance 
Status; FDA = United States Food and Drug Administration; MRI = magnetic resonance imaging; PK = pharmacokinetic;
a Performed on those patients who discontinue the DDI phase prior to Day 28 and those patients who choose not to continue in the post-DDI phase.
b Patients who continue in the post-DDI phase will only be followed for safety. Safety should be monitored by assessing physical examination, hematology and chemistry 
laboratory testing and any other pertinent testing required as part of the safety profile of the compound (ophthalmic exams, cardiac profiles) until discontinuation. Investigators 
will be required to report any Grade 3-4 AEs and all SAEs as described in Section 10.1.3.
c Day 30 Safety Follow-up Visit to occur approximately 30 days after the last dose of study drug. Additional safety assessments may be performed at the Day 30 Safety Follow-
up Visit to monitor any safety concerns identified during the safety follow-up phase.
d Fresh or archive tumor biopsy if prior documentation of BRAF mutation is not available. Analysis of BRAF mutation will be determined by local laboratory.
e Baseline disease assessments based on RECIST v1.1 (imaging and /or caliper measurements; can be up to Day -49 but must be confirmed by Day -7; if a patient has had an 
imaging assessment up to 6 weeks prior to Day -7 [Day -49 to Day -7], repeat assessment is not required).
f Eligibility criteria to be collected at screening and reconfirmed on Day -7 at Hour 0.
g Medical history includes alcohol and nicotine history over the 3 months before screening.
h All prior cancer treatments are to be recorded; other prior treatments (i.e., other than cancer treatments) taken within 4 weeks of screening should also be recorded.
i A dermatological exam is recommended to be performed every 8 weeks and up to 6 months after discontinuation of encorafenib.
j Vital signs include blood pressure, pulse rate, and temperature.


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Table 7.
Schedule of Events – Arms 1 and 2
Study Procedures
Prescreen
Screen
DDI Phase
Post DDI Phase
Days →
-57 to -36
-35 to -8
Day -7, Day 1 and Day 14
Day 28 / End 
of DDI 
Phase 
Treatmenta
Every 3-4 
weeksb
Day 30 
Safety 
Follow-up 
Visitc
Hours →
0
1
2
3
4
6
8
k Three 12-lead ECGs are to be performed over a period of 5 to 10 minutes. Triplicate 12-lead ECGs will be performed at predose (up to 30 minutes before any study drug 
administration) and for all protocol specified post-baseline assessments. Postdose ECGs are to be performed at all protocol specified post-baseline assessments (± 30 minutes). 
Triplicate 12-lead ECGs are to be performed during the post-DDI phase if clinically indicated.
l ECHO/MUGA to be performed at Screening and at EOT. In the post-DDI phase, it is recommended that ECHO/MUGA scans be performed approximately every 8 to 12 
weeks or more frequently if clinically indicated. 
m Ophthalmic examinations are to be performed as needed during on-study treatment phase and at EOT. In the post-DDI phase, it is recommended that ophthalmic examinations 
be conducted approximately every 8 to 12 weeks and as clinically indicated if visual symptoms are reported. 
n Urine cotinine test at screening for Arm 1 only. Drug and alcohol screen only to be done on Day -7 at Hour 0.
o For females only. For females of childbearing potential serum pregnancy tests are to be performed at screening; serum or urine pregnancy tests may be performed at 
subsequent time points during the study. For postmenopausal females, serum FSH to be performed to confirm postmenopausal status.
p Encorafenib/binimetinib will be dosed daily beginning on Day 1.
q Urine PK for patients in Arm 1 only.
r The predose urine sample will be separate from subsequent samples. All urine collected over the 0 to 8 hour period will be pooled. All PK samples up to and including the 8-
hour time point must be obtained within 15 minutes of the designated collection time. Predose PK samples must be obtained prior to, but within 30 minutes of, administration 
of any study drug or probe substrate.
s Confinement in unit or returns, as necessary.
t Encorafenib/binimetinib – dispense and/or assess compliance – not done on Day -7.


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Table 8.
Schedule of Events – Arm 3
Study Procedures
Prescreen
Screen
DDI Phase
Post DDI Phase
Days →
-50 to -29
-28 to -1
Day 1 and 
Day 15a
Day 14 and Day 21
Day 28 / 
End of DDI 
Phase 
Treatmentb
Every 3-4 
weeksc
Day 30 
Safety 
Follow-up 
Visitd
Hours →
0
2
4
0
1
2
3
4
6
8
Mutation Prescreen Consente
X
Tumor Samplee
X
Confirm BRAF Mutation Statuse
X
Informed Consent
X
Disease Assessments (imaging and 
/or caliper measurements)f
X
Inclusion/Exclusion Criteriag
X
X
Demographics
X
Medical Historyh
X
Prior Treatmentsi
X
Full Physical Examination
X
X
Xj
RECIST v1.1
X
ECOG PS
X
Height
X
Weight
X
X
X
X
Vital Signsk
X
X
X
X
X
X
X
X
X
X
Triplicate 12-Lead ECGl
X
X
X
X
X
X
X
X
X
X
X
ECHO/MUGAm
X
X
X
Ophthalmic Examinationn
X
X
X
Hematology
X
X
X
X
X
Clinical Chemistry
X
X
X
X
X
Coagulation
X
X
X
X
Urinalysiso
X
X
X
X
Pregnancy Testp
X
X
X
X
Serum FSHp
X
AE Monitoringc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant Medication Monitoring
X
X
X
X
X
X
Modafinil QD Administrationq
X
X


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Table 8.
Schedule of Events – Arm 3
Study Procedures
Prescreen
Screen
DDI Phase
Post DDI Phase
Days →
-50 to -29
-28 to -1
Day 1 and 
Day 15a
Day 14 and Day 21
Day 28 / 
End of DDI 
Phase 
Treatmentb
Every 3-4 
weeksc
Day 30 
Safety 
Follow-up 
Visitd
Hours →
0
2
4
0
1
2
3
4
6
8
Encorafenib QD/ Binimetinib BID 
Administrationr
X
X
Blood for PKs
X
X
X
X
X
X
X
Confinement in the CRUt
X
X
X
X
X
X
X
X
X
X
Dispense and /or Assess Compliance
X
X
X
X
Determine BOR per Investigator and 
date of progression
X
AE = adverse event; BOR = best overall response; CT = computed tomography; ECG = electrocardiogram; ECOG PS = Eastern Conference Oncology Group Performance Status; 
FDA = United States Food and Drug Administration; MRI = magnetic resonance imaging; PK = pharmacokinetic;
a Verification of eligibility criteria, weight, chemistry, coagulation, urinalysis, pregnancy test and concomitant medication monitoring only required for Day 1.
b Performed on those patients who discontinue the DDI phase prior to Day 28 and those patients who choose not to continue in the post-DDI phase.
c Patients who continue in the post-DDI phase will only be followed for safety. Safety should be monitored by assessing physical examination, hematology and chemistry laboratory 
testing and any other pertinent testing required as part of the safety profile of the compound (ophthalmic exams, cardiac profiles) until discontinuation. Investigators will be 
required to report any Grade 3-4 AEs and all SAEs as described in Section 10.1.3.
d Day 30 Safety Follow-up Visit to occur approximately 30 days after the last dose of study drug. Additional safety assessments may be performed at the Day 30 Safety Follow-up 
Visit to monitor any safety concerns identified during the safety follow-up phase.
e Fresh or archive tumor biopsy if prior documentation of BRAF mutation is not available. Analysis of BRAF mutation will be determined by local laboratory.
f Baseline disease assessments based on RECIST v1.1 (imaging and /or caliper measurements; can be up to Day -42 but must be confirmed by Day 1; if a patient has had an 
imaging assessment up to 6 weeks prior to Day 1 [Day -42 to Day 1], repeat assessment is not required).
g Eligibility criteria to be collected at screening and reconfirmed on Day 1 at Hour 0.
h Medical history includes alcohol and nicotine history over the 3 months before screening.
i All prior cancer treatments are to be recorded; other prior treatments (i.e., other than cancer treatments) taken within 4 weeks of screening should also be recorded.
j A dermatological exam is recommended to be performed every 8 weeks and up to 6 months after discontinuation of encorafenib.
k Vital signs include blood pressure, pulse rate, and temperature.
l Three 12-lead ECGs are to be performed over a period of 5 to 10 minutes. Triplicate 12-lead ECGs will be performed at predose (up to 30 minutes before any study drug 
administration) and for all protocol specified post-baseline assessments. Postdose ECGs are to be performed at 
all protocol specified post-baseline assessments (± 30 minutes). Triplicate 12-lead ECGs are to be performed during the post-DDI phase if clinically indicated.
m ECHO/MUGA to be performed at Screening and at EOT. In the post-DDI phase, it is recommended that ECHO/MUGA scans be performed approximately every 8 to 12 weeks or 
more frequently if clinically indicated. 
n Ophthalmic examinations are to be performed as needed during on-study treatment phase and at EOT. In the post-DDI phase, it is recommended that ophthalmic examinations be 
conducted approximately every 8 to 12 weeks and as clinically indicated if visual symptoms are reported.
o Drug and alcohol screen only to be done on Day 1 at Hour 0.
p For females only. For females of childbearing potential serum pregnancy tests are to be performed at screening; serum or urine pregnancy tests may be performed at subsequent 
time points during the study. For postmenopausal females, serum FSH to be performed to confirm postmenopausal status.


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Table 8.
Schedule of Events – Arm 3
Study Procedures
Prescreen
Screen
DDI Phase
Post DDI Phase
Days →
-50 to -29
-28 to -1
Day 1 and 
Day 15a
Day 14 and Day 21
Day 28 / 
End of DDI 
Phase 
Treatmentb
Every 3-4 
weeksc
Day 30 
Safety 
Follow-up 
Visitd
Hours →
0
2
4
0
1
2
3
4
6
8
q Modafinil will be administered once daily on Day 15 to Day 21.
r Encorafenib/binimetinib will be dosed daily beginning on Day 1.
s All PK samples up to and including the 8-hour time point must be obtained within 15 minutes of the designated collection time. Predose PK samples must be obtained prior to, but 
within 30 minutes of, administration of any study drug or probe substrate.
t Confinement in unit or returns, as necessary.


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9. STUDY DISCONTINUATION
9.1. Treatment Discontinuation for Individual Patients
Patients may withdraw their consent to participate in the study at any time for any reason 
without prejudice to their future medical care by the physician or at the institution. Patients 
who request to discontinue receipt of study treatment will remain in the study and must 
continue to be followed for protocol-specified follow-up procedures. The only exception to 
this is when a patient specifically withdraws consent for any further contact with him or her 
or persons previously authorized by the patient to provide this information. Patients should 
notify the Investigator in writing of the decision to withdraw consent from future follow-up, 
whenever possible. The withdrawal of consent should be explained in detail in the medical 
records by the Investigator, as to whether the withdrawal is only from further receipt of study 
treatment or also from study procedures and/or posttreatment study follow-up and entered on 
the appropriate CRF page. In the event that vital status (whether the patient is alive or dead) 
is being measured, publicly available information should be used to determine vital status 
only as appropriately directed in accordance with local law. Patient data collected up to the 
date of consent withdrawal will be included in the analyses. Any blood or tissue samples 
collected up to the date of consent withdrawal will be analyzed.
Wherever possible, the tests and evaluations listed for the Day 30 Safety Follow-up Visit 
should be carried out and an effort should be made to continue follow-up. The Sponsor 
should be notified of all study withdrawals through the designated eCRFs in a timely manner.
Patients meeting any of the following criteria should discontinue study drug treatment:

Withdrawal of consent (no further participation and thus no further protected health 
information may be collected),

Adverse event requiring discontinuation of study drugs or rendering the patient 
unsuitable for further treatment in the judgment of the Investigator (includes delay in 
the post-DDI phase of more than 28 days to restart treatment due to an AE),

Progressive disease,

Pregnancy,

Significant protocol deviation that, in the opinion of the Investigator and/or Sponsor, 
renders the patient unsuitable for further study treatment,

Lost to follow-up,

Death,

Discretion of Investigator,

Study termination by Sponsor.


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Please see Appendix 13 for alternative study measures to be followed during public 
emergencies, including the COVID-19 pandemic.
9.2. Replacement of Patients
Patients who discontinue or require a dose reduction of study drug(s), in particular, 
encorafenib prior to completion of the last PK sampling on Day 14 in Arms 1 and 2 or on 
Day 21 in Arm 3 may be considered unevaluable for PK analyses and may be replaced. If a 
patient misses 3 or more consecutive doses of encorafenib in any arm or 3 or more doses of 
modafinil in Arm 3 prior to completion of the last PK sampling on Day 14 in Arms 1 and 2 
or on Day 21 in Arm 3 due to noncompliance, the patient may remain on treatment but may 
be replaced if limited data are available from the patient. In addition, patients who miss a 
dose of study drugs on any of the PK days, or who vomit within 4 hours after dosing on any 
of the PK days, may be replaced but may remain on treatment. All patients receiving at least 
one dose of study drug will be evaluated for safety.


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10. SAFETY MONITORING: DEFINITIONS AND REPORTING
10.1. Adverse Events and Serious Adverse Events
The definitions of an AE and an SAE can be found in Appendix 10.
AEs will be reported by the patient (or, when appropriate, by a caregiver, surrogate, or the 
patient's legally authorized representative). 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
and obtain adequate information both to determine the outcome and to assess whether the 
event meets the criteria for classification as an SAE or caused the patient to discontinue the 
study drug.
The patient will be questioned about the occurrence of AEs in a nonleading manner.
In addition, the Investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion.
10.1.1. Time Period and Frequency for Collecting AE and SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each patient begins from the time the patient provides informed consent, which 
is obtained before the patient’s participation in the study (ie, before undergoing any 
study-related procedure and/or receiving study treatment), through and including a minimum 
of 30 calendar days, except as indicated below, after the last administration of the study 
treatment. 
During the long-term follow-up period in this study for survival, only SAEs will be actively 
elicited and collected after completion of the active collection period described above. The 
SAEs identified during long-term follow-up will be reported to Pfizer Safety on the CT SAE 
Report Form only if considered reasonably related to the study treatment.
Follow-up by the Investigator continues throughout and after the active collection period and 
until the AE or SAE or its sequelae resolve or stabilize at a level acceptable to the 
Investigator and Pfizer concurs with that assessment.
For patients who are screen failures, the active collection period ends when screen failure 
status is determined.
If the patient withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn.
If a patient definitively discontinues or temporarily discontinues study treatment because of 
an AE or SAE, the AE or SAE must be recorded on the CRF and the SAE reported using the 
CT SAE Report Form.
Investigators are not obligated to actively seek AEs or SAEs after the patient has concluded 
study participation.  However, if the Investigator learns of any SAE, including a death, at any 


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time after a patient has completed the study, and he/she considers the event to be reasonably 
related to the study treatment, the Investigator must promptly report the SAE to Pfizer using 
the CT SAE Report Form.
10.1.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a patient during the active collection period as described in 
Section 7.1.1. are reported to Pfizer Safety on the CT SAE Report Form immediately upon 
awareness and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 10. The Investigator will submit any updated SAE data to the Sponsor within 
24 hours of it being available.
If a patient begins a new anticancer therapy, SAEs occurring during the above-indicated 
active collection period must still be reported to Pfizer Safety irrespective of any intervening 
treatment.  Note that a switch to a commercially available version of the study treatment is 
considered as a new anticancer therapy for the purposes of SAE reporting.
10.1.1.2. Recording Nonserious AEs and SAEs on the CRF
All nonserious AEs and SAEs occurring in a patient during the active collection period, 
which begins after obtaining informed consent as described in Section 7.1.1, will be recorded 
on the AE section of the CRF.
The Investigator is to record on the CRF all directly observed and all spontaneously reported 
AEs and SAEs reported by the patient.
If a patient begins a new anticancer therapy, the recording period for nonserious AEs ends at 
the time the new treatment is started; however, SAEs must continue to be recorded on the 
CRF during the above-indicated active collection period.  Note that a switch to a 
commercially available version of the study drug is considered as a new anticancer therapy 
for the purposes of SAE reporting.
10.1.2. Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 10.
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the patient is the preferred method to inquire about 
AE occurrences.
10.1.3. Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each patient 
at subsequent visits/contacts.  For each event, the Investigator must pursue and obtain 
adequate information until resolution, stabilization, the event is otherwise explained, or the 
patient is lost to follow-up.
In general, follow-up information will include a description of the event in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 


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possible causality.  Any information relevant to the event, such as concomitant medications 
and illnesses, must be provided.  In the case of a patient death, a summary of available 
autopsy findings must be submitted as soon as possible to Pfizer Safety. 
Further information on follow-up procedures is given in Appendix 10.
10.1.4. Regulatory Reporting Requirements for SAEs
Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of patients and the safety of a study 
drug under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study drug under clinical investigation.  The 
Sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs/ECs, and Investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to Investigators as necessary.

An Investigator who receives SUSARs or other specific safety information (eg, 
summary or listing of SAEs) from the Sponsor will review and then file it along with 
the SRSD(s) for the study and will notify the IRB/EC, if appropriate according to 
local requirements.
10.1.5. Exposure During Pregnancy or Breastfeeding, and Occupational Exposure
Exposure to the study drug under study during pregnancy or breastfeeding and occupational 
exposure are reportable to Pfizer Safety within 24 hours of Investigator awareness.
10.1.5.1. Exposure During Pregnancy
An EDP occurs if: 
•
A female patient is found to be pregnant while receiving or after discontinuing study 
drug. 
•
A male patient who is receiving or has discontinued study drug exposes a female 
partner prior to or around the time of conception. 
•
A female is found to be pregnant while being exposed or having been exposed to 
study drug due to environmental exposure.  Below are examples of environmental 
exposure during pregnancy:  
•
A female family member or healthcare provider reports that she is pregnant 
after having been exposed to the study drug by ingestion.
•
A male family member or healthcare provider who has been exposed to the 
study drug by ingestion then exposes his female partner prior to or around the time of 
conception. 


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The Investigator must report EDP to Pfizer Safety within 24 hours of the Investigator’s 
awareness, irrespective of whether an SAE has occurred.  The initial information submitted 
should include the anticipated date of delivery (see below for information related to 
termination of pregnancy). 
•
If EDP occurs in a patient or a patient’s partner, the Investigator must report this 
information to Pfizer Safety on the CT SAE Report Form and an EDP Supplemental 
Form, regardless of whether an SAE has occurred.  Details of the pregnancy will be 
collected after the start of study drug and until 3 months after the last dose. 
•
If EDP occurs in the setting of environmental exposure, the Investigator must report 
information to Pfizer Safety using the CT SAE Report Form and EDP Supplemental 
Form.  Since the exposure information does not pertain to the patient enrolled in the 
study, the information is not recorded on a CRF; however, a copy of the completed 
CT SAE Report Form is maintained in the Investigator site file.
Follow up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The Investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow up to the initial EDP Supplemental Form.  In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth.  In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
preprocedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
Abnormal pregnancy outcomes are considered SAEs.  If the outcome of the pregnancy meets 
the criteria for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal 
demise, neonatal death, or congenital anomaly [in a live born baby, a terminated fetus, an 
intrauterine fetal demise, or a neonatal death]), the investigator should follow the procedures 
for reporting SAEs.  Additional information about pregnancy outcomes that are reported to 
Pfizer Safety as SAEs follows: 
•
Spontaneous abortion including miscarriage and missed abortion;
•
Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the study drug. 
Additional information regarding the EDP may be requested by the Sponsor.  Further follow 
up of birth outcomes will be handled on a case by case basis (eg, follow up on preterm 
infants to identify developmental delays).  In the case of paternal exposure, the Investigator
will provide the patient with the Pregnant Partner Release of Information Form to deliver to 
his partner.  The Investigator must document in the source documents that the patient was 
given the Pregnant Partner Release of Information Form to provide to his partner.


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10.1.5.2. Exposure During Breastfeeding
An exposure during breastfeeding occurs if: 
•
A female patient is found to be breastfeeding while receiving or after discontinuing 
study drug.
•
A female is found to be breastfeeding while being exposed or having been exposed to 
study drug (ie, environmental exposure).  An example of environmental exposure 
during breastfeeding is a female family member or healthcare provider who reports 
that she is breastfeeding after having been exposed to the study drug by inhalation or 
skin contact.  
The Investigator must report exposure during breastfeeding to Pfizer Safety within 24 hours 
of the Investigator’s awareness, irrespective of whether an SAE has occurred.  The 
information must be reported using the CT SAE Report Form.  When exposure during 
breastfeeding occurs in the setting of environmental exposure, the exposure information does 
not pertain to the patient enrolled in the study, so the information is not recorded on a CRF.  
However, a copy of the completed CT SAE Report Form is maintained in the Investigator
site file.
An exposure during breastfeeding report is not created when a Pfizer drug specifically 
approved for use in breastfeeding women (eg, vitamins) is administered in accord with 
authorized use.  However, if the infant experiences an SAE associated with such a drug, the 
SAE is reported together with the exposure during breastfeeding.
10.1.5.3. Occupational Exposure
An occupational exposure occurs when a person receives unplanned direct contact with the 
study drug, which may or may not lead to the occurrence of an AE.  Such persons may 
include healthcare providers, family members, and other roles that are involved in the trial 
patient’s care.
The Investigator must report occupational exposure to Pfizer Safety within 24 hours of the 
Investigator’s awareness, regardless of whether there is an associated SAE.  The information 
must be reported using the CT SAE Report Form.  Since the information does not pertain to a 
patient enrolled in the study, the information is not recorded on a CRF; however, a copy of 
the completed CT SAE Report Form is maintained in the Investigator site file.
10.1.6. Cardiovascular and Death Events
Not applicable. 
10.1.7. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs
Not applicable. 


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10.1.8. Adverse Events of Special Interest
Not applicable.
10.1.8.1. Lack of Efficacy
Lack of efficacy is reportable to Pfizer Safety only if associated with an SAE.
10.1.9. Medical Device Deficiencies
Not applicable.
10.1.10. Medication Errors
Medication errors may result from the administration or consumption of the study drug by 
the wrong patient, or at the wrong time, or at the wrong dosage strength.
Exposures to the study drug under study may occur in clinical trial settings, such as 
medication errors.
Safety Event
Recorded on the AE 
CRF
Reported on the CT SAE Report 
Form to Pfizer Safety Within 24 
Hours of Awareness
Medication errors Only if associated with an 
AE or SAE
Only if associated with an SAE
Medication errors include:

Medication errors involving patient exposure to the study drug;

Potential medication errors or uses outside of what is foreseen in the protocol that 
do or do not involve the study patient.
In the event of a medication dosing error, the Sponsor should be notified within 24 hours.
If applicable, any associated AE(s), serious and nonserious, are recorded on the AE page of 
the CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
10.2. Treatment of Overdose
Pfizer does not recommend specific treatment for an overdose.
In the event of an overdose, the Investigator/treating physician should:
1. Contact the medical monitor within 24 hours.


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2. Closely monitor the patient for any AEs/SAEs and laboratory abnormalities for at 
least 5 half-lives or 28 calendar days after the overdose of study treatment (whichever 
is longer).  Closely monitor the patient for any AEs/SAEs.
3. Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF.
4. Overdose is reportable to Safety only when associated with an SAE.
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Sponsor Medical Monitor based on the clinical evaluation of the 
patient.


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11. STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
11.1. General Considerations
A detailed statistical analysis plan (SAP) will be prepared by the Sponsor. This plan may 
modify the statistical methods outlined in the protocol; however, any major modifications of 
the primary endpoint definition or analysis will also be described in a protocol amendment.
11.1.1. Sample Size
For Arm 1, sample size was determined by the substrate in the CYP probe cocktail with the 
highest reported difference in standard deviation (Ryu et al. 2007). The coefficient of 
variation of the difference between 2 AUClast values for the same patient for omeprazole is 
approximately 38%. Assuming a 2-sided significance level of 0.05 and a power of 0.8, 
approximately 20 patients would need to be evaluable to detect a difference of 25% in mean 
AUClast. Additionally, these values are similar to other cocktail studies run in oncology 
patients (Goh 2010).
For Arm 2, the coefficient of variation of the ratio between 2 rosuvastatin AUClast values for 
the same patient for rosuvastatin is approximately 47% (Stopfer 2016). Assuming a 2-sided 
significance level of 0.05 and a power of 0.8, approximately 10 patients would need to be 
evaluable to detect a difference of 50% in mean AUClast. Assuming an intrasubject variation 
of 23% for bupropion AUC0-8 (Bosilkovska 2014), there is an 80% probability with 10 
subjects that a treatment difference will be detected if the true effect size is 33%.
For Arm 3, PK data will be analysed after the first 6 patients to look for an indication that the 
moderate inducer is having a significant effect on encorafenib PK. If there is a ≥ 20% change 
in mean encorafenib AUC, then an additional 6 patients will be enrolled to more fully 
characterize the effect. Assuming an intrasubject variation of 36.4% for encorafenib AUCtau
(Clinical Study CMEK162X2110), there is an 80% probability with fixed sample sizes of 6 
and 12 subjects that a treatment difference will be detected if the true effect size is 74 and 
46%, respectively. 
11.1.2. Safety Analysis
During the DDI phase, all safety data for all three arms will be recorded in the patient’s 
source documents and eCRFs. Adverse events including SAEs, laboratory profiles 
(hematology, biochemistry, coagulation, cardiac/muscle enzymes, urinalysis), physical 
examination (including vital signs, ophthalmic and dermatological examinations), ECOG PS
assessment, and cardiac profiles (ECG and MUGA or ECHO), concomitant medications 
and/or therapies will be recorded.
All patients who receive at least one dose of study drug will be included in the safety 
analyses.
Safety data from the DDI phase will be presented in tabular and/or graphical format and 
summarized descriptively by treatment group and study day, where appropriate. Adverse 
events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
Incidence tables will be presented for all AEs by maximum severity, SAEs, AEs assessed as 


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related to study drug and AEs resulting in discontinuation of study drug. Changes in ECG 
and laboratory measurements will be summarized. Listings of all safety data sorted by 
treatment group, patient and assessment date will be provided.
During the post-DDI phase, it is recommended that safety evaluations occur every 3 to 4 
weeks, unless otherwise specified. Safety should be monitored by assessing physical 
examination, hematology and chemistry laboratory testing and any other pertinent testing 
required as part of the safety profile of the compound (dermatological examinations, 
ophthalmic exams, cardiac profiles) until discontinuation. Investigators will be required to 
report any SAEs to the Sponsor or designee using the SAE form.
11.1.3. Pharmacokinetic Analysis
Patients who have sufficient concentration data to calculate at least one PK parameter on Day 
-7, Day 1, Day 14 and Day 21 (as appropriate), will be included in the PK analyses. Plasma 
or urine concentrations of midazolam, 1-OH midazolam, caffeine, paraxanthine, omeprazole, 
5-hydroxy omeprazole, rosuvastatin, losartan, E-3174, dextromethorphan, dextrorphan, 
bupropion, hydroxybupropion, binimetinib, AR00426032, encorafenib and LHY746 will be 
determined using validated bioanalytical methods. Standard noncompartmental PK 
parameters will be estimated for each analyte in plasma by day and patient. For each analyte 
in urine, the Ae0-8, the fe into urine and the renal clearance (CLR) will be calculated. 
Descriptive statistics of PK parameters will be reported for each analyte by day. 
 
 
Remaining plasma PK samples from Arm 3 may also be analyzed 
for modafinil using either a nonvalidated or validated bioanalytical method.
For the primary analysis in Arms 1 and 2, an analysis of variance (ANOVA) will be 
performed on the natural log (ln)-transformed Cmax and AUClast of midazolam, 1-OH 
midazolam, caffeine, paraxanthine, omeprazole, 5-hydroxy omeprazole, rosuvastatin, 
bupropion and hydroxybupropion and the urine losartan, E-3174, dextromethorphan and 
dextrorphan Ae0-8. For the primary analysis in Arm 3, an ANOVA will be performed on the 
encorafenib ln-transformed Cmax and AUC. The ANOVA model will include treatment as 
fixed effect and patient as the random effect. Each ANOVA will include calculation of least 
squares means (LSM), the difference between treatment LSM, and the standard error 
associated with this difference. 
Ratios of LSM will be calculated using the exponentiation of the difference between 
treatment LSM from the analyses on the ln-transformed parameters. In Arms 1 and 2, these 
ratios will be expressed as a percentage of Day 1 (test) relative to Day -7 (reference), Day 14
(test) relative to Day 1 (reference) and Day 14 (test) relative to Day -7 (reference). In Arm 3, 
these ratios will be expressed as a percentage of Day 21 (test) relative to Day 14 (reference).
Consistent with the 2 one-sided test, 90% confidence intervals (CIs) for the ratios will be 
derived by exponentiation of the CIs obtained for the difference between treatment LSM 
resulting from the analyses on the ln-transformed parameters. In Arms 1 and 2, the CIs will 
be expressed as a percentage of Day 1 (test) relative to Day -7 (reference), Day 14 (test) 
CCI


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relative to Day 1 (reference) and Day 14 (test) relative to Day -7 (reference). In Arm 3, these 
ratios will be expressed as a percentage of Day 21 (test) relative to Day 14 (reference).
Similarly, an ANOVA will be performed on the ln-transformed MRAUC and MRCmax
calculated for 1-OH midazolam/midazolam, paraxanthine/caffeine, 5-hydroxy 
omeprazole/omeprazole, hydroxybupropion/bupropion and LHY746/encorafenib and MRAe0-
8 for E-3174/losartan and dextrorphan/dextomethorphan. 
Additional modeling of PK data using alternate methodologies (e.g., compartmental, 
population-based nonlinear mixed effects models or physiologically-based PK methods) may 
be conducted.  Results will be reported separately.
CCI


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12. DATA RECORDING, RETENTION AND MONITORING
12.1. Case Report Forms
Data will be collected using (source documents/an electronic data capture system [EDC]) at 
the clinical site. The Investigator or designee will record data specified in the protocol using 
eCRFs. Changes or corrections to eCRFs will be made by the Investigator or an authorized 
member of the study staff according to the policies and procedures at the site.
It is the Investigator’s responsibility to ensure eCRFs are complete and accurate. Following 
review and approval, the Investigator will electronically sign and date the pages. This 
signature certifies that the Investigator has thoroughly reviewed and confirmed all data on the 
eCRF.
A portable document format (PDF) file of the eCRFs will be provided to the site after all data 
have been monitored and reconciled. An electronic copy will be archived at the site.
12.2. Data Monitoring
This study will be closely monitored by representatives of the Sponsor throughout its 
duration. Monitoring will include personal visits with the Investigator and study staff as well 
as appropriate communications by telephone, fax, mail, email or use of the EDC system, if 
applicable. It is the monitor’s responsibility to inspect eCRFs at regular intervals throughout 
the study to verify the completeness, accuracy and consistency of the data and to confirm 
adherence to the study protocol and to GCP guidelines. The Investigator agrees to cooperate 
with the monitor to ensure that any problems detected during the course of this study are 
resolved promptly. The Investigator and site will permit study-related monitoring, audits, EC
review and regulatory inspection, including direct access to source documents.
It is understood that study monitors and any other personnel authorized by the Sponsor may 
contact and visit the Investigator and will be permitted to inspect all study records (including 
eCRFs and other pertinent data) on request, provided that patient confidentiality is 
maintained and that the inspection is conducted in accordance with local regulations.
Every effort will be made to maintain the anonymity and confidentiality of patients during 
this study. However, because of the experimental nature of this treatment, the Investigator 
agrees to allow representatives of the Sponsor as well as authorized representatives of 
regulatory authorities to inspect the facilities used in the conduct of this study and to inspect, 
for purposes of verification, the hospital or clinic records of all patients enrolled in the study.
12.3. Quality Control and Quality Assurance
Quality control procedures will be conducted according to the Sponsor’s internal procedures. 
The study site may be audited by a quality assurance representative of the Sponsor. All 
necessary data and documents will be made available for inspection.


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13. REGULATORY, ETHICAL AND LEGAL OBLIGATIONS
13.1. Good Clinical Practice
The study will be performed in accordance with the protocol, guidelines for Good Clinical 
Practice (GCP) established by the International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) and applicable local 
regulatory requirements and laws.
13.2. Ethics Committee Approval
The Investigator must inform and obtain approval from the EC for the conduct of the study at 
named sites, the protocol, informed consent documents and any other written information 
that will be provided to the patients and any advertisements that will be used. Written 
approval must be obtained prior to recruitment of patients into the study and shipment of 
study drug.
Proposed amendments to the protocol and aforementioned documents must be submitted to 
the Sponsor for review and approval, then to the EC. Amendments may be implemented only 
after a copy of the approval letter from the EC has been transmitted to the Sponsor. 
Amendments that are intended to eliminate an apparent immediate hazard to patients may be 
implemented prior to receiving Sponsor or EC approval. However, in this case, approval 
must be obtained as soon as possible after implementation.
Per GCP guidelines, the Investigator will be responsible for ensuring that an annual update is 
provided to the EC to facilitate continuing review of the study and that the EC is informed 
about the end of the study. Copies of the update, subsequent approvals and final letter must 
be sent to the Sponsor.
13.3. Regulatory Authority Approval
The study will be performed in accordance with the requirements of [each country’s 
regulatory authorities, e.g., U.S. FDA and Health Canada] and will also meet all of the 
requirements of ICH GCP guidance. Amendments to the protocol will be submitted to the 
[relevant authorities, e.g. FDA or Health Canada] prior to implementation in accordance with 
applicable regulations.
13.4. Other Required Approvals
In addition to EC and regulatory authority approval, all other required approvals (e.g. 
approval from the local research and development board or scientific committee) will be 
obtained prior to recruitment of patients into the study and shipment of study drug.
13.5. Informed Consent
Informed consent is a process that is initiated prior to the patient’s agreeing to participate in 
the study and continues throughout the patient’s study participation. It is the Investigator’s 
responsibility (or designee) to obtain written informed consent from each patient after 
adequate explanation of the aims, methods, anticipated benefits and potential hazards of the 
study and before any study procedures are initiated. Each patient should be given a copy of 


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the informed consent document and associated materials. The original copy of the signed and 
dated informed consent document must be retained at the site and is subject to inspection by 
representatives of the Sponsor or regulatory authorities. If any amendments occur throughout 
the course of the study that affect the informed consent form (i.e. when new study procedures 
or assessments have been added), all active patients should be re-consented using the same 
process for the initial consent.
13.6. Patient Confidentiality
The Investigator must ensure that the patient’s privacy is maintained. On the eCRF or other 
documents submitted to the Sponsor, patients will be identified by a patient number only. 
Documents that are not submitted to the Sponsor (e.g., signed informed consent documents) 
should be kept in a confidential file by the Investigator.
The Investigator shall permit authorized representatives of the Sponsor, regulatory authorities
and ethics committees to review the portion of the patient’s medical record that is directly 
related to the study. As part of the required content of informed consent documents, the 
patient must be informed that his/her records will be reviewed in this manner.
13.7. Disclosure of Information
Information concerning the study, patent applications, processes, scientific data or other 
pertinent information is confidential and remains the property of the Sponsor. The 
Investigator may use this information for the purposes of the study only.
It is understood by the Investigator that the Sponsor will use information obtained in this 
clinical study in connection with the clinical development program, and therefore may 
disclose it as required to other clinical Investigators and to regulatory authorities. In order to 
allow the use of the information derived from this clinical study, the Principal Investigator 
understands that he/she has an obligation to provide complete test results and all data 
obtained during this study to the Sponsor.
Verbal or written discussion of results prior to study completion and full reporting should 
only be undertaken with written consent from the Sponsor.
13.8. Publication of Study Data
The conditions regulating dissemination of the information derived from this study are 
described in the Clinical Trial Agreement.
13.8.1. Data Sharing
Pfizer provides researchers secure access to patient-level data or full CSRs for the purposes 
of “bonafide scientific research” that contributes to the scientific understanding of the 
disease, target, or compound class.  Pfizer will make available data from these trials 
24 months after study completion.  Patient-level data will be anonymized in accordance with 
applicable privacy laws and regulations.  CSRs will have personally identifiable information 
redacted.


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Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses.  Research teams must include a biostatistician.  Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes.


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14. ADHERENCE TO THE PROTOCOL
Investigators must apply due diligence to avoid protocol deviations, and the Sponsor (and 
designee[s]) will not pre-authorize deviations. If the Investigator believes a change to the 
protocol would improve the conduct of the study, this must be considered for implementation 
in a protocol amendment. Protocol deviations will be recorded.
14.1. Amendments to the Protocol
Only the Sponsor may modify the protocol. Amendments to the protocol will be made only 
after consultation and agreement between the Sponsor and the Investigator. The only 
exception is when the Investigator considers that a [subject’s/patient’s] safety is 
compromised without immediate action. In these circumstances, immediate approval of the 
chairman of the EC must be sought, and the Investigator should inform the Sponsor and the 
full EC within 5 working days after the emergency occurred. All amendments that have an 
impact on [subject/patient] risk or the study objectives or require revision of the informed 
consent document must receive approval from the EC prior to implementation.


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Appendix 1. Recommended Guidelines for the Management of Encorafenib-Induced 
and/or Binimetinib-Induced Skin Toxicity
Clinical judgment and experience of the treating physician should guide the management 
plan of each patient. In general, the following interventions are in addition to the 
encorafenib-induced and/or binimetinib-induced rash dosing guidelines provided in Table 5,
respectively, of the protocol.
The Initial Rash Treatment Regimen may be initiated as prophylactic treatment 24 hours 
prior to the first treatment, or later as needed to treat mild rash (CTCAE Grade 1).
Initial Rash Treatment Regimen:

Application of topical agents to the most commonly affected skin areas such as face, 
scalp, neck, upper chest and upper back. Topical agents include the following:
o
Non-oily sunscreen (PABA-free, SPF ≥ 30, UVA/UVB protection);
o
Topical steroids, preferably mometasone cream (e.g., Elocon®);
o
Topical erythromycin (e.g., Eryaknen®);
o
Topical pimocrolimus.
Note: Topical agents should be applied on a daily basis starting on Day 1 of study treatment 
or 24 hours prior to first treatment, and more often as needed.

Possibly oral doxycycline (100 mg daily) for the first 2 to 3 weeks of study drug 
administration.
Other effective medications are antihistamines, other topical corticosteroids, other topical 
antibiotics and low-dose systemic corticosteroids.
The treatment algorithm based on CTCAE grade is as follows:
Mild Rash (CTCAE Grade 1) Treatment Regimen:

Initiate Initial Rash Treatment Regimen, if not already started.

Use of topical corticosteroid (e.g., mometasone cream) and/or topical antibiotic (e.g., 
erythromycin 2%) is recommended.

The patient should be reassessed within a maximum of 2 weeks, or as per Investigator 
opinion.


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Moderate Rash (CTCAE Grade 2) Treatment Regimen:

Use of topical erythromycin or clindamycin (1%) plus topical mometasone or topical 
pimecrolimus (1% cream) plus oral antibiotics, such as lymecycline (408 mg QD), 
doxycycline (100 mg BID) or minocycline (50 to 100 mg BID).

Although there has been no evidence of phototoxicity or photosensitivity in patients 
treated with binimetinib, doxycycline (or minocycline as second line) should be used 
with thorough UV protection (i.e., avoidance of direct exposure to sunlight, use of 
sunscreen and sunglasses, etc.).

Use of acitretin is not recommended.
Severe Rash (CTCAE Grade 3-4) Treatment Regimen:
CTCAE Grade 3:

In addition to the interventions recommended for moderate rash, consider oral 
prednisolone at a dose of 0.5 mg/kg. Upon improvement, taper the dose in a stepwise 
manner (25 mg for 7 days, subsequently decreasing the dose by 5 mg/day every day).

Alternatively, in addition to the interventions recommended for moderate rash, 
consider oral isotretinoin (low dose, i.e., 0.3 to 0.5 mg/kg) (Lacouture et al. 2011).

Use of acitretin is not recommended.
CTCAE Grade 4 Treatment Regimen:

Immediately discontinue the patient from study drug and treat the patient with oral or 
topical medications (see recommendation CTCAE Grade 3).
Symptomatic Treatment Regimen:
It is strongly recommended that patients who develop rash/skin toxicities receive 
symptomatic treatment:

For pruritic lesions: use cool compresses and oral antihistamine agents.

For fissuring: use Monsel’s solution, silver nitrate or zinc oxide cream. If not 
sufficient, use mild corticosteroid ointments or ointments containing a combination of 
corticosteroid and antibiotic such as Fucicort®.

For desquamation: use emollients that are mild pH 5/neutral (recommended to 
contain 10% urea).

For paronychia: use antiseptic bath and local potent corticosteroids, use oral 
antibiotics, and, if no improvement is seen, refer to a dermatologist or surgeon.


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
For infected lesions: obtain bacterial and fungal cultures and treat with topical or 
systemic antibiotics, if indicated, based on sensitivity of culture.
References:
Lacouture ME, Anadkat MJ, Bensadoun RJ et al. Clinical practice guidelines for the 
prevention and treatment of EGFR inhibitor-associated dermatologic toxicities. Support Care 
Cancer 2011;19:1079–95.


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Appendix 2. Recommended Guidelines for the Management of Encorafenib-Induced 
Hand-Foot Skin Reactions (HFSR)
Clinical judgment and experience of the treating physician should guide the management 
plan of each patient. In addition to the HFSR dosing guidelines in Table 5 of the protocol, the 
following algorithm is recommended for the management of HFSR based on the severity of 
HFSR (adapted from Nardone et al. 2012).
Algorithm for the Management of HFSR Based on the Severity of HFSR
HFSR severity
Intervention
No HFSR
Maintain Frequent Contact with physician to ensure early 
diagnosis of HFSR
Therapy initiation
Full body-skin examination, pedicure, evaluation by podiatrist or 
orthotist; wear thick cotton gloves and/or socks; avoid hot water, 
constrictive footwear and excessive friction
If symptoms develop, proceed to next step
Grade 1
Maintain current dose of BRAF inhibitor; monitor patient 
for change in severity
Minimal skin changes or dermatitis 
without pain e.g.:
●
Numbness
●
Tingling
●
Dysesthesia
●
Paresthesia
●
Erythema
●
Edema
●
Hyperkeratosis
No interference with ADL
Avoid hot water; use moisturizing cream for relief; wear thick 
cotton gloves and/or socks; use a 20-40% urea , salicylic acid 3-
6%; ammonium lactate 12 % or lactic acid 12 % based creams to 
aid exfoliation.
If symptoms worsen, proceed to next steps
Grade 2
Maintain current dose of BRAF inhibitor; monitor patient 
for change in severity
Skin changes with pain e.g.
Peeling
●
Blisters
●
Bleeding
●
Edema
●
Hyperkeratosis
Limited instrumental ADL
Treat as with Grade 1 toxicity, with the following additions: 
clobetasol 0.05% ointment, 2-4% lidocaine, opiates, NSAIDS, or 
GABA agonists for pain; follow dose modifications listed in 
Table 5
If no improvement within 15 days, proceed to next steps.


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HFSR severity
Intervention
Grade 3
Interrupt dose until improvement to Grade 0-1
Severe skin changes with pain e.g.
Peeling
●
Blisters
●
Bleeding
●
Edema
●
Hyperkeratosis
Limiting self-care ADL
Treat as in Grades 1 and 2
Follow dose modifications listed in Table 5.
The following supportive care measures for the prevention, and/or management of HFSR 
summarized in the table below should be instituted along with proper patient education.
Supportive Care for the Prevention and Management of HFSR
Stage
Recommendations
Prior to initiation of study treatment
Educate the patient about the early signs and symptoms of 
HFSR and discuss the importance of early reporting. HFSR 
could start as early as 2-5 days after study drug initiation, and 
mostly expected to occur during the first 2 months of treatment.
Prevention of HFSR for the first 2 months 
of treatment with encorafenib
Monitor the patient for signs and symptoms of HFSR. Instruct 
the patient to:
- Apply emollient cream regularly to hands and feet: use 20-
40% urea , salicylic acid 3-6%; ammonium lactate 12% or 
lactic acid 12 % based creams
- Wear cotton socks or gloves to bed to enhance the absorption 
of creams
- Avoid tight, irritating or ill-fitting clothing and shoes
- Avoid repetitive activity or staying in one position for long 
periods of time
- Pat (do not rub) skin dry with towels
- Avoid extremes of temperature, pressure and friction
- Avoid performing mechanically stressful manual work
- Cushioning of callused areas
- Use of moisturizing and keratolytic creams to control existing 
palmar and plantar hyperkeratosis
Treatment of HFSR
1) Ensure that patient follows treatment interruption or dosage 
reduction guidelines
2) Monitor the patient for worsening/resolution of HFSR
(Normal frequency monthly, except if patient has Grade 2 or 3 
HFSR, where bi weekly- visits are recommended)
3) Prescribe analgesics if necessary
4) Instruct the patient to:
- Continue the use of prevention strategies
- Cushion sore skin
- For control or relief of pain symptoms, patient may submerge 
hands and feet in cool water baths or apply cold compresses for 
relief
a Wear loose-fitting clothing made of soft, natural fabrics and shoes that are wide and comfortable. Avoid tight belts, 
panties and bras.
This table is adapted from (van Moos et al. 2008).


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References:
Nardone B, Hensley JR, Kulik L, et al. (2012). The effect of hand-foot skin reaction 
associated with the multikinase inhibitors sorafenib and sunitinib on health-related quality of 
life. Journal of Drugs in Dermatology Nov 2011: 11;11:e61-5.
Van Moos R, Thuerlimann B, Chair M, etal. (2008) Pegylated liposomal doxorubicin-
associated hand-foot syndrome: Recommendations of an international panel of experts. Eur J 
Cancer: 1016:1-10.


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Appendix 3. Recommended Guidelines for the Management of Binimetinib-Induced 
Diarrhea
Proactively Investigate for Occurrence of Diarrhea and Educate Patient:
1.
Remind patients at each visit to contact the Investigator immediately upon the first 
sign of loose stool or symptoms of abdominal pain. Additionally, at each study visit, 
each patient should be asked regarding occurrence of diarrhea or diarrhea-related 
symptoms. If the patient has had symptoms, the patient should be asked regarding the 
actions taken for these symptoms and re-instruct if indicated.
2.
Patients should be instructed on dietary modification and early warning signs of 
diarrhea and potentially life-threatening illnesses (e.g., severe cramping might be a 
sign of severe diarrhea; fever with diarrhea might be a sign of infection; fever and 
dizziness on standing might be a sign of shock). 
3.
Patients should be educated about what to report to the Investigator (i.e., number of 
stools, stool composition, stool volume).
Anti-diarrhea Therapy:
In order to effectively manage diarrhea and mitigate the escalation in severity or duration of 
diarrhea, patient education as outlined above, as well as proper management of diarrhea is 
important. 
Management of diarrhea should be instituted at the first sign of abdominal cramping, loose 
stools or overt diarrhea. All concomitant therapies /used for treatment of diarrhea must be 
recorded on the eCRF. It is recommended that patients be provided loperamide tablets and be 
instructed on the use of loperamide on the first day of binimetinib dosing. In addition to the 
binimetinib-induced diarrhea dosing guidelines provided in Table 5 of the protocol, these 
instructions should be provided at each visit and the site should ensure that the patient 
understood the instructions. 
See Table 5 in the protocol to explain the frequency of diarrhea and its relationship to NCI 
CTCAE, v.4.03 grading and to determine if diarrhea is complicated or uncomplicated.
Rule out Other or Concomitant Causes:
These may include:

Infection with Candida, Salmonella, Clostridium difficile, Campylobacter. Giardia, 
Entamoeba or Cryptosporidium species, which can lead to severe infections in 
immunosuppressed patients.

Medication-induced diarrhea.

Malabsorption/lactose intolerance.


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
Fecal impaction, partial bowel obstruction.
For Uncomplicated Grade 1/2 Diarrhea:

Stop all lactose-containing products and alcohol, and eat frequent small meals that 
include bananas, rice, applesauce or toast.

Stop laxatives, bulk fiber (e.g., Metamucil®), and stool softeners (e.g., docusate 
sodium, Colace®).

Stop high-osmolar food supplements (e.g., Ensure® Plus, Jevity® Plus [with fiber]).

Drink 8 to 10 large glasses of clear liquids per day (e.g., water, Pedialyte®, 
Gatorade®, broth).

Consider administration of a standard dose of loperamide: initial administration 4 mg, 
then 2 mg every 4 hours (maximum of 16 mg/day) or after each unformed stool.

Discontinue loperamide after 12-hours diarrhea-free (Grade 0) interval.

Consider temporary interruption of binimetinib until resolved to Grade ≤ 1. Re-
treatment may then be resumed at current dose level.

If uncomplicated Grade 1 to Grade 2 diarrhea persists for more than 24 hours, 
escalate to high-dose loperamide: 2 mg every 2 hours (maximum of 16 mg/day) or 
after each unformed stool.
Note: Oral antibiotics may be started as prophylaxis for infections under the discretion of the 
physician.

If uncomplicated Grade 1 to Grade 2 diarrhea persists after 48 hours of treatment with 
loperamide, discontinue loperamide and begin a second-line agent which can be an 
opiate (opium tincture or paregoric), octreotide acetate or steroid (budesonide).
For Complicated Grade 1/2 Diarrhea or Any Grade 3/4 Diarrhea:

The patient must call the Investigator immediately.

Temporarily interrupt binimetinib treatment until resolved to Grade ≤ 1. Restart 
binimetinib at a reduced dose level.

If loperamide has not been intitiated, initiate loperamide immediately. Initial 
administration 4 mg, then 2 mg every 4 hours (maximum of 16 mg/day) or after each 
unformed stool.

Administer IV fluids and electrolytes as needed. In case of severe hydration, replace 
loperamide with octreotide acetate.


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
Monitor/continue IV fluids and antibiotics as needed. Intervention should be 
continued until the patient is diarrhea-free for at least 24 hours.

Hospitalization may need to be considered.


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Appendix 4. Recommended Guidelines for the Management of Binimetinib-Induced 
Interstitial lung disease
Clinical judgment and experience of the treating physician should guide the management 
plan of each patient. In general, the following interventions are in addition to the binimetinib-
induced interstitial lung disease (ILD) dosing guidelines provided in Table 5 of the protocol.
Drug-induced ILD or pneumonitis is a clinical diagnosis based on clinical signs and 
symptoms, radiological changes, pulmonary function tests (PFT) and exclusion of other 
possible etiologies of parenchymal lung disease. The most common symptoms of ILD are 
nonspecific and include dyspnea, dry cough, fever, fatigue, hypoxia, and occasional 
hemoptysis. The CTCAE v.4.03 criteria for ILD (pneumonitis) are provided below.
CTCAE v. 4.03 Criteria for Pneumonitis
Grade
Adverse Event
1
2
3
4
5
Pneumonitis
Asymptomatic; 
clinical or 
diagnostic 
observations 
only; 
intervention not 
indicated
Symptomatic; 
medical 
intervention 
indicated; 
limiting 
instrumental 
ADL
Severe 
symptoms; 
limiting self 
care ADL; 
oxygen 
indicated
Life-
threatening 
respiratory 
compromise; 
urgent 
intervention 
indicated (e.g., 
tracheotomy or 
intubation)
Death
Definition: A disorder characterized by inflammation or diffusely affecting the lung parenchyma.
All patients should be instructed to immediately report new or worsening respiratory 
symptoms. Diagnostic procedures include PFT and high-resolution CT scans (HCRT). The 
principal management of ILD consists of drug interruption and/or dose reduction and 
treatment with steroids as specified below. Empirical antibiotics directed at likely pathogens 
should also be considered while the results of diagnostic procedures and cultures are pending. 

Prednisolone 40 mg oral, daily
o
Reduce dose by 10 mg every 2 weeks × 2 (until dose reduced to 20 mg oral,
daily)
o
Reduce dose by 5 mg weekly × 4 weeks

Combine with empirical antimicrobial therapy while awaiting results of diagnostic 
procedures
Reference: Shah R. Tyrosine kinase inhibitor-induced interstitial lung disease: Clinical 
features, diagnostic challenges, and therapeutic dilemmas. Drug Saf. 2016;39:1073-1091.


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Appendix 5. Snellen Equivalence (Visual Acuity Conversion Chart)
References:
Holladay JT. Visual acuity measurements. J Cataract Refract Surg. 2004;30:287-90.


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Appendix 6. List of Concomitant Medications
Table A:
List of CYP450 Substrates to be Used With Caution*
CYP2C8
CYP2C9
CYP2C19
CYP3A**
Amodiaquine
Acenocoumarol
Clopidogrel
Alfentanil 1,2
Ergotamine 2
Cerivastatin
Celecoxib
Diazepam
Alpha-
dihydroergocryptine 1
Everolimus 1
Repaglinide
Diclofenac
Esoprazole
Alprazolam
Felodipine 1
Rosiglitazone
Glipizide
Lansoprazole
Amlodipine
Fentanyl 2
Torasemide
Irbesartan
Moclobemide
Aplaviroc
Fluticasone 1
Losartan
Omeprazole
Aprepitant 1
Indinavir 1
Phenytoin 2
Pantoprazole
Aripiprazole
Lopinavir 1
Piroxicam
Phenobarbitone
Atorvastatin
Lovastatin 1
S-ibuprofen
Phenytoin 2
Boceprevir
Maraviroc 1
Sulfamethoxazole
Proguanil
Brecanavir
Midazolam 1
Tolbutamide
Rabeprazole
Brotizolam 1
Nifedipine
Torasemide
S-mephenytoin
Budesonide 1
Nisoldipine
Buspirone 1
Nitrendipine
capravirine
Perospirone 1
casopitant
Quinine
Conivaptan 1
Saquinavir 1
Cyclosporine 2
Sildenafil 1
Darifenacin 1
Simvastatin 1
Darunavir 1
Sirolimus 1,2
Diazepam
Telaprevir
Diergotamine 2
Tipranavir 1
Diltiazem
Tolvaptan
Ebastine 1
Triazolam 1
Eletriptan 1
Verapamil
Eplerenone 1
*Table was compiled from the Indiana University School of Medicine’s “Clinically Relevant” table, a list by the United 
States Food and Drug Administration (FDA) 
fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm080499.htm, and 
the University of Washington’s Drug Interaction Database.
1 Sensitive substrates: Drugs whose plasma area under concentration-time curve (AUC) values have been shown to 
increase 5-fold or higher when co-administered with a potent inhibitor of the respective enzyme.
2 Substrates with narrow therapeutic index (NTI): Drugs whose exposure-response indicates that increases in their 
exposure levels by the concomitant use of potent inhibitors may lead to serious safety concerns (e.g., TdP).


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Table B:
List of CYP450 Substrates to be Used With Caution – CYP2B6
CYP2B6*
bupropion 1
cyclophosphamide
Efavirenz 1
Ifosfamide
Methadone
Thiotepa
*Table was compiled from the Indiana University School of Medicine’s “Clinically Relevant” table, a list by the FDA 
(http://.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm080499.htm) 
and the University of Washington’s Drug Interaction Database.
1 Sensitive substrates: The area under the concentration-time curves (AUCs) of these substrates were not increased by 5-
fold or more with a CYP2B6 inhibitor, but they represent the most sensitive substrates studied with available inhibitors 
evaluated to date.
Table C:
Strong/moderate CYP3A4 Inhibitors and CYP3A4 Inducers to be 
Prohibited or Administered With Caution when Co-administered with 
Encorafenib
Strong Inhibitors (prohibited)
boceprevir 
nefazodone 
Clarithromycin
Nelfinavir
Conivaptan
posaconazole
Indinavir
Ritonavir
Itraconazole
Saquinavir
Ketoconazole
telithromycin
Lopinavir
troleandomycin
Telaprevir
Grapefruit juice (citrus paradisi fruit juice)
Mibefradil
Voriconazole
Moderate inhibitors (use with caution)
Ciprofloxacin
Erythromycin
Fluconazole
Amprenavir
Verapamil
Imatinib
Atazanavir
Schisandra sphenanthera
Aprepitant
Casopitant
Cyclosporine
Cimetidine
Tofisopam
Dronedarone
Fosamprenavir
Darunavir
Diltiazem
Strong Inducers (use with caution)
Avasimibe
Rifampin
Carbamazepine
St. John’s wort
Phenytoin
Reproduced from 
fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm080499.htm


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Table D:
Substrates of BCRP, OAT, OCT s and OATPs to be Administered With 
Caution
Substrates
BCRP
imatinib, irrinotecan, lapatinib, methotrexate, mitoxantrone, rosuvastatin, sulfasalazine, topotecan
P-gp
Aliskiren, ambrisentan, colchicine, dabigatran etexilate, digoxin, everolimus, fexofenadine, imatinib, 
lapatinib, maraviroc, nilotinib, posaconazole, ranolazine, saxagliptin, sirolimus, sitagliptin, talinolol, 
tolvaptan, topotecan 
OCT2
Amantadine, amiloride, cimetidine, dopamine, famotidine, memantine, metformin, pindolol, 
procainamide, ranitidine, varenicline, oxaliplatin
OAT1
Adefovir, captopril, furosemide, lamivudine, methotrexate, oseltamivir, tenofovir, zalcitabine, 
zidovudine
OAT3
Acyclovir, bumetanide, ciprofloxacin, famotidine, furosemide, methotrexate, zidovudine, oseltamivir 
acid, (the active metabolite of oseltamivir), penicillin G, pravastatin, rosuvastatin, sitagliptin
OATP1B1
Atrasentan, atorvastatin, bosentan, ezetimibe, fluvastatin, glyburide, SN-38 (active metabolite of 
irinotecan), rosuvastatin, simvastatin acid, pitavastatin, pravastatin, repaglinide, rifampin, valsartan, 
olmesartan
OATP1B3
Atorvastatin, rosuvastatin, pitavastatin, telmisartan, valsartan, olmesartan
Reproduced from 
fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm080499.htm
Table E:
Pg-P and BCRP Inhibitors/Inducers to be Used With Caution
Transporter
Gene
Inhibitor 1
Inducer 2
P-gp
ABCB1
Amiodarone, azithromycin,captopril, carvedilol, 
clarithromycin, conivaptan, cyclosporine, diltiazem, 
dronedarone, erythromycin, felodipine, itraconazole, 
ketoconazole, lopinavir and ritonavir, quercetin, 
quinidine, ranolazine, verapamil
Avasimibe,carbamazepine,phenytoin, 
rifampin, St John’s wort, 
tipranavir/ritonavir
BCRP
ABCG2
Cyclosporine, elacridar (GF120918), eltrombopag, 
gefitinib
Not known
Reproduced from 
fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm080499.htm
1. Inhibitors listed for P-gp are those that showed > 25% increase in digoxin area under the concentration-time curve 
(AUC) or otherwise indicated if substrate is other than digoxin.
2. Inducers listed for P-gp are those that showed > 20% decrease in digoxin AUC or otherwise indicated if substrate is 
other than digoxin.
Table F:
List of Inhibitors of UGT1A1 to be Used With Caution
Inhibitors of UGT1A1
atazanavir, erlotinib, flunitrazepam, gemfibrozil, indinavir, ketoconazole, 
nilotinib, pazopanib, propofol, regorafenib, sorafenib


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Table G:
List of Potential QT Prolonging Drugs
Drug
QT risk*
Comment
Alfuzosin
possible risk
Amantadine
possible risk
Amiodarone
known risk 
Females > Males, TdP risk regarded as low
Amitriptyline
conditional risk
Risk of TdP with overdosage. Substrate of CYP2C19
Arsenic trioxide
known risk 
Astemizole
known risk 
No Longer available in U.S. Substrate for 3A4
Atazanavir
possible risk
Azithromycin
possible risk
Rare reports
Bepridil
known risk 
Females > Males
Chloral hydrate
possible risk
Chloroquine
known risk 
Chlorpromazine
known risk 
Ciprofloxacin
conditional risk
Drug metabolism inhibitor- Risk for drug interactions
Cisapride
known risk 
No longer available in the U.S.; available in Mexico. Substrate for 3A4
Citalopram
known risk 
Clarithromycin
known risk 
Substrate for 3A4
Clomipramine
conditional risk
Clozapine
possible risk
Desipramine
conditional risk
Risk of TdP with overdosage
Diphenhydramine
conditional risk
Risk of QT increase/TdP in overdosages
Disopyramide
known risk 
Females > Males
Dofetilide
known risk 
Dolasetron
possible risk
Domperidone
known risk 
Not available in the U.S.
Doxepin
conditional risk
Dronedarone
possible risk
Substrate for 3A4
Droperidol
known risk 
Eribulin
possible risk
Erythromycin
known risk 
Females>Males. Substrate for 3A4
Escitalopram
possible risk
Famotidine
possible risk
Felbamate
possible risk
Fingolimod
possible risk
Flecainide
known risk 
Fluconazole
conditional risk
Drug metabolism inhibitor- Risk for drug interactions
Fluoxetine
conditional risk
Foscarnet
possible risk
Fosphenytoin
possible risk
Galantamine
conditional risk
Gatifloxacin
possible risk
Gemifloxacin
possible risk
Granisetron
possible risk
Halofantrine
known risk 
Females>Males


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Table G:
List of Potential QT Prolonging Drugs
Drug
QT risk*
Comment
Haloperidol
known risk 
When given intravenously or at higher-than- recommended doses, risk 
of sudden death, QT prolongation and torsades increases. Substrate for 
3A4
Ibutilide
known risk 
Females>Males
Imipramine
conditional risk
Risk of TdP in overdosage
Indapamide
possible risk
Isradipine
possible risk
Itraconazole
conditional risk
Drug metabolism inhibitor- Risk for drug interactions
Ketoconazole
conditional risk
Drug metabolism inhibitor
Levofloxacin
possible risk
Levomethadyl
known risk 
Not available in the U.S.
Lithium
possible risk
Mesoridazine
known risk 
Methadone
known risk 
Females>Males. Substrate for 3A4
Moexipril/HCTZ
possible risk
Moxifloxacin
known risk 
Nicardipine
possible risk
Nortriptyline
conditional risk
Octreotide
possible risk
Ofloxacin
possible risk
Ondansetron
possible risk
Oxytocin
possible risk
Paliperidone
possible risk
Paroxetine
conditional risk
Pentamidine
known risk 
Females > Males
Perflutren lipid 
microspheres
possible risk
Pimozide
known risk 
Females > Males. Substrate for 3A4
Probucol
known risk 
No longer available in U.S.
Procainamide
known risk 
Protriptyline
conditional risk
Quetiapine
possible risk
Substrate for 3A4
Quinidine
known risk 
Females > Males. Substrate for 3A4
Ranolazine
possible risk
Risperidone
possible risk
Ritonavir
conditional risk
Substrate for 3A4
Roxithromycin*
possible risk
*not available in the United States
Sertindole
possible risk
Sertraline
conditional risk
Solifenacin
conditional risk
Sotalol
known risk 
Females > Males
Sparfloxacin
known risk 
Tacrolimus
possible risk
Substrate for 3A4
Telithromycin
possible risk
Substrate for 3A4


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Table G:
List of Potential QT Prolonging Drugs
Drug
QT risk*
Comment
Terfenadine
known risk 
No longer available in U.S.Substrate for 3A4
Thioridazine
known risk 
Tizanidine
possible risk
Trazodone
conditional risk
Substrate for 3A4
Trimethoprim-Sulfa
conditional risk
Trimipramine
conditional risk
Vandetanib
known risk 
Vardenafil
possible risk
Substrate for 3A4
Venlafaxine
possible risk
Voriconazole
possible risk
Ziprasidone
possible risk
* Classification according to the Qtdrugs.org Advisory Board of the Arizona CERT


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Appendix 7. Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1
1.0
MEASURABILITY OF TUMOUR AT BASELINE
1.1
Definitions
At baseline, tumour lesions/lymph nodes will be categorized measurable or non-measurable 
as follows:
1.1.1
Measurable
Tumour lesions: Must be accurately measured in at least one dimension (longest diameter in 
the plane of measurement is to be recorded) with a minimum size of:

10 mm by CT scan (CT scan slice thickness no greater than 5 mm);

10 mm caliper measurement by clinical examination (lesions which cannot be 
accurately measured with calipers should be recorded as non-measurable);

20 mm by chest X-ray.
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis 
will be measured and followed.
1.1.2
Non-measurable
All other lesions, including small lesions (longest diameter < 10 mm or pathological lymph 
nodes with ≥10 to < 15 mm short axis) as well as truly non-measurable lesions. Lesions 
considered truly non-measurable include: leptomeningeal disease, ascites, pleural or 
pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, 
abdominal masses/abdominal organomegaly identified by physical examination that is not 
measurable by reproducible imaging techniques.
1.1.3
Special Considerations Regarding Lesion Measurability
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment:
Bone lesions:

Bone scan, PET scan or plain films are not considered adequate imaging techniques 
to measure bone lesions. However, these techniques can be used to confirm the 
presence or disappearance of bone lesions.

Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as CT 


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or MRI can be considered measurable lesions if the soft tissue component meets the 
definition of measurability described above.

Blastic bone lesions are non-measurable.
Cystic lesions:

Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts.

‘Cystic lesions’ thought to represent cystic mestastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same patient, these are preferred for 
selection as target lesions.
Lesions with prior local treatment:

Tumour lesions situated in a previously irradiated area, or in an area subjected to 
other loco-regional therapy, are usually not considered measurable unless there has 
been demonstrated progression in the lesion. Study protocols should detail the 
conditions under which such lesions would be considered measurable.
1.2
Specifications by Methods of Measurements
1.2.1
Measurement of Lesions
All measurements should be recorded in metric notation, using calipers if clinically assessed. 
All baseline evaluations should be performed as close as possible to the treatment start and 
never more than 4 weeks before the beginning of the treatment.
1.2.2
Method of Assessment
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation 
should always be done rather than clinical examination unless the lesion(s) being followed 
cannot be imaged but are assessable by clinical exam.
Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial and ≥ 10 mm diameter as assessed using calipers (e.g., skin nodules). For the case 
of skin lesions, documentation by colour photography including a ruler to estimate the size of 
the lesion is suggested. As noted above, when lesions can be evaluated by both clinical 
examination and imaging, imaging evaluation should be undertaken since it is more objective 
and may also be reviewed at the end of the study.
Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 


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lesions. However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung.
CT, MRI: CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less. When CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice 
the slice thickness. MRI is also acceptable in certain situations (e.g., for body scans). 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to 
the next. If new lesions are identified by ultrasound in the course of the study, confirmation 
by CT or MRI is advised. If there is concern about radiation exposure at CT, MRI may be 
used instead of CT in selected instances.
Endoscopy, laparoscopy: The utilization of these techniques for objective tumour evaluation 
is not advised. However, they can be useful to confirm complete pathological response when 
biopsies are obtained or to determine relapse in trials were recurrence following complete 
response or surgical resection is an endpoint.
Tumour markers: Tumour markers alone cannot be used to assess objective tumour response. 
If markers are initially above the upper normal limit, however, they must normalize for a 
patient to be considered in complete response. Because tumour markers are disease specific, 
instructions for their measurement should be incorporated into protocols on a disease specific 
basis.
Cytology, histology: These techniques can be used to differentiate between PR and CR in rare 
cases if required by protocol (for example, residual lesions in tumour types such as germ cell 
tumours, where known residual benign tumours can remain).When effusions are known to be
a potential adverse effect of treatment (e.g., with certain taxane compounds of angiogenesis 
inhibitors), the cytological confirmation of the neoplastic origin of any effusion that appears 
or worsens during treatment can be considered if the measurable tumour has met criteria for 
response or stable disease in order to differentiate between response (or stable disease) and 
progressive disease.
2.0
TUMOUR RESPONSE EVALUATION
2.1
Assessment of Overall Tumour Burden and Measurable Disease
To assess objective response or future progression, it is necessary to estimate the overall 
tumour burden at baseline and use this as a comparator for subsequent measurements. 
Measurable disease is defined by the presence of at least one measurable lesion (as detailed 
above). 


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2.2
Baseline Documentation of ‘Target’ and ‘Non-Target’ Lesions
When more than one measurable lesion is present at baseline all lesions up to a maximum of 
five lesions total (and a maximum of two lesions per organ) representative of all involved 
organs should be identified as target lesions and will be recorded and measured at baseline 
(this means in instances where patients have only one or two organ sites involved, a 
maximum of two and four lesions respectively will be recorded). 
Target lesions should be selected on the basis of their size (lesions with the longest diameter), 
be representative of all involved organs, but in addition should be those that lend themselves 
to reproducible repeated measurements. It may be the case that, on occasion, the largest 
lesion does not lend itself to reproducible measurement in which circumstance the next 
largest lesion which can be measured reproducibly should be selected. 
Lymph nodes merit special mention since they are normal anatomical structures which may 
be visible by imaging even if not involved by tumour. As previously noted, pathological 
nodes which are defined as measurable and may be identified as target lesions must meet the 
criterion of a short axis of ≥ 15 mm by CT scan. Only the short axis of these nodes will 
contribute to the baseline sum. The short axis of the node is the diameter normally used by 
radiologists to judge if a node is involved by solid tumour. Nodal size is normally reported as 
two dimensions in the plane in which the image is obtained (for CT scan this is almost 
always the axial plane; for MRI the plane of acquisition may be axial, saggital, or coronal). 
The smaller of these measures is the short axis. For example, an abdominal node which is 
reported as being 20 mm X 30 mm has a short axis of 20 mm and qualifies as a malignant, 
measurable node. In this example, 20 mm should be recorded as the node measurement. All 
other pathological nodes (those with short axis ≥10 mm but < 15 mm) should be considered 
non-target lesions. Nodes that have a short axis < 10 mm are considered non-pathological 
and should not be recorded or followed.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters. If lymph nodes 
are to be included in the sum, then as previously noted, only the short axis is added into the 
sum. The baseline sum diameters will be used as reference to further characterize any 
objective tumour regression in the measurable dimension of the disease.
All other lesions (or sites of disease) including pathological lymph nodes should be identified 
as non-target lesions and should also be recorded at baseline. Measurements are not required 
and these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal 
progression’ (more details to follow). In addition, it is possible to record multiple non-target 
lesions involving the same organ as a single item on the case record form (e.g., ‘multiple 
enlarged pelvic lymph nodes’ or ‘multiple liver metastases’).
2.3
Response Criteria
This section provides the definitions of the criteria used to determine objective tumour 
response for target lesions.


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2.3.1
Evaluation of Target Lesions
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to < 10 mm.
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters.
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm. The appearance of one or more new lesions is also 
considered progression.
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study.
2.3.2
Special Notes on the Assessment of Target Lesions
Lymph nodes. Lymph nodes identified as target lesions should always have the actual short 
axis measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the nodes regress to below 10 mm on study. This means that when 
lymph nodes are included as target lesions, the ‘sum’ of lesions may not be zero even if 
complete response criteria are met, since a normal lymph node is defined as having a short 
axis of < 10 mm. Case report forms (CRFs) or other data collection methods may therefore 
be designed to have target nodal lesions recorded in a separate section where, in order to 
qualify for CR, each node must achieve a short axis < 10 mm. For PR, SD, and PD, the 
actual short axis measurement of the nodes is to be included in the sum of target lesion.
Target lesions that become ‘too small to measure’. While on study, all lesions (nodal and 
non-nodal) recorded at baseline should have their actual measurements recorded at each 
subsequent evaluation, even when very small (e.g., 2 mm). However, sometimes lesions or 
lymph nodes which are recorded as target lesions at baseline become so faint on CT scan that 
the radiologist may not feel comfortable assigning an exact measure and may report them as 
being ‘too small to measure’. When this occurs it is important that a value be recorded on the 
CRF. If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm. If the lesion is believed to be present and is faintly 
seen but too small to measure, a default value of 5 mm should be assigned (Note: It is less 
likely that this rule will be used for lymph nodes since they usually have a definable size 
when normal and are frequently surrounded by fat such as in the retroperitoneum; however, 
if a lymph node is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned in this circumstance as well). This default value is 
derived from the 5 mm CT slice thickness (but should not be changed with varying CT slice 
thickness). The measurement of these lesions is potentially non-reproducible, therefore 
providing this default value will prevent false responses or progressions based upon 
measurement error. If the radiologist is able to provide an actual measurement, that should be 
recorded, even if below 5 mm.


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Lesions that split or coalesce on treatment. When non-nodal lesions ‘fragment’, the longest 
diameters of the fragmented portions should be added together to calculate the target lesion 
sum. Similarly, as lesions coalesce, a plane between them may be maintained that would aid 
in obtaining maximal diameter measurements of each individual lesion. If the lesions have 
truly coalesced such that they are no longer separable, the vector of the longest diameter in 
this instance should be the maximal longest diameter for the ‘coalesced lesion’.
2.3.3
Evaluation of Non-Target Lesion
This section provides the definitions of the criteria used to determine the tumour response for 
the group of non-target lesions. While some non-target lesions may actually be measurable, 
they need not be measured and instead should be assessed only qualitatively at the time 
points specified in the protocol.
Complete Response (CR):  Disappearance of all non-target lesions and normalization of 
tumour marker level. All lymph nodes must be non-pathological in size (< 10 mm short axis).
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of 
tumour marker level above the normal limits.
Progressive Disease (PD): Unequivocal progression of existing non-target lesions. The 
appearance of one or more new lesions is also considered progression.
2.3.4
Special Notes on Assessment of Progression of Non-Target Disease
The concept of progression of non-target disease requires additional explanations as follows:
When the patient also has measurable disease. In this setting, to achieve ‘unequivocal 
progression’ on the basis of the non-target disease, there must be an overall level of 
substantial worsening in non-target disease such that, even in presence of SD or PR in target 
disease, the overall tumour burden has increased sufficiently to merit discontinuation of 
therapy. A modest ‘increase’ in the size of one or more non-target lesions is usually not 
sufficient to qualify for unequivocal progression status. The designation of overall 
progression solely on the basis of change in non-target disease in the face of SD or PR of 
target disease will therefore be extremely rare. 
When the patient has only non-measurable disease. This circumstance arises in some phase 
III trials when it is not a criterion of study entry to have measurable disease. The same 
general concepts apply here as previously noted, however, in this instance there is no 
measurable disease assessment to factor into the interpretation of an increase in non-
measurable disease burden. Because worsening in non-target disease cannot be easily 
quantified, a useful test that can be applied when assessing patients for unequivocal 
progression is to consider if the increase in overall disease burden based on the change in 
non-measurable disease is comparable in magnitude to the increase that would be required to 
declare PD for measurable disease: i.e., an increase in tumour burden representing an 
additional 73% increase in ‘volume’ (which is equivalent to a 20% increase in diameter in a 
measurable lesion). Examples include an increase in a pleural effusion from ‘trace’ to ‘large’, 


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an increase in lymphangitic disease from localized to widespread, or may be described in 
protocols as ‘sufficient to require a change in therapy’. If ‘unequivocal progression’ is seen, 
the patient should be considered to have had overall PD at that point. While it would be ideal 
to have objective criteria to apply to non-measurable disease, the very nature of that disease 
makes it impossible to do so, therefore the increase must be substantial.
2.3.5
New Lesions
The appearance of new malignant lesions denotes disease progression. There are no specific 
criteria for the identification of new radiographic lesions; however, the finding of a new 
lesion should be unequivocal: i.e., not attributable to differences in scanning technique, 
change in imaging modality or findings thought to represent something other than tumour. 
This is particularly important when the patient’s baseline lesions show partial or complete 
response.
A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. An example of this 
is the patient who has visceral disease at baseline and while on study has a CT or MRI brain 
scan ordered which reveals metastases. The patient’s brain metastases are considered to be 
evidence of PD even if he/she did not have brain imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of the 
initial scan. 
While FDG-PET response assessments need additional study, it is sometimes reasonable to 
incorporate the use of FDG-PET scanning to complement CT scanning in assessment of 
progression (particularly possible ‘new’ disease). New lesions on the basis of FDG-PET 
imagine can be identified according to the following algorithm:
a.
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a 
sign of PD based on a new lesion. A ‘positive’ FDG-PET scan lesion is one 
which is FDG avid with an uptake greater than twice that of the surrounding 
tissue on the attenuation corrected image.
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:
If the positive FDG-PET at follow-up corresponds to a new site of disease 
confirmed by CT, this is PD.
If the positive FDG-PET at follow-up is not confirmed as a new site of disease on 
CT, additional follow-up CT scans are needed to determine if there is truly 
progression occurring at that time (if so, the date of PD will be the date of the
initial abnormal FDG-PET scan).


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If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease 
on CT that is not progressing on the basis of the anatomic images, this is not PD.
2.4
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the study treatment 
until the end of treatment taking into account any requirement for confirmation. On occasion 
a response may not be documented until after the end of therapy so protocols should be clear 
if post-treatment assessments are to be considered in determination of best overall response. 
Protocols must specify how any new therapy introduced before progression will affect best 
response designation. The patient’s best overall response assignment will depend on the 
findings of both target and non-target disease and will also take into consideration the 
appearance of new lesions. Furthermore, depending on the nature of the study and the 
protocol requirements, it may also require confirmatory measurement. Specifically, in non-
randomised trials where response is the primary endpoint, confirmation of PR or CR is 
needed to deem either one the ‘best overall response’. 
2.4.1
Time Point Response
It is assumed that at each protocol specified time point, a response assessment occurs. Table 
1 provides a summary of the overall response status calculation at each time point for 
patients who have measurable disease at baseline.
Table 1- Time point response: patients with target (± non-target) disease.
Target lesions
Non-target lesions
New lesions
Overall response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all evaluated
No
PR
SD
Non-PD or not all evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR=complete response, PR=partial response, SD=stable disease, PD=progressive disease, NE=inevaluable
When patients have non-measurable (therefore non-target) disease only, Table 2 is to be 
used.


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Table 2 – Time point response: patients with non-target disease only.
Non-target lesions
New lesions
Overall response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PDa
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
a ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used as 
endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be measured 
is not advised.
2.4.2
Missing Assessments and Inevaluable Designation
When no imaging/measurement is done at all at a particular time point, the patient is not 
evaluable (NE) at that time point. If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered NE at that time point, unless convincing 
argument can be made that the contribution of the individual missing lesion(s) would not 
change the assigned time point response. This would be most likely to happen in the case of 
PD. 
2.4.3
Best Overall Response: All Time Points
The best overall response is determined once all the data for the patient is known. 
Best response is defined as the best response across all time points (for example, a patient 
who has SD at first assessment, PR at second assessment, and PD on last assessment has a 
best overall response of PR). When SD is believed to be the best response, it must also meet 
the protocol specified minimum time from baseline. If the minimum time is not met when SD 
is otherwise the best time point response, the patient’s best response depends on the 
subsequent assessments. For example, a patient who has SD at first assessment, PD at second 
and does not meet minimum duration for SD, will have a best response of PD. The same 
patient lost to follow-up after the first SD assessment would be considered inevaluable. 
2.4.4
Special Notes on Response Assessment
When nodal disease is included in the sum of target lesions and the nodes decrease to 
‘normal’ size (< 10 mm), they may still have a measurement reported on scans. This 
measurement should be recorded even though the nodes are normal in order not to overstate 
progression should it be based on the increase in size of the nodes. As noted earlier, this 
means that patients with CR may not have total sum of ‘zero’ on the CRF.


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Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
‘symptomatic deterioration’. Every effort should be made to document objective progression 
even after discontinuation of treatment. Symptomatic deterioration is not a descriptor of an 
objective response: it is a reason for stopping study therapy. The objective response status of 
such patients is to be determined by evaluation of target and non-target disease.
Conditions that define ‘early progression, early death and inevaluability’ are study specific 
and should be clearly described in each protocol (depending on treatment duration, treatment 
periodicity).
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends upon this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) before 
assigning a status of complete response. FDG-PET may be used to upgrade a response to a 
CR in a manner similar to a biopsy in cases where a residual radiographic abnormality is 
thought to represent fibrosis or scarring. The use of FDG-PET in this circumstance should be 
prospectively described in the protocol and supported by disease specific medical literature 
for the indication. However, it must be acknowledged that both approaches may lead to false 
positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity.
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes or necrosis in existing lesion), treatment may continue until the next scheduled 
assessment. If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected.
Reference: 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(2):228-47.


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Appendix 8. Child-Pugh Classification
CTP score is obtained by adding the score for each parameter in the table below. 
CTP class:
A = 5-6 points
B = 7-9 points
C = 10-15 points
Child Pugh Points
Parameter
1
2
3
Encephalopathy
None
Grade 1-2 (or 
precipitant-induced)
Grade 3-4 (or chronic)
Ascites
None 
Mild/moderate 
(diuretic-
responsive)
Severe (diuretic-
refractory)
Bilirubin (mg/dL)
< 2
2-3
> 3
Albumin (g/dL)
> 3.5
2.8 – 3.5
< 2.8
PR (sec prolonged) or 
INR
< 4
< 1.7
4-6
1.7 – 2.3
> 6
> 2.3


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Appendix 9. Eastern Cooperative Oncology Group Performance Status
Grade 
Eastern Cooperative Oncology Group Performance Status
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work activities; up and 
about more than 50% of waking hours
3
Capable of only limited selfcare; confined to bed or chair more than 50% of waking hours
4
Completely disabled; cannot carry on any selfcare; totally confined to bed or chair
5
Dead
Reference: Oken MM, Creech RH, Tormey DC, et al. Toxicity And Response Criteria Of 
The Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5:649-655.


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Appendix 10. Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting
10.1 Definition of AE
AE Definition

An AE is any untoward medical occurrence in a patient or clinical study 
patient, temporally associated with the use of study drug, whether or not 
considered related to the study drug.

NOTE: An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease (new or 
exacerbated) temporally associated with the use of study drug.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or 
urinalysis) or other safety assessments (e.g., ECG, radiological scans, vital sign 
measurements), including those that worsen from baseline, considered 
clinically significant in the medical and scientific judgment of the Investigator  
Any abnormal laboratory test results that meet any of the conditions below 
must be recorded as an AE:

Is associated with accompanying symptoms;

Requires additional diagnostic testing or medical/surgical intervention;

Leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional 
concomitant drug treatment, or other therapy.

Exacerbation of a chronic or intermittent preexisting condition including either 
an increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either 
study drug or a concomitant medication.  Overdose per se will not be reported 
as an AE/SAE unless it is an intentional overdose taken with possible 


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suicidal/self-harming intent.  Such overdoses should be reported regardless of 
sequelae.

The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as an AE or SAE if they fulfill the definition of an AE or SAE 
and meet the requirements as per Section 10.1.8.1.  Also, “lack of efficacy” or 
“failure of expected pharmacological action” does not constitute an AE or SAE.
Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the patient’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
patient’s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.

Worsening of signs and symptoms of the malignancy under study should be 
recorded as AEs in the appropriate section of the CRF.  Disease progression 
assessed by measurement of malignant lesions on radiographs or other methods 
should not be reported as AEs.
10.2 Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, death 
due to progression of disease).


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An SAE is defined as any untoward medical occurrence that, at any dose:
a. Results in death
b. Is life-threatening
The term “life-threatening” in the definition of “serious” refers to an event in which the 
patient was at risk of death at the time of the event.  It does not refer to an event that 
hypothetically might have caused death if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the patient has been detained (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 outpatient setting.  
Complications that occur during hospitalization are AEs.  If a complication prolongs 
hospitalization or fulfills any other serious criteria, the event is serious.  When in doubt as 
to whether “hospitalization” occurred or was necessary, the AE should be considered 
serious.
Hospitalization for elective treatment of a preexisting condition that did not worsen from 
baseline is not considered an AE.
d. Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g., sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but 
may jeopardize the patient or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition.  These events 
should usually be considered serious.

Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 


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convulsions that do not result in hospitalization, or development of drug 
dependency or drug abuse.

Progression of the malignancy under study (including signs and symptoms of 
progression) should not be reported as an SAE unless the outcome is fatal within 
the active collection period.  Hospitalization due to signs and symptoms of disease 
progression should not be reported as an SAE.  If the malignancy has a fatal 
outcome during the study or within the active collection period, then the event 
leading to death must be recorded as an AE on the CRF, and as an SAE with 
CTCAE Grade 5 (see the Assessment of Intensity section).
10.3 Recording/Reporting and Follow-up of AEs and/or SAEs
AE and SAE Recording/Reporting
The table below summarizes the requirements for recording adverse events on the CRF 
and for reporting serious adverse events on the CT SAE Report Form to Pfizer Safety.  
These requirements are delineated for 3 types of events: (1) SAEs; (2) nonserious adverse 
events (AEs); and (3) exposure to the study drug under study during pregnancy or 
breastfeeding, and occupational exposure. 
It should be noted that the CT SAE Report Form for reporting of SAE information is not 
the same as the AE page of the CRF.  When the same data are collected, the forms must be 
completed in a consistent manner.  AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE 
Report Form for reporting of SAE information.
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
SAE
All
All
Nonserious AE
All
None
Exposure to the study 
drug under study during 
pregnancy or 
breastfeeding, and 
occupational exposure
All AEs/SAEs associated 
with exposure during 
pregnancy or breastfeeding
Occupational exposure is 
not recorded.
All (and EDP supplemental 
form for EDP)  
Note:  Include all SAEs 
associated with exposure 
during pregnancy or 
breastfeeding. Include all 
AEs/SAEs associated with 
occupational exposure.


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
When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostic 
reports) related to the event.

The Investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the Investigator to send photocopies of the patient’s medical 
records to Pfizer Safety in lieu of completion of the CT SAE Report Form/AE/SAE 
CRF page.

There may be instances when copies of medical records for certain cases are 
requested by Pfizer Safety.  In this case, all patient identifiers, with the exception of 
the patient number, will be redacted on the copies of the medical records before 
submission to Pfizer Safety.

The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  Whenever possible, the diagnosis 
(not the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The Investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 
GRADE
Clinical Description of Severity
1
MILD adverse event
2
MODERATE adverse event
3
SEVERE adverse event
4
LIFE-THREATENING consequences; urgent intervention indicated
5
DEATH RELATED TO adverse event

Assessment of Causality

The Investigator is obligated to assess the relationship between study treatment and 
each occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.


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
The Investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
administration, will be considered and investigated.

The Investigator will also consult the IB and/or product information, for marketed 
products, in his/her assessment.

For each AE/SAE, the Investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred, and the Investigator has 
minimal information to include in the initial report to the Sponsor.  However, it is 
very important that the Investigator always make an assessment of causality 
for every event before the initial transmission of the SAE data to the Sponsor.

The Investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.

If the Investigator does not know whether or not the study treatment caused the 
event, then the event will be handled as “related to study treatment” for reporting 
purposes, as defined by the Sponsor.  In addition, if the Investigator determines that 
an SAE is associated with study procedures, the Investigator must record this 
causal relationship in the source documents and CRF, and report such an 
assessment in the dedicated section of the CT SAE Report Form and in accordance 
with the SAE reporting requirements.
Follow-up of AEs and SAEs

The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
Sponsor to elucidate the nature and/or causality of the AE or SAE as fully as 
possible.  This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other healthcare providers.

New or updated information will be recorded in the originally completed CRF.

The Investigator will submit any updated SAE data to the Sponsor within 24 hours 
of receipt of the information.


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10.4 Reporting of SAEs
SAE Reporting to Pfizer Safety via CT SAE Report Form

Facsimile transmission of the CT SAE Report Form is the preferred method to 
transmit this information to Pfizer Safety.

In circumstances when the facsimile is not working, notification by telephone is 
acceptable with a copy of the CT SAE Report Form sent by overnight mail or 
courier service.

Initial notification via telephone does not replace the need for the Investigator to 
complete and sign the CT SAE Report Form pages within the designated reporting 
time frames.


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Appendix 11. Liver Safety: Suggested Actions and Follow-up Assessments
Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury, but adapt 
are termed “adaptors.”  In some patients, transaminase elevations are a harbinger of a more 
serious potential outcome.  These patients fail to adapt and therefore are "susceptible" to 
progressive and serious liver injury, commonly referred to as DILI.  Patients who experience 
a transaminase elevation above 3 × ULN should be monitored more frequently to determine 
if they are an “adaptor” or are “susceptible.”
In the majority of DILI cases, elevations in AST and/or ALT precede TBili elevations (>2 ×
ULN) by several days or weeks.  The increase in TBili typically occurs while AST/ALT 
is/are still elevated above 3 × ULN (ie, AST/ALT and TBili values will be elevated within 
the same laboratory sample).  In rare instances, by the time TBili elevations are detected, 
AST/ALT values might have decreased.  This occurrence is still regarded as a potential DILI.  
Therefore, abnormal elevations in either AST OR ALT in addition to TBili that meet the 
criteria outlined below are considered potential DILI (assessed per Hy’s law criteria) cases 
and should always be considered important medical events, even before all other possible 
causes of liver injury have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the patients’s 
individual baseline values and underlying conditions.  Patients who present with the 
following laboratory abnormalities should be evaluated further as potential DILI (Hy’s law) 
cases to definitively determine the etiology of the abnormal laboratory values:

Patients with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available.

For patients with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:

Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values >2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is 
smaller).

Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches 
>3 × ULN (whichever is smaller).
Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the Sponsor.  


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The patient should return to the Investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment.  
In addition to repeating measurements of AST and ALT and TBili for suspected cases of 
Hy’s law, additional laboratory tests should include albumin, CK, direct and indirect 
bilirubin, GGT, PT/INR, total bile acids, and alkaline phosphatase.  Consideration should 
also be given to drawing a separate tube of clotted blood and an anticoagulated tube of blood 
for further testing, as needed, for further contemporaneous analyses at the time of the 
recognized initial abnormalities to determine etiology.  A detailed history, including relevant 
information, such as review of ethanol, acetaminophen/paracetamol (either by itself or as a 
coformulated product in prescription or over-the-counter medications), recreational drug, 
supplement (herbal) use and consumption, family history, sexual history, travel history, 
history of contact with a jaundiced person, surgery, blood transfusion, history of liver or 
allergic disease, and potential occupational exposure to chemicals, should be collected.  
Further testing for acute hepatitis A, B, C, D, and E infection and liver imaging (e.g., biliary 
tract) and collection of serum samples for acetaminophen/paracetamol drug and/or protein 
adduct levels may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the LFT abnormalities has yet been found.  Such potential DILI (Hy’s law) 
cases are to be reported as SAEs, irrespective of availability of all the results of the 
investigations performed to determine etiology of the LFT abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.


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Appendix 12. ECG Findings of Potential Concern
ECG Findings That May Qualify as AEs

Marked sinus bradycardia (rate <40 bpm) lasting minutes.

New PR interval prolongation >280 msec.

New prolongation of QTcF to >480 msec (absolute) or by 60 msec from baseline.

New-onset atrial flutter or fibrillation, with controlled ventricular response rate: ie, 
rate <120 bpm.

New-onset type I second-degree (Wenckebach) AV block of >30 seconds’ 
duration.

Frequent PVCs, triplets, or short intervals (<30 seconds) of consecutive ventricular 
complexes.
ECG Findings That May Qualify as SAEs

QTcF prolongation >500 msec.

New ST-T changes suggestive of myocardial ischemia.

New-onset left bundle branch block (QRS >120 msec).

New-onset right bundle branch block (QRS >120 msec).

Symptomatic bradycardia. 

Asystole:

In awake, symptom-free patients in sinus rhythm, with documented periods of 
asystole ≥3.0 seconds or any escape rate <40 bpm, or with an escape rhythm 
that is below the AV node; 

In awake, symptom-free patients with atrial fibrillation and bradycardia with 1 
or more pauses of at least 5 seconds or longer; 

Atrial flutter or fibrillation, with rapid ventricular response rate: rapid = rate 
>120 bpm.

Sustained supraventricular tachycardia (rate >120 bpm) (“sustained” = short 
duration with relevant symptoms or lasting >1 minute).


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
Ventricular rhythms >30 seconds’ duration, including idioventricular rhythm (heart 
rate <40 bpm), accelerated idioventricular rhythm (HR 40 bpm to <100 bpm), and 
monomorphic/polymorphic ventricular tachycardia (HR >100 bpm (such as 
torsades de pointes)).

Type II second-degree (Mobitz II) AV block.

Complete (third-degree) heart block.
ECG Findings That Qualify as SAEs

Change in pattern suggestive of new myocardial infarction. 

Sustained ventricular tachyarrhythmias (>30 seconds’ duration).

Second- or third-degree AV block requiring pacemaker placement.

Asystolic pauses requiring pacemaker placement.

Atrial flutter or fibrillation with rapid ventricular response requiring cardioversion.

Ventricular fibrillation/flutter.

At the discretion of the Investigator, any arrhythmia classified as an adverse 
experience.
The enumerated list of major events of potential clinical concern are recommended as “alerts” or 
notifications from the core ECG laboratory to the Investigator and Pfizer study team, and not to be 
considered as all inclusive of what to be reported as AEs/SAEs.


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Appendix 13. Alternative Measures During Public Emergencies
The alternative study measures described in this section are to be followed during public 
emergencies, including the COVID-19 pandemic. This appendix applies for the duration of 
the COVID-19 global pandemic and will become effective for other public emergencies only 
upon written notification from Pfizer. 
Use of these alternative study measures are expected to cease upon the return of business as 
usual circumstances (including the lifting of any quarantines and travel bans/advisories). 
While SARSCoV-2 testing is not mandated for this study, local clinical practice standards for 
testing should be followed. A patient should be excluded if he/she has a positive test result 
for SARS-CoV-2 infection, is known to have asymptomatic infection, or is suspected of 
having SARS-CoV-2. Patients with active infections are excluded from study participation as 
per exclusion criteria 16. When the infection resolves, the patient may be considered for re-
screening.
13.1 Telehealth Visits
In the event that in-clinic study visits cannot be conducted, every effort should be made to 
follow up on the safety of study patients at scheduled visits per the Schedule of 
Activities (Section 8) or unscheduled visits. Telehealth visits may be used to continue to 
assess patient safety and collect data points. Telehealth includes the exchange of healthcare 
information and services via telecommunication technologies (e.g., audio, video, video-
conferencing software) remotely, allowing the patient and the Investigator to communicate 
on aspects of clinical care, including medical advice, reminders, education, and safety 
monitoring. The following assessments must be performed during a telehealth visit: 

Review and record study treatment(s), including compliance and missed doses.

Review and record any AEs and SAEs since the last contact. Refer to Section 10.

Review and record any new concomitant medications or changes in concomitant 
medications since the last contact.

Review and record contraceptive method and results of pregnancy testing. Confirm 
that the patient is adhering to the contraception method(s) required in the protocol. 
Refer to Section 7.1.9 and Section 13.2.1 of this appendix regarding pregnancy tests.
Study patients must be reminded to promptly notify site staff about any change in their health 
status.
13.2 Alternative Facilities for Safety Assessments
13.2.1 Laboratory Testing
If a study patient is unable to visit the site for protocol-specified safety laboratory 
evaluations, testing may be conducted at a local laboratory if permitted by local 
regulations. The local laboratory may be a standalone institution or within a hospital. The 
following safety laboratory evaluations may be performed at a local laboratory:  

Refer to Section 7.1.6 Clinical Safety Laboratory Assessments, Table 6 for the list of 
safety laboratory evaluations, including pregnancy testing required per protocol.


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If a local laboratory is used, qualified study site personnel must order, receive, and review 
results. Site staff must collect the local laboratory reference ranges and certifications/
accreditations for filing at the site. Laboratory test results are to be provided to the site staff 
as soon as possible.  The local laboratory reports should be filed in the patient’s source 
documents/medical records. Relevant data from the local laboratory report should 
be recorded on the CRF. 
If a patient requiring pregnancy testing cannot visit a local laboratory for pregnancy testing, a 
home urine pregnancy testing kit with a sensitivity of at least 25 IU/mL may be used by the 
patient to perform the test at home, if compliant with local regulatory requirements. The 
pregnancy test outcome should be documented in the patient’s source documents/medical 
records and relevant data recorded on the CRF. Confirm that the patient is adhering to the 
contraception method(s) required in the protocol. 
13.2.2 Imaging
If the patient is unable to visit the study site for safety imaging assessments (e.g., CT, MRI, 
X-ray, ECHO or MUGA), the patient may visit an alternative facility to have the safety 
imaging assessments performed. Qualified study site personnel must order, receive, and 
review results. 
13.2.3 Electrocardiograms
If the patient is unable to visit the study site for ECGs, the patient may visit an alternative 
facility to have the ECGs performed. Qualified study site personnel must order, receive, and 
review results. 
13.2.4 Study Treatment
If the safety of a trial patient is at risk because they cannot complete required evaluations or 
adhere to critical mitigation steps, then discontinuing that patient from study treatment must 
be considered.
Study drugs may be shipped by courier to study patients if permitted by local regulations and 
in accordance with storage and transportation requirements for the study drugs. Pfizer does 
not permit the shipment of study drugs by mail. The tracking record of shipments and the 


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chain of custody of study drugs must be kept in the patient’s source documents/medical 
records.
The following is recommended for the administration of study drugs for patients who have 
active [confirmed (positive by regulatory authority-approved test) or presumed (test 
pending/clinical suspicion)] SARS-CoV-2 infection:

For symptomatic patients with active SARS-CoV-2 infection, study drugs should be 
delayed for at least 14 days from the start of symptoms. This delay is intended to allow 
the resolution of symptoms of SARS-CoV-2 infection.

Prior to restarting treatment, the patient should be afebrile for 72 hours, and SARS-
CoV-2-related symptoms should have recovered to ≤ Grade 1 for a minimum of 72 
hours.  Notify the study team when treatment is restarted.

Continue to consider potential drug-drug interactions as described in protocol 
Section 5.4.2 for any concomitant medication administered for treatment of SARS-
CoV-2 infection.
13.2.5 Home Health Visits
A home health care service may be utilized to facilitate scheduled visits per the Schedule of 
Activities. Home health visits include a healthcare provider conducting an in-person study 
visit at the patient’s location, rather than an in-person study visit at the site. The following 
may be performed during a home health visit:

Physical exam including dermatological lesions and vital signs

Review and record study treatment(s), including compliance and missed doses.

Review and record any AEs and SAEs since the last contact. Refer to Section 10.

Review and record any new concomitant medications or changes in concomitant 
medications since the last contact.

Review and record contraceptive method and results of pregnancy testing. Confirm 
that the patient is adhering to the contraception method(s) required in the protocol. 
Refer to Section 7.1.9 and Section 13.2.1 of this appendix regarding pregnancy tests.
13.2.6 Adverse Events and Serious Adverse Events
If a patient has COVID-19 during the study, this should be reported as an adverse event (AE) 
or serious adverse events (SAE) and appropriate medical treatment provided. Temporary 
discontinuation of the study treatment may be medically appropriate until the patient has 
recovered from COVID-19.
It is recommended that the Investigator discuss temporary or permanent discontinuation of
the study drug with the study medical monitor. 

SAP_001.pdf: 
Clinical Trial Protocol C4221003 (ARRAY-818-103) 
 
An Open-label Phase 1 Study to Evaluate Drug-Drug Interactions 
of Agents Co-Administered with Encorafenib and Binimetinib in 
Patients with BRAF V600-mutant Unresectable or Metastatic 
Melanoma or Other Advanced Solid Tumors 
 
 
 
 
 
SAP  Statistical Analysis Plan Version 5.0 


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Approval Signatures 
 
 
 
Date 
 
 
 
 
 
 
Date 
 
 
 
 
 
Date 
 
 
 
 
 
 
Date 
 
 
 
 
 
Date 
 
 
 
 
 
Date 
PPD 


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Table of Contents 
Approval Signatures .................................................................................................................... 2 
Table of Contents ................................................................................................................. 3 
List of Tables ....................................................................................................................... 5 
List of Figures ...................................................................................................................... 5 
List of Abbreviations ........................................................................................................... 6 
1 
Introduction .......................................................................................................................... 8 
2 
Study Objectives and Design ............................................................................................... 8 
2.1 
Study Objectives and Endpoints .............................................................................. 8 
2.2 
Study Design .......................................................................................................... 11 
2.2.1 
DDI Phase .............................................................................................. 12 
2.2.2 
Post-DDI Phase ...................................................................................... 13 
2.3 
Sample Size Justification ....................................................................................... 14 
2.4 
Analysis Sets .......................................................................................................... 15 
2.4.1 
All Enrolled Set ..................................................................................... 15 
2.4.2 
Safety Set ............................................................................................... 15 
2.4.3 
Pharmacokinetic Set .............................................................................. 15 
2.4.4 
Evaluable Pharmacokinetic Set ............................................................. 15 
2.5 
Treatment Assignment ........................................................................................... 16 
2.5.1 
Doses and Schedule of Administration .................................................. 16 
2.5.2 
Duration of Treatment ........................................................................... 16 
2.5.3 
Cumulative Dose ................................................................................... 16 
2.5.4 
Dose Intensity and Relative Dose Intensity ........................................... 16 
2.5.5 
Dose Modifications ................................................................................ 17 
2.6 
Center Pooling Method .......................................................................................... 18 
2.7 
Imputation Rules for Partial or Missing Dates ....................................................... 18 
2.7.1 
Concomitant Medication Date Imputation ............................................ 18 
2.7.2 
Adverse Event Date Imputation ............................................................ 20 
2.7.3 
Antineoplastic Therapies Date Imputation ............................................ 20 
2.7.4 
Date of Initial Diagnosis of Cancer, and Date of Most Recent 
Recurrence ............................................................................................. 21 
2.7.5 
Imputation of Last Date of Study Drug Administration ........................ 22 
2.7.6 
Incomplete Death Date .......................................................................... 22 
2.7.7 
Incomplete Assessment Dates ............................................................... 23 
2.8 
Imputation Rules for Other Missing Data .............................................................. 23 
2.9 
Subgroup Analyses ................................................................................................ 23 


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3 
Data Analysis Methods ...................................................................................................... 23 
3.1 
Definitions .............................................................................................................. 23 
3.1.1 
Study Day .............................................................................................. 23 
3.1.2 
Observation Period ................................................................................ 23 
3.1.3 
Baseline ................................................................................................. 23 
3.2 
Patient Demographics and Other Baseline Characteristics .................................... 24 
3.2.1 
Demographics and Baseline Characteristics .......................................... 24 
3.2.2 
Patient Disposition ................................................................................. 24 
3.2.3 
Protocol Deviations ............................................................................... 25 
3.2.4 
Medical History ..................................................................................... 25 
3.2.5 
Disease History ...................................................................................... 25 
3.2.6 
Prior Antineoplastic Therapy ................................................................ 25 
3.2.7 
Concomitant Therapy ............................................................................ 26 
3.3 
Safety Analysis ...................................................................................................... 26 
3.3.1 
Adverse Events ...................................................................................... 27 
3.3.2 
Physical Examinations ........................................................................... 28 
3.3.3 
Ophthalmic Examinations ..................................................................... 28 
3.3.4 
Electrocardiograms (ECGs) ................................................................... 28 
3.3.5 
MUGA/Echocardiogram ........................................................................ 29 
3.3.6 
Vital Signs ............................................................................................. 30 
3.3.7 
Laboratory Data ..................................................................................... 30 
3.3.8 
Pregnancy Test ...................................................................................... 32 
3.4 
Pharmacokinetics and CCI 
 ............................................................................... 32 
3.4.1 
Pharmacokinetics ................................................................................... 32 
CCI  
3.5 
Other Analysis ........................................................................................................ 38 
4 
Data reported in the unscheduled visit forms of the eCRFs will be listed only in the 
final supplemental CSR for the Post-DDI Phase.Changes from the Analysis 
Described in the Protocol ................................................................................................... 39 
4.1 
Caffeine Dose ......................................................................................................... 39 
5 
Changes to the Statistical Analysis Plan ............................................................................ 39 
6 
References .......................................................................................................................... 41 


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List of Tables 
Table 2-1 
Objectives and Related Endpoints ........................................................... 8 
Table 2-2 
Concomitant Medication Start Date Imputation Example Scenarios .... 19 
Table 2-3 
Concomitant Medication End Date Imputation Example Scenarios ..... 20 
Table 3-1 
Criteria for Notable ECG Values .......................................................... 29 
Table 3-2 
Criteria for Notable Vital Sign Values .................................................. 30 
Table 3-3 
Laboratory Parameters and Directions for which CTCAE Grades 
are Defined ............................................................................................ 31 
Table 3-4 
Laboratory Parameters (without CTCAE Grades) for which 
Laboratory Reference Ranges are Defined ............................................ 32 
 
 
List of Figures 
Figure 2-1 Study Schema .......................................................................................................... 13 


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List of Abbreviations 
ADaM 
Analysis Data Model 
AE 
adverse event 
Ae0-8 
amount eliminated via urine over an 8-hour period 
ANOVA 
analysis of variance 
ARAUClast 
accumulation ratio of AUClast on Day 14 compared to Day 1 
ARCmax 
 accumulation ratio of Cmax on Day 14 compared to Day 1 
AUC 
area under the curve 
AUClast 
concentration time curve from time zero to the time of last quantifiable concentration 
AUCinf 
 concentration time curve from time zero extrapolated to infinity 
AUC%extrap 
percent of concentration time curve extrapolated 
AUCtau 
AUC over the final dosing interval (tau) 
BCRP 
breast cancer resistance protein, sometimes referred to as ABCG2 
BID 
twice daily 
BLQ 
BMI 
below the limit of quantification 
body mass index 
BRAF 
BRAF proto-oncogene serine-threonine protein kinase 
CI 
confidence interval 
CL/F 
apparent total body clearance after extravascular administration 
Cmax 
plasma maximum concentration 
COVID-19 
coronavirus disease 2019 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
[CumA]e 
cumulative amount excreted in urine during each collection interval 
Curine 
 urine concentration 
CV 
coefficient of variation 
CYP 
cytochrome P450 enzyme (1A2, 2B6, 2C9, 2C19, 2D6, 3A4, 3A5 refer to isoforms) 
DDI 
drug-drug interaction 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
[Fe]% 
FU 
GGT 
IR 
percentage of dose recovered in urine for a given drug or metabolite 
follow-up 
gamma-glutamyl transferase 
immediate release 
Kel 
apparent terminal elimination rate constant 
LH 
luteinizing hormone 
LHY746 
LLOQ 
lower limit of quantitation 
LSM 
least squares means 
LVEF 
left ventricular ejection fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
MR 
metabolite ratio 


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MRAe0-8 
ratio of Ae0-8 values of the metabolite compared to parent 
MRAUClast 
ratio of AUClast values of the metabolite compared to parent 
MRAUCinf 
 ratio of AUCinf values of the metabolite compared to parent 
MRCmax 
 ratio of Cmax values of the metabolite compared to parent 
MUGA 
 multigated acquisition scan 
NCI 
National Cancer Institute 
OATP 
organic anion-transporting polypeptide 
CCI 
 
PK 
pharmacokinetic(s) 
PR 
partial response 
QD 
once daily 
QTcF 
QT interval corrected for heart rate using the Fridericia formula 
RBC 
red blood cell(s) 
RP2D 
recommended Phase 2 dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SDTM 
Study Data Tabulation Model 
T1/2 
terminal elimination half-life 
TLF 
tables, listings, and figures 
Tmax 
time to the plasma maximum concentration 
UDP 
uridine diphosphate 
UGT1A1 
uridine diphosphate (UDP)-glucuronosyl transferase 1A1 
Vol 
collected urine volume during 0-8 hours post dose collection interval on Days -7, 1 and 
14 
VZ/F 
apparent total volume of distribution after extravascular administration 
WBC 
white blood cell(s) 
WHO 
World Health Organization 


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1 
Introduction 
This document provides the detailed statistical methodology for the analysis of data from study 
ARRAY-818-103. The table, listing, and figure shells of the statistical analysis plan (SAP) can 
be found in a separate SAP shell document. 
The analyses described herein are based on protocol Version 8.0, dated 7DEC2020. All changes 
to the planned analysis described in this document will be made prior to database lock. 
2 
Study Objectives and Design 
2.1 
Study Objectives and Endpoints 
The study objectives and corresponding endpoints are shown in the table below. 
Table 2-1 
Objectives and Related Endpoints 
 
Objective 
Endpoint 
Primary 
To evaluate the effect of single and 
multiple oral doses of encorafenib 
in combination with binimetinib 
on the single oral dose 
pharmacokinetics (PK) of the 
cytochrome P450 (CYP) enzyme 
probe substrates, losartan 
(CYP2C9), midazolam (CYP3A4), 
caffeine (CYP1A2), omeprazole 
(CYP2C19), and 
dextromethorphan (CYP2D6) and 
selected metabolites, in patients 
with BRAF V600-mutant 
unresectable or metastatic 
melanoma or other advanced solid 
tumors. 
To evaluate the effect of single and 
multiple oral doses of encorafenib 
in combination with binimetinib 
on the single oral dose PK of 
rosuvastatin, an organic anion- 
transporting polypeptide (OATP) 
/breast cancer resistance protein 
(BCRP) substrate, and on the 
single oral dose PK of bupropion 
(a CYP2B6 substrate) and 
hydroxybupropion, in patients with 
Changes in plasma maximum concentration 
(Cmax) and area under the concentration time 
curve from time zero to the time of last 
quantifiable concentration (AUClast): 
midazolam, 1-hydroxymidazolam, caffeine, 
paraxanthine, omeprazole, 5- 
hydroxyomeprazole, rosuvastatin, bupropion 
and hydroxybupropion. 
Changes in the amount eliminated via urine 
over an 8-hour period (Ae0-8): losartan and its 
metabolite (E-3174), dextromethorphan and 
dextrorphan. 
Changes in plasma encorafenib and LHY746 
Cmax and area under the concentration time 
curve (AUC) in Arm 3. 


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BRAF V600-mutant unresectable 
or metastatic melanoma or other 
advanced solid tumors. 
To evaluate the effect of multiple 
doses of modafinil, a moderate 
CYP3A4 inducer, on the multiple 
oral dose PK of encorafenib and its 
metabolite, LHY746, in patients 
with BRAF V600-mutant 
unresectable or metastatic 
melanoma or other advanced solid 
tumors. 


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Secondary 
To assess the single and multiple 
dose PK of encorafenib, LHY746 
and binimetinib (and its 
metabolite, AR00426032) after 
coadministration with a single oral 
dose of the CYP probe cocktail, 
rosuvastatin, and bupropion. 
Metabolite ratios (MRAUC and MRCmax) for 1- 
hydroxymidazolam/midazolam, 
paraxanthine/caffeine, 5-hydroxy 
omeprazole/omeprazole, 
hydroxybupropion/bupropion and 
LHY746/encorafenib and MRAe0-8 for E- 
3174/losartan and 
dextrorphan/dextromethorphan. 
Pharmacokinetic parameters (e.g., time to 
reach Cmax [Tmax], AUC from time zero 
extrapolated to infinity [AUCinf], percent of 
AUC extrapolated [AUC%extrap], apparent 
terminal elimination rate constant [Kel], 
apparent terminal elimination half-life [T1/2], 
apparent total body clearance after 
extravascular administration [CL/F], and 
apparent total volume of distribution after 
extravascular administration [Vz/F]) where 
calculable, for midazolam, 1- 
hydroxymidazolam, caffeine, paraxanthine, 
omeprazole, 5-hydroxy omeprazole, 
rosuvastatin, bupropion and 
hydroxybupropion. 
Pharmacokinetic parameters (e.g., urine 
concentration [Curine], quantity of urine 
excreted during each collection interval [Vol], 
cumulative amount excreted in urine during 
each collection interval [CumA]e, and 
percentage of dose recovered in urine [Fe] %) 
for losartan, E-3174, dextromethorphan and 
dextrorphan. Pharmacokinetic parameters 
(e.g., Cmax, AUClast, Tmax, AUCinf, AUC%extrap, 
Kel, T1/2, CL/F, and Vz/F) for encorafenib, 
LHY746, binimetinib and AR00426032 where 
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To assess the safety and 
tolerability of single and multiple 
oral doses of encorafenib in 
combination with binimetinib 
when administered with a single 
oral dose of the CYP probe 
cocktail, rosuvastatin and 
bupropion during the drug-drug 
interaction (DDI) portion of the 
study. 
To assess safety and tolerability of 
multiple oral doses of encorafenib 
in combination with binimetinib 
when administered with multiple 
doses of modafinil during the DDI 
portion of the study. 
Safety will be evaluated by monitoring 
adverse events (AEs), physical examinations, 
ophthalmic examinations, vital sign 
measurements, 12-lead electrocardiograms 
(ECGs), echocardiogram (ECHO)/multigated 
acquisition scan (MUGA), and clinical 
laboratory tests. 
 
 
 
 
 
 
 
 
 
2.2 
Study Design 
This is an open-label, 3-arm, fixed-sequence study to evaluate the effect of single and multiple 
oral doses of encorafenib in combination with binimetinib on the single oral dose PK of CYP 
enzyme probe substrates using a probe cocktail, on an OATP/BCRP substrate using rosuvastatin 
and on a CYP2B6 substrate using bupropion. In addition, this study will evaluate the effect of 
multiple doses of modafinil, a moderate CYP3A4 inducer, on the multiple oral dose PK of 
encorafenib. 
The study will have 2 treatment phases, a drug-drug interaction (DDI) phase followed by a 
post-DDI phase. The DDI phase is from Day -7 to Day 28 Visit for Arm 1 and Arm 2, and from 
Day 1 to Day 28 Visit for Arm 3. The DDI visit days are -7, 1, 14 and 28 for Arm 1 and Arm 2, 
and Days 1, 14, 15, 21 and 28 for Arm 3, respectively. During the DDI phase patients will 
receive the CYP probe drug cocktail (Arm 1), the OATP/BCRP probe substrate, rosuvastatin 
and CYP2B6 substrate, bupropion (Arm 2), or the CYP3A4 inducer, modafinil (Arm 3) and 
encorafenib in combination with binimetinib. 
During the post-DDI phase patients may continue to receive treatment with encorafenib in 
combination with binimetinib until treatment discontinuation criteria are met. The combination 
of encorafenib 450 mg once daily (QD) and binimetinib 45 mg twice daily (BID) has been 
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evaluated in over 300 patients with BRAF V600 mutant melanoma in previous studies including 
192 patients in the pivotal Phase 3 trial, COLUMBUS. Since the safety and efficacy of the 
combination has already been extensively studied in previous trials, in the post-DDI phase of 
the current trial, patients will be treated as per local standard-of-care practice for patients with 
BRAF V600-mutant unresectable or metastatic melanoma or other advanced solid tumors and 
only limited data will be collected. The data collection required in the post-DDI phase will 
include concomitant medications and administration of encorafenib and binimetinib as well as 
tumor assessments. There will also be collection of all AEs and all serious adverse events 
(SAEs). Other safety evaluations conducted are not required to be reported in the CRF. 
2.2.1 
DDI Phase 
The study schema for Arm 1, Arm 2 and Arm 3 are presented in Figure 2-1. 
 
For each individual patient, the DDI phase starts on the day of the first study drug dose and 
ends on the day of the Day 28 Visit conducted before Day 35. In the scenario that Day 28 
assessments are not all completed on the same day, the date of the latest assessment required 
for the Day 28 Visit performed before Day 35 will be considered as the end of DDI phase for 
that patient. 
Arm 1 
Patients will receive a single oral dose of the CYP probe cocktail (losartan, midazolam, caffeine, 
omeprazole, and dextromethorphan) on Day -7. Encorafenib, administered 450 mg QD and 
binimetinib, administered 45 mg BID will be initiated on Day 1. Patients will then receive a 
single oral dose of the CYP probe cocktail on Day 1 and Day 14 within 5 minutes after the 
encorafenib/binimetinib administration. Blood and urine PK sampling will be conducted from 
0 to 8 hours on Day -7, Day 1 and Day 14. Arm 1 will enroll 20 subjects. 
Arm 2 
Patients will receive a single oral dose of rosuvastatin and bupropion Day -7. Encorafenib, 
administered 450 mg QD and binimetinib, administered 45 mg BID will be initiated on Day 1. 
Patients will then receive a single oral dose of rosuvastatin and bupropion on Day 1 and Day 14 
within 5 minutes after the encorafenib/binimetinib administration. Blood PK sampling will be 
conducted from 0 to 8 hours on Day -7, Day 1, and Day 14. Arm 2 will enroll 10 subjects. 
Arm 3 
Patients will start continuous treatment with encorafenib 450 mg QD and binimetinib 45 mg 
BID on Day 1. Patients will then receive continuous treatment of modafinil on Day 15 through 
Day 21. Blood PK sampling will be conducted from 0 to 8 hours on Day 14 and Day 21. Arm 
3 will enroll 6 to 12 subjects. 
On each arm, all drugs will be taken within 10 minutes total time. 


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Figure 2-1 Study Schema 
 
 
 
2.2.2 
Post-DDI Phase 
During the post-DDI phase, patients may continue to receive the encorafenib/binimetinib 
combination as long as none of the treatment discontinuation criteria are met: disease 
progression, AE requiring discontinuation of study drugs or rendering the patient unsuitable for 
further treatment, withdrawal of consent, pregnancy, significant protocol deviation(s), loss to 
follow up, Investigator decision, death, or study termination by Sponsor. If patients choose to 
not continue in the post-DDI phase, the Day 30 Safety Follow-up Visit assessments will be 
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If a patient in the post-DDI phase permanently discontinues treatment with binimetinib, he/she 
may continue treatment with encorafenib as monotherapy at its recommended Phase 2 dose 
(RP2D) of 300 mg QD. However, due to the limited efficacy of binimetinib alone in previous 
study populations, if a patient permanently discontinues treatment with encorafenib, he/she 
must discontinue treatment with binimetinib and complete the Day 30 Safety Follow-up Visit. 
 
It is recommended that patients be evaluated according to standard practice during the post-DDI 
phase. Safety should be monitored by assessing physical examinations, hematology and 
chemistry laboratory results and any other pertinent results required as part of the safety profile 
of the compound (e.g., dermatological examinations, ophthalmic exams, cardiac profiles) until 
discontinuation. Adverse events will be collected at every visit. In the post-DDI phase, all AEs 
and all SAEs will be captured on the AE CRF and SAEs will be reported to the Sponsor or 
designee using the SAE form. 
The recommended timelines for the reviews and examinations are as follows: 
 
Every 3-4 weeks: 
o Review of concomitant medications 
o Review of AEs 
o Physical examination, hematology and chemistry laboratory testing 
o If clinically indicated: triplicate 12-lead electrocardiogram (ECG) within 
approximately 5 to 10 minutes total time 
o Assess compliance with administration of encorafenib and binimetinib 
 
Every 8-12 weeks: 
o Efficacy assessment in order to assess continued benefit 
o Echocardiogram (ECHO)/multigated acquisition scan (MUGA) (more frequent 
if clinically indicated) 
o Ophthalmic examination (and as clinically indicated if visual symptoms are 
reported) 
o Dermatologic examination every 8 weeks to be continued up to 6 months after 
discontinuing encorafenib 
2.3 
Sample Size Justification 
For Arm 1 (CYP probe cocktail), the sample size was based on the substrate in the CYP probe 
cocktail with the highest reported difference in standard deviation (SD) (Ryu 2007). The 
coefficient of variation (CV) of the difference between 2 AUClast values for the same patient for 
omeprazole is approximately 38%. Assuming a 2-sided significance level of 0.05 and a power 
of 0.8, approximately 20 patients would need to be evaluable to detect a difference of 25% in 
mean AUClast. These values are similar to those in other cocktail studies run in oncology patients 
(Goh 2010). 
For Arm 2 (rosuvastatin and bupropion), the CV of the ratio between 2 rosuvastatin AUClast 
values for the same patient is approximately 47% (Stopfer 2016). Assuming a 2-sided 
significance level of 0.05 and a power of 0.8, approximately 10 patients would need to be 
evaluable to detect a difference of 50% in mean AUClast. Assuming an intrapatient variation of 


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23% for bupropion AUC0-8 (Bosilkovska 2014), there is an 80% probability with 10 patients 
that a treatment difference will be detected if the true effect size is 33%. 
For Arm 3 (modafinil), PK data will be analyzed after the first 6 patients have been dosed to 
look for an indication that the moderate inducer is having a significant effect on encorafenib 
enrolled to more fully characterize the effect. Assuming an intrapatient variation of 36.4% for 
encorafenib AUCtau (Clinical Study CMEK162X2110), there is an 80% probability with fixed 
sample sizes of 6 and 12 patients that a treatment difference will be detected if the true effect 
size is 74% and 46%, respectively. 
Up to approximately 42 patients with unresectable or metastatic BRAF V600-mutant cancer are 
planned for enrollment; 20 patients in Arm 1, 10 patients in Arm 2 and up to 12 patients in Arm 
3. 
2.4 
Analysis Sets 
2.4.1 
All Enrolled Set 
For Arm 1 only, all patients who receive at least one dose of any study drug will be included in 
the All Enrolled Set. 
2.4.2 
Safety Set 
For all arms, all patients who receive at least one dose of encorafenib and/or binimetinib will 
be included in the Safety Set. 
2.4.3 
Pharmacokinetic Set 
The Pharmacokinetic (PK) Set includes all patients who receive at least one dose of any study 
drug and have at least one post-baseline PK sample with an associated bioanalytical result. The 
PK Set will be used for summaries of concentration data, summaries of PK parameters, plots of 
individual concentration data and PK parameters and all PK listings. Additional exclusions may 
be applied to the PK Set on a per analyte basis at the discretion of the Pharmacokineticist. 
2.4.4 
Evaluable Pharmacokinetic Set 
The Evaluable PK Set includes all patients in the PK Set with sufficient concentration data to 
calculate at least one PK parameter for a probe drug on Days -7, 1, and 14 (for binimetinib 
and encorafenib on Days 1 and 14 [Arm 1 and Arm 2] and for binimetinib and encorafenib on 
Days 14 and 21 [Arm 3]). Patients who discontinue or require a dose reduction of encorafenib 
prior to completion of the last PK sampling on Day 14 in Arms 1 and 2 or on Day 21 in Arm 3 
may be considered unevaluable for PK analyses and may be replaced at the discretion of the 
Pharmacokineticist. If a patient misses 3 or more consecutive doses of encorafenib in any arm 
or 3 or more consecutive doses of modafinil in Arm 3 prior to completion of the last PK 
sampling on Day 14 in Arms 1 and 2 or on Day 21 in Arm 3, the patient may be excluded 
from Evaluable PK set at the discretion of the Pharmacokineticist. In addition, patients who 
miss any dose of study drugs on any of the PK days, or who vomit within 4 hours after dosing 
on any of the PK days may be replaced but may be excluded from Evaluable PK set at the 
discretion of the Pharmacokineticist. Patients who are excluded due to the above reasons will 
be excluded from the Evaluable PK Set which will be used for summaries of concentration 


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data and plots of summarized concentration data, and summaries of PK parameters, statistical 
analyses, and plots of summarized PK parameters. Additional exclusions may be applied to 
the Evaluable PK Set on a per analyte basis at the discretion of the Pharmacokineticist. Full 
details will be recorded in the CSR. 
2.5 
Treatment Assignment 
2.5.1 
Doses and Schedule of Administration 
CYP probe cocktail (once on Day -7, Day 1, and Day 14 for Arm 1 only) taken in the following 
order: 
 
25 mg losartan oral tablet (50 mg losartan prior to protocol Version 5) 
 
30 mg dextromethorphan oral capsule 
 
50 mg caffeine as oral liquid (100 mg caffeine, 20 mg/mL oral liquid prior to protocol 
Version 5) 
 
20 mg omeprazole oral capsule 
 
2 mg midazolam oral syrup 
Rosuvastatin and bupropion (once on Day -7, Day 1 and Day 14 for Arm 2 only): 
 
10 mg rosuvastatin oral tablet 
 
75 mg bupropion immediate release (IR) oral tablet 
Modafinil (continuous daily dosing starting on Day 15 through Day 21 for Arm 3 only): 
 
400 mg (2 × 200 mg) modafinil tablets QD 
Binimetinib/encorafenib (continuous daily starting on Day 1 for all arms): 
 
450 mg (6 × 75 mg) encorafenib oral capsules QD 
 
45 mg (3 × 15 mg) binimetinib oral tablet BID 
2.5.2 
Duration of Treatment 
For encorafenib/binimetinib: 
 
Duration of exposure (days) = date of last (non-zero) dose of study drug  date of first 
dose of study drug + 1. 
See Section 2.7.5 for imputation rules of last date of study drug administration. 
2.5.3 
Cumulative Dose 
For encorafenib/binimetinib: 
 
Cumulative dose (mg) = sum of all actual doses taken during the dosing period. 
2.5.4 
Dose Intensity and Relative Dose Intensity 
For encorafenib/binimetinib: 


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Planned dose intensity (mg/day) = is 450 mg/day (450 mg QD) for encorafenib and 90 
mg/day (45 mg BID) for binimetinib; 
 
Dose intensity (mg/day) = cumulative dose (mg) / duration of exposure (days); 
 
Relative dose intensity = 100*[Dose intensity (mg/day) / planned dose intensity 
(mg/day)]. 
A summary of exposure, including duration, dose intensity, and relative dose intensity 
(including categories <50%, 50%-<75%, 75%-<90%, 90%-
 
will be presented for encorafenib and binimetinib by treatment arm and overall. Date and time 
of administration of CYP probe cocktail, rosuvastatin, bupropion, modafinil, binimetinib, and 
encorafenib will be listed. Duration of exposure, cumulative dose, dose intensity, and relative 
dose intensity will be listed for binimetinib and encorafenib for each patient by treatment group. 
2.5.5 
Dose Modifications 
For patients who do not tolerate the encorafenib and/or binimetinib initial dosing schedule, dose 
reduction is permitted to allow the patient to continue on study drug. Patients who require a 
dose reduction of study drug(s), in particular encorafenib, prior to completion of the last PK 
sampling on Day 14 in Arms 1 and 2 or on Day 21 in Arm 3 may be considered to be unevaluable 
for PK analyses and may be replaced at the discretion of PK analyst. A detailed dose modification 
and reduction plan is presented in Section 6.5 of the protocol. Dose modifications will be 
summarized in tables and dose modification details will be provided in the listings. 
Dose Reduction: 
A dose reduction is defined as a decrease in dose from the protocol planned dose (450 mg QD 
encorafenib or 45 mg BID binimetinib) or a decrease from the previous non-zero dose, even if 
this decrease has been directly preceded by an interruption. For example, for encorafenib, in 
the sequence of total daily dose 450 mg  0 mg  300 mg, the 300 mg dose will be counted as 
a reduction. 
If a patient moves from a higher than protocol planned dose down to the planned dose then 
this is not to be counted as a reduction, however if the patient moves directly from a higher 
than planned dose down to a lower than protocol planned dose, then this is counted as a 
reduction. 
If the dose on the first dosing record is lower than protocol planned dose this is also counted 
as a reduction. 
 
Dose Interruption: 
For encorafenib/binimetinib, a dose interruption is defined as an actual dose equal to zero(where 
the planned dose is not zero), between the first and the last non-zero doses, following a non- 
zero actual dose. 
Frequency counts and percentages of patients who have encorafenib/binimetinib dose 
reductions or interruptions, and the corresponding reasons, will be provided separately. The 
number of dose interruptions per patient, and the duration of dose interruptions (days) will also 


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be summarized. Dose administration details for CYP probe cocktail, rosuvastatin/buproprion, 
modafinil, and encorafenib/binimetinib will be provided in listings. 
2.6 
Center Pooling Method 
The data from participating centers will be combined, so that an adequate number of patients 
will be available for analysis. Due to the small number of patients expected per center, no center 
effect will be assessed. 
2.7 
Imputation Rules for Partial or Missing Dates 
For computation of time intervals (e.g., elapsed time between initial diagnosis and first 
recurrence/relapse), the time interval should be set to missing when the imputation rule leads to 
a negative value. 
For patients who discontinue the study with ongoing events, the discontinuation date will be 
used as the completion date of the event. 
For AEs, concomitant medications, and antineoplastic therapies, imputation rules for partial or 
missing dates are described below. 
For imputations that are based on last contact date, note that last contact date will be derived 
for patients not known to have died on or before the analysis cutoff date. Imputed dates will not 
be considered for the determination of last contact date. Only dates associated with patient visits 
or actual assessment of the patient will be used in the derivation. Dates associated with a 
technical operation unrelated to patient status (e.g., the date a blood sample was processed) will 
not be used. Assessment dates after the cutoff date will not be applied to derive the last contact 
date. Last contact date will only be derived using the latest complete date among the following: 
 
Study drug start and end dates with non-missing dose (doses of 0 are allowed) 
 
RECIST assessment date with evaluation marked as done 
 
Laboratory/PK collection date with sample collection marked as done 
 
Vital sign, ECG, physical exam and ophthalmic exam assessment date with non-missing 
parameter value 
 
Performance status date with non-missing performance status 
 
Start/end date of AEs with non-missing verbatim term 
 
Start/end date of antineoplastic therapies administered after study treatment; 
discontinuation with non-missing medication/procedure term 
 
Cardiac imaging assessment date 
 
CCI 
 
2.7.1 
Concomitant Medication Date Imputation 
Incomplete concomitant medication dates will be imputed as follows: 
Medication start date 
 
If only day is missing, 


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 If month and year match that of the treatment start date, impute as (treatment start 
date + 1). 
 If month and year is prior to the treatment start date, impute as the 15th day of the 
month. 
 If month and year is after the treatment start date, impute as the first day of the 
month. 
 
If both day and month are missing, 
 If the year matches that of the treatment start date, impute as (treatment start 
date + 1). 
 If the year is prior to the treatment start date, impute as July 1 
 If the year is after the treatment start date, impute as January 1 
 
In all other cases the incomplete medication start date will not be imputed. 
 
Medication end date 
 
If only day is missing, 
 If month and year match that of last contact date, and the medication is ongoing, 
impute as the last day of the month. Otherwise, impute as last contact date. 
 If month and year is prior to last contact date, impute as the last day of the month. 
 
If both day and month are missing, 
 If the year matches that of last contact date, and the medication is ongoing, impute 
as December 31. Otherwise, impute as last contact date. 
 If the year is prior to or after last contact date, impute as December 31. 
 
If the medication end date is completely missing and the medication is ongoing, impute 
as last contact date. 
 
In all other cases the incomplete medication end date will not be imputed. 
Table 2-2 and Table 2-3 provide examples for different scenarios of imputing concomitant 
medication start and end dates, respectively. 
Table 2-2 
Concomitant Medication Start Date Imputation Example Scenarios 
Temporal Relationship 
Partial Concomitant 
Medication Start Date 
Treatment Start Date 
Compared to 
Treatment Start 
Imputed Date 
 
12mmyyyy 
20OCT2001 
Uncertain 
<blank> 


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Partial Concomitant 
Medication Start Date 
Treatment Start Date 
Temporal Relationship 
Compared to 
Treatment Start 
Imputed Date 
ddmmm2000 
20OCT2001 
Before 
01JUL2000 
ddmmm2002 
20OCT2001 
After 
01JAN2002 
ddmmm2001 
20OCT2001 
Uncertain 
21OCT2001 
ddSEP2001 
20OCT2001 
Before 
15SEP2001 
ddOCT2001 
20OCT2001 
Uncertain 
21OCT2001 
ddNOV2001 
20OCT2001 
After 
01NOV2001 
 
 
Table 2-3 
Concomitant Medication End Date Imputation Example Scenarios 
 
Partial Concomitant 
Medication End Date 
Minimum (Last 
Contact date, 30-Day 
FU Date) 
Ongoing 
Imputed Date 
Missing 
20OCT2001 
Yes 
20OCT2001 
ddmmm2000 
20OCT2001 
No 
31DEC2000 
ddmmm2002 
20OCT2001 
No 
31DEC2002 
ddmmm2001 
20OCT2001 
No 
20OCT2001 
ddmmm2001 
20OCT2001 
Yes 
31DEC2001 
ddSEP2001 
20OCT2001 
No 
30SEP2001 
ddOCT2001 
20OCT2001 
No 
20OCT2001 
ddOCT2001 
20OCT2001 
Yes 
31OCT2001 
 
2.7.2 
Adverse Event Date Imputation 
The imputation of the start date and end date of AEs will follow the same conventions as for 
the concomitant medication start and end dates. AEs that are completely missing a start date 
will be considered as treatment emergent if the end date of the AE is either missing or occurs 
after the treatment start date. In this case, the AE start date will be imputed to be the treatment 
start date. 
2.7.3 
Antineoplastic Therapies Date Imputation 
Prior Therapies 
Start date: 
In general, the same rules for imputation of an AE and concomitant medication start date will 
be followed, except: 
 
Completely missing start dates: 


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o Impute as treatment start date - 1. 
 
Partial missing start dates: 
o If only day is missing and month and year match that of the treatment start date, impute 
as treatment start date - 1; 
o If day and month are missing, and the year matches that of the treatment start date, 
impute as treatment start date - 1. 
End date: 
 
Completely missing end dates: 
o Do not impute 
 
Partial missing end dates: 
o Imputed date = min(treatment start date - 1, last day of the month), if day is missing; 
o Imputed date = min(treatment start date - 1, 31DEC), if month and day are missing. 
 
Post Therapies 
Start date: 
 
Completely missing start dates: 
o Impute as last date of study drug + 1. 
 
Partial missing start dates: 
o Imputed date = max(last date of study drug + 1, first day of the month), if day is missing; 
o Imputed date = max(last date of study drug + 1, 01JAN), if day and month are missing. 
Last date of study drug is the date of treatment discontinuation as collected from the disposition 
page. 
End date: 
No imputation. 
2.7.4 
Date of Initial Diagnosis of Cancer, and Date of Most Recent Recurrence 
Initial Diagnosis of Cancer 
 
Incomplete dates will be imputed as follows: 
o 
If only day is missing, impute as 15. 
o 
If both day and month are missing, and the year is prior to the year of first dose 
start date, impute as July 1. 
o 
If both day and month are missing and the year is same as the year of the first dose 
date, imputed as January 1. 


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o 
If the date is completely missing, no imputation will be performed. 
Date of Most Recent Recurrence 
 
Incomplete dates will be imputed as follows: 
o 
If only day is missing, impute as 15. 
o 
If both day and month are missing, and year matches that of the first study treatment, 
impute as max (initial diagnosis date, January 1). 
o 
If both day and month are missing, and year is prior to the year of first study 
treatment, impute as max (initial diagnosis date, July 1). 
o 
If the date is completely missing, no imputation will be performed. 
2.7.5 
Imputation of Last Date of Study Drug Administration 
If the last date of study drug is completely missing and there is no end of treatment electronic 
case report form (eCRF) page and no death date, the patient should be considered as on-going 
and use the cut-off date for the analysis as the last dosing date. 
If the last date of study drug is completely or partially missing and there is either an end of 
treatment eCRF page or a death date, then imputed last dose date will be as follows: 
 
= 31DECYYYY, if only Year is available and Year < Year of min (EOT date, death 
date) 
 
= Last day of the month, if both Year and Month are available and Year = Year of min 
(EOT date, death date) and Month < the month of min (EOT date, death date) 
 
= Last day of the month, if both Year and Month are available and Year < Year of min 
(EOT date, death date) 
 
= min (EOT date, death date), for all other cases 
The imputed date will be compared with start date of study treatment: 
 
If the imputed date < start date of study drug, then last date of study drug is set to start 
date of study drug; 
 
Otherwise, use the imputed date. 
2.7.6 
Incomplete Death Date 
Missing or partial death dates will be imputed based on the last contact date: 
 
If the date is completely missing, it will be imputed as the day after last contact date. 
o 
Note: 
date. In this case, 
death date will be imputed as the day after the last 
contact date. Therefore, he would be still alive as of the data cutoff date. 


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If the day or both day and month are missing, death date will be imputed to the maximum 
of the full (non-imputed) [last contact date (excluding the date of death) + 1] and the 
following: 
o 
Missing day: 15th day of the month and year of death 
o 
Missing day and month: July 1 of the year of death 
2.7.7 
Incomplete Assessment Dates 
No incomplete assessment dates will be imputed. 
2.8 
Imputation Rules for Other Missing Data 
Other missing data will simply be noted as missing on appropriate tables/listings. 
2.9 
Subgroup Analyses 
The study data for Arm 2 will be summarized by Non-Asian and Overall subgroups. 
3 
Data Analysis Methods 
 
be presented as frequencies and percentages. For continuous data, mean, SD, median, minimum, 
and maximum will be presented. 
3.1 
Definitions 
3.1.1 
Study Day 
Study day is defined in the following manner: 
 
Study Day 1 is defined as start date for encorafenib/binimetinib. In Arm 1, if 
encorafenib/binimetinib was not administered, Study Day 1 will be defined as the date the 
CYP probe cocktail was administered. 
 
On or after Study Day 1: the study day will be calculated as (date of assessment)  (date of 
Study Day 1) + 1. 
 
Before Study Day 1: the study day will be calculated as (date of assessment)  (date of Study 
Day 1). 
3.1.2 
Observation Period 
The overall observation period includes the DDI phase and post-DDI phase as defined in 
Section 2.2. AEs in DDI phase and post-DDI phase will be summarized separately. For other 
safety summary tables, any safety assessments beginning from Day -7 for Arm 1 and Arm 2, 
and from Day 1 for Arm 3, respectively, to the end of DDI phase will be considered. 
All data, regardless of observation period, will be listed. 
3.1.3 
Baseline 
Baseline is the last available and valid assessment performed before the first administration of 
any study treatment, unless otherwise stated under the related assessment section of the protocol 


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and/or the SAP. Baseline can be the day before first treatment administration or the same day 
as first treatment administration if a predose assessment/value is available (e.g., ECG, PK 
samples, CCI 
). 
If time is recorded for the first treatment dose and for a specific assessment performed the day 
of first dose, this assessment will be considered as baseline only if it is actually performed 
before the first dose, as checked using both times (i.e., time of the first treatment dose and time 
of the assessment). 
If no time is provided for an assessment on the day of the first administration of the study 
treatment, it will be treated as predose assessment. 
Patients with no data on a particular parameter before the first treatment administration will 
have a missing baseline for this parameter. 
For safety comparisons with baseline (e.g., for laboratory parameters, vital signs, weight, etc.), 
baseline is considered as the last available assessment or value collected prior to start of 
treatment. If no time is provided for an assessment on the day of the first administration of the 
study treatment, it will be treated as predose assessment. 
The ECG baseline will be the average of triplicate ECG measurements prior to the start of 
treatment. 
3.2 
Patient Demographics and Other Baseline Characteristics 
Unless specified otherwise, summary tables described in this section will be based on the Safety 
set and listings will be based on All Enrolled set for Arm 1 to include those participants who 
were enrolled but did not receive encorafenib and/or binimetinib and Safety set for Arms 2 and 
3. 
3.2.1 
Demographics and Baseline Characteristics 
Demographic, and other baseline data including age, gender, race, ethnicity, height, weight, 
body mass index (BMI) = weight (kg)/height2 (m2), and Eastern Cooperative Oncology Group 
(ECOG) performance status will be listed individually by patient and summarized by study arm 
using descriptive statistics (continuous data) or contingency tables (categorical data). 
Additionally, smoking status (non-smoker, occasional smoker, or smoker) will be individually 
listed by patient and summarized by study arm for Arms 2 and 3. 
3.2.2 
Patient Disposition 
The number and percent of patients in safety analysis set will be summarized separately for 
DDI phase and post-DDI phase: 
 
Number (%) of patients who discontinued the study treatment; 
 
Number (%) of patients who are still on-treatment; 
 
Number (%) of patients who completed treatment; 
 
Primary reasons for treatment discontinuation; 
 
Number (%) of patients who completed the study; 


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Primary reasons for study phase completion. 
 
For Arm 1, below additional summary will be included based on All enrolled set. 
 
Number (%) of patients who discontinued the study treatment prior to encorafenib and/or 
binimetinib; 
 
Number (%) of patients who received at least one dose of encorafenib and/or binimetinib; 
 
Primary reasons for treatment discontinuation prior to encorafenib and/or binimetinib; 
 
Primary reasons for study discontinuation prior to encorafenib and/or binimetinib. 
 
Patient disposition will also be listed. 
3.2.3 
Protocol Deviations 
All protocol deviations will be finalized before database lock. Reasons for exclusions from 
populations will be listed by patient. All protocol deviations will be listed. In addition, a separate 
listing will be created for protocol deviations related to COVID-19. 
3.2.4 
Medical History 
Past and current medical history will be summarized and listed. The summary will be presented 
by primary system organ class and preferred term. Medical history will be coded using Medical 
Dictionary for Regulatory Activities (MedDRA) as per latest version available at time of 
database lock. 
3.2.5 
Disease History 
Tumor types and their stages at the study entry will be summarized. The details of disease 
history including primary site of cancer, histological grade, predominant histology/cytology, 
additional histology/cytology, stage grouping at initial diagnosis, primary tumor stage initial 
diagnosis, lymph nodes stage at initial diagnosis, metastases stage at initial diagnosis, stage 
grouping at study entry, primary tumor stage at study entry, lymph nodes stage at study entry, 
metastases stage at study entry, metastases sites, time from initial diagnosis of primary site to 
start of study treatment (months), and time from most recent relapse/progression to start of study 
treatment (months) will be listed. Days will be converted to months by dividing the number of 
days by 30.4375. 
Incomplete dates will be handled as described in Section 2.7.4. 
3.2.6 
Prior Antineoplastic Therapy 
Prior anti-neoplastic therapies will be listed and the latest therapy will be summarized in 
three separate tables for medications, radiotherapy, and surgery. 
 
For medications, the total number of medication regimens along with its descriptive 
statistics, the setting (e.g., adjuvant), the best response, duration of best response, reason for 
discontinuation of therapy, and time between end of last medication to start of treatment 


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(using continuous statistics and categories: <1 month, 1- <6 months, 6- <12 months, 
12 months) will be summarized by treatment arm. 
 
For radiotherapy, the location, setting (e.g., neoadjuvant), method, time between end of last 
radiotherapy to start of treatment (as categories: <1 month, 1- <6 months, 6- <12 months, 
12 months) and prior radiotherapy 30% of bone marrow will be summarized by treatment 
arm. 
 
For surgery, procedure and the time since last surgery to start of treatment (as categories: 
<1 month, 1- <6 months, 6- <12 months, 12 months) will be summarized by treatment arm. 
Incomplete dates will be handled as described in Section 2.7.3. Days will be converted to 
months by dividing the number of days by 30.4375. 
3.2.7 
Concomitant Therapy 
Concomitant therapies are defined as any medications (excluding study drug and prior 
antineoplastic treatments), and significant non-drug therapies administered in the study. 
Concomitant therapies are recorded in the Prior and Concomitant Medications  and the 
Surgical and Medical Procedures  eCRF, respectively. Concomitant therapies will be coded 
using the latest version of the World Health Organization (WHO) Drug Dictionary available 
prior to database lock. 
Concomitant therapies will be summarized by Anatomical Therapeutic Chemical (ATC) class 
and preferred term. These summaries will include 
1) Medications starting on or after the start of study treatment but starting no later than 
30 days after last dose of study drug and 
2) Medications starting prior to the start of study drug and continuing after the start of study 
treatment. 
All concomitant medications will be listed. Those collected during the post-DDI phase are to 
be flagged. Incomplete dates will be handled as described in Section 2.7.1. 
Prohibited concomitant medications are specified in the protocol. Several general and 
arm-specific exclusion criteria involve prohibited concomitant medications and are referred to 
in general and treatment arm-specific exclusion criteria. No separate outputs will be produced 
related specifically to prohibited concomitant medications. 
3.3 
Safety Analysis 
The Safety Set will be used in all safety tables and listings for Arms 2 and 3. The All Enrolled 
set will be used in all safety listings for Arm 1. 
In all three 
 eCRF. 
The assessment of safety will be based on AEs (including SAEs), laboratory profiles 
(hematology, biochemistry, coagulation, cardiac/muscle enzymes, and urinalysis), physical 
examination (including vital signs, ophthalmic and dermatological examinations), and cardiac 
profiles (ECG and MUGA or ECHO). A listing will be generated for study disruptions due to 
COVID-19 including protocol deviations, adverse events, treatment discontinuation, study 


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discontinuation and deaths. All safety data will be listed and summarized as detailed in the 
sections below. 
3.3.1 
Adverse Events 
An AE is any untoward medical occurrence, including the exacerbation of a pre-existing 
condition, in a patient administered a pharmaceutical product regardless of causality. Adverse 
events will be assessed by direct observation and patient interviews. Patients should be 
questioned using non-leading questions. 
Adverse events will be coded using MedDRA as per latest version available at time of database 
lock. The severity of each AE will be categorized using the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE), v4.03. The severity rating of an 
AE refers to its intensity. 
Treatment-emergent AEs (TEAEs) will be defined as: 
 
Any new event that starts after the 1st administration of encorafenib/binimetinib 
 
 
days after treatment discontinuation 
 
Any event that was ongoing when treatment with study drug started and the severity/grade 
after treatment was higher than the Baseline value (fluctuations below the Baseline 
severity/grade are not considered as treatment emergent) 
 
Any new event that starts >30 days after treatment discontinuation and is assessed by the 
Investigator as related to study treatment. 
 
Any new event that is completely missing a start date and the end date is either missing or 
occurs after the treatment start date 
Only Treatment-emergent AE summaries will be produced as follows: 
 
Overall summary of AEs, including the number and percentage of patients with at least one 
AE, SAE, AE leading to study drug discontinuation, AE leading to dose interruption/dose 
reduction, and AE leading to additional therapy. Summaries will be provided for all AEs 
and AEs suspected to be related to study drug. The number of on-treatment deaths will also 
be summarized 
 
AEs, regardless of study drug relationship by primary system organ class and preferred term 
(overall and Grade 3 or higher) 
 
AEs, regardless of study drug relationship by preferred term (overall and Grade 3 or higher) 
 
AEs with suspected study drug relationship by primary system organ class and preferred 
term (overall and Grade 3 or higher) 
 
AEs with suspected study drug relationship by preferred term (overall and Grade 3 or higher) 
 
AEs, regardless of study drug relationship by primary system organ class, preferred term 
and maximum grade 
 
SAEs, regardless of study drug relationship, by primary system organ class and preferred 
term (overall and Grade 3 or higher) 


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SAEs with suspected study drug relationship, by primary system organ class and preferred 
term (overall and Grade 3 or higher) 
 
Non-SAEs, regardless of study drug relationship, by primary system organ class and 
preferred term (overall and Grade 3 or higher) 
 
AEs leading to study drug discontinuation, regardless of study drug relationship, by primary 
system organ class and preferred term (overall and Grade 3 or higher) 
 
AEs requiring dose reduction or study-drug interruption, regardless of study drug 
relationship, by primary system organ class and preferred term (overall and Grade 3 or 
higher) 
 
Deaths (on treatment), by primary system organ class and preferred term. 
Treatment-emergent AEs, as defined above, in the DDI phase and the post-DDI phase will be 
summarized separately; treatment-emergent AEs in the DDI phase will be included in these 
summaries regardless of whether the patient participates in the post-DDI phase. For patients 
who do not enter post-DDI phase, AEs that occur within 30 days after the last DDI dose and 
AEs that occur at >30 days that are study drug related will be reported in DDI phase tables. 
Adverse Events will be counted only in the phase in which the AE began. For the post-DDI 
phase, only Grade 3 and 4 AEs and SAEs will be summarized. All AEs and SAEs will be listed 
and AEs collected during the post-DDI phase will be flagged. Listings of all deaths, SAEs, and 
AEs leading to study drug discontinuation will also be provided. 
Incomplete dates will be handled as described in Section 2.7.2. 
3.3.2 
Physical Examinations 
Physical examination dates will be presented in a data listing. Any clinically-relevant abnormal 
findings reported as AEs will be reported in the appropriate AE listings and summary tables. 
3.3.3 
Ophthalmic Examinations 
All ophthalmic examinations (i.e., visual acuity, fundoscopy examination, slit lamp 
examination, optical coherence tomography, fluorescein angiography, and intraocular pressure 
assessment) will be listed. 
3.3.4 
Electrocardiograms (ECGs) 
Triplicate 12-lead ECGs will be performed as specified in Table 7 (Arms 1 and 2) and Table 8 
(Arm 3) in the protocol. Triplicate 12-lead ECGs will be performed at predose (up to 30 minutes 
before any study drug administration) and for all protocol-specified post-baseline assessments. 
Post-dose ECGs are to be performed at all protocol-specified, post-baseline assessments 
(± 30 minutes). Triplicate 12-lead ECGs are to be performed during the post-DDI phase if 
clinically indicated. 
The mean of the triplicate ECG measurements performed at baseline and postdose will serve as 
 and post-dose values for comparisons. 


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An abnormal ECG (e.g., QTcF of >500 ms or with a change in QTcF 
 
may be repeated if it cannot be interpreted by the Investigator. ECG tracings should be made 
available if requested by the Sponsor for central assessment by an independent reviewer. 
QT interval values will be corrected for heart rate using the Fridericia formula (QTcF). 
The following summaries will be provided for each applicable ECG parameter: 
 
Descriptive statistics at baseline, worst post-baseline and change from baseline to worst 
value in terms of absolute change. The highest post-baseline value for QT, QTcF, heart rate, 
PR, and QRS will be considered as the worst value. 
 
Frequency counts and percentages of patients having notable ECG values according to 
Table 3-1. 
Table 3-1 
Criteria for Notable ECG Values 
 
ECG parameter 
Criteria for ECG notable values 
QT, QTcF (ms) 
Increase from baseline >30-60 ms, >60 ms 
New QT interval >450-480, >480-500, >500 ms 
HR (bpm) 
Increase from baseline >25% and value >100 bpm 
Decrease from baseline >25% and value <60 bpm 
PR (ms) 
Increase from baseline >25% and value >200 ms 
QRS (ms) 
Increase from baseline >25% and value >110 ms 
ECG evaluations will be listed and notable ECG values (including notable QT interval values) 
will be flagged in the listings. 
3.3.5 
MUGA/Echocardiogram 
Left ventricular ejection fraction (LVEF) abnormalities will be defined according to CTCAE 
grade Version 4.03. Patients will be considered as having a LVEF abnormality if the worst 
post-baseline value is Grade 2, 3, or 4 according to the following classification: 
 
Grade 0: Non-missing value below Grade 2; 
 
Grade 2: LVEF between 40% and 50% or absolute change from baseline between -10% and 
<-20%; 
 
Grade 3: LVEF between 20% and 39% or absolute change from baseline lower than or equal 
to -20%; 
 
Grade 4: LVEF lower than 20%. 
The following summaries will be produced for LVEF by treatment arm: 
 
Descriptive statistics at baseline, at Day 28 Visit/end of DDI phase treatment and absolute 
changes from baseline. 
 
Shift tables using CTCAE grades to compare baseline to Day 28 Visit. 
All LVEF assessments will be listed. 


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3.3.6 
Vital Signs 
Vital signs (blood pressure, pulse, and temperature) will be measured per institutional standards 
as part of the physical examination. Height will be measured only at screening. All physical 
examinations occurring on dosing days must be performed prior to study drug administration. 
Significant findings (in the i 
) prior to the start of study drug must be 
included in the R 
eCRF. Significant findings made after signing the study informed consent that meet the 
definition of an AE must be recorded on the AE eCRF. 
Table 3-2 
Criteria for Notable Vital Sign Values 
 
Vital sign 
Criteria for clinically notable vital sign values 
Systolic blood pressure 
[mmHg] 
 
Diastolic blood pressure 
[mmHg] 
 
Pulse rate [bpm] 
 
Temperature [°C] 
Arms 1 and 3: 37.5°C
35°C; Arms 2: 37.5°C
36°C 
Weight [kg] 
20% decrease/ 10% increase from baseline 
Descriptive statistics will be provided for baseline, for worst post-baseline value (lowest/highest 
value) and change from baseline to worst post-baseline value (change from baseline to 
lowest/highest value) for each vital sign measure. 
Frequency counts and percentages of patients having notable vital sign values according to 
Table 3-2 will be summarized. Clinically notable vital sign values will be flagged in the listings. 
3.3.7 
Laboratory Data 
For laboratory tests covered by CTCAE, Version 4.03, a Grade 0 will be assigned for all 
non-
  
 
normal range (NR), the grade will be reset to 0. Grade 5 will not be used. For laboratory tests 
where grades are not defined by CTCAE, results will be graded by the low/normal/high 
classifications based on laboratory normal ranges. 
Valu
 x is a numerical value, will be considered as x for the 
analysis. 
The following by-treatment summaries will be generated separately for hematology, 
biochemistry, and urinary laboratory tests: 
 
Shift tables using CTCAE grades to compare baseline to the worst on-treatment value. 
 
Incidence of clinically notable shifts in laboratory parameters based on CTCAE grade for 
specific laboratory evaluations will be summarized, where clinically notable is defined as 
For laboratory tests where CTCAE grades are not defined, shift tables using the 
low/normal/high/(low and high) classification to compare baseline to the worst on-treatment 
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Listing of all laboratory data with values flagged to show the corresponding CTCAE grades 
and the classifications relative to the laboratory normal ranges. 
 
Urinalysis results including appearance, color, specific gravity, pH, ketones, protein, 
glucose, blood, nitrates, leukocyte esterase, and urine microscopy results including WBC, 
RBC, epithelial cells, and casts, will be listed. 
Table 3-3 and Table 3-4 list all laboratory parameters that will be summarized. 
Table 3-3 Laboratory Parameters and Directions for which CTCAE Grades are Defined 
Hematology and coagulation 
Biochemistry 
 
White Blood Cells (WBC) 
 
Creatinine 
Hemoglobin 
 
Glucose 
Platelets counts 
 
Magnesium 
Neutrophils 
 
Albumin 
Lymphocytes 
 
AST 
Prothrombin Intl. Normalized Ratio 
 
ALT 
Activated Partial Thromboplastin Time 
 
Total Bilirubin 
Direct 
bilirubin 
(if 
total 
 
bilirubin values are abnormal) 
Amylase 
Lipase 
GGT 
Creatinine phosphokinase/CK 
 
Alkaline phosphatase 


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Table 3-4 
Laboratory Parameters (without CTCAE Grades) for which Laboratory 
Reference Ranges are Defined 
Hematology and Coagulation 
Biochemistry 
 
RBC 
BUN 
Hematocrit 
Calcium 
Basophils 
LDH 
Eosinophils 
Bicarbonate 
Monocytes 
Chloride 
Prothrombin Time 
3.3.8 
Pregnancy Test 
A listing will be produced for the urine and serum pregnancy test and will include all female 
patients regardless of test result. 
3.4 
Pharmacokinetics and CCI 
 
3.4.1 
Pharmacokinetics 
3.4.1.1 
Plasma Concentration 
Blood samples for PK assessments of midazolam and its metabolite (1-hydroxymidazolam, free 
[unconjugated] and total [unconjugated and glucuronide conjugated]), caffeine and its 
metabolite (paraxanthine), omeprazole and its metabolite (5-hydroxy omeprazole), rosuvastatin, 
bupropion and its metabolite (hydroxybupropion), encorafenib and its metabolite (LHY746), 
and binimetinib and its metabolite (AR00426032), will be collected from all patients on Days - 
7, 1, 14 and 21 (as appropriate) at the following time points: predose, and 1, 2, 3, 4, 6 and 8 
hours postdose. 
Plasma concentrations of free (unconjugated) and total (unconjugated and glucuronide 
conjugated) 1-hydroxymidazolam will be determined in Arm 1 patients using validated assays. 
Plasma concentrations of glucuronide conjugated 1-hydroxymidazolam will be derived as 
below: 
glucuronide conjugated 1-hydroxymidazolam = total 1-hydroxymidazolam 
 free 1- 
hydroxymidazolam. 
Where glucuronide conjugated 1-hydroxymidazolam derived concentrations are negative, these 
will be treated as below the limit of quantification (BLQ) and set to zero. 
Plasma concentrations of each analyte mentioned above will be summarized over scheduled 
time points by arm and study day using the following descriptive statistics: number of 
observations (n), number on non-zero observations (m), mean, SD, geometric mean, CV, 
geometric CV, median, minimum and maximum. In addition, plasma concentrations of 
rosuvastatin, encorafenib and its metabolite (LHY746), and binimetinib and its metabolite 
(AR00426032) in Arm 2 will be summarized over scheduled time points by race (non-Asian 
and overall). Dose normalization may be used where appropriate for summarization of plasma 
concentration data. Individual plasma concentration of each analyte will be presented in data 
listings. Data from patients excluded from the PK Set will be presented in the data listings but 


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not included in the calculation of summary statistics. Concentrations below the lower limit of 
quantitation (LLOQ) will be treated as zero and will be displayed in the listings as zero and 
flagged. Missing values of concentrations will not be imputed and will be excluded from the 
calculations. 
Mean and individual concentration-time profiles for each analyte will be presented in figures 
on linear and semi-logarithmic scales for each arm and study day. 
3.4.1.1.1 Caffeine Plasma Concentration 
 
must be excluded 48 hours before PK assessments and the day of PK assessments (i.e., Days 
-9 to -7, -2 to 1, and 
 unobvious dietary sources of caffeine 
beyond coffee and tea that may be difficult for patients to avoid (e.g., multiple types of soda, 
chocolate in cookies, pudding, hot chocolate and baked goods, and even decaffeinated coffee 
can have significant levels of caffeine). Therefore, the caffeine PK data will be examined for 
obvious deviations, based on comparison with historical caffeine PK data. Clear deviations 
will be defined as: 
 
Predose caffeine concentration >1000 ng/mL. In one study, the observed Cmax after a 
100-mg caffeine dose taken in coffee was 1335 ng/mL (Bosilkovska 2014). Predose 
values greater than 1000 ng/mL would be observed after a 48-hour washout only with 
dietary caffeine intake during the washout period. 
 
Caffeine Cmax that takes place at Tlast. Caffeine has relatively quick absorption (Nehlig 
2018), and so a Cmax at 8 hours is clear evidence that the patient had dietary caffeine 
during the PK day. 
If a patient has a caffeine PK profile that meets either of these 2 criteria on any PK day, that 
 and its metabolite paraxanthine data will not be included in the Evaluable 
PK Set, and the affected profile(s) will not be included in the PK Set. 
Caffeine has variable PK with CYP1A2 gene polymorphism and other factors contributing to 
interindividual differences (Nehlig 2018). Variations in the half-life of caffeine from 2.3 to 
9.9 hours have been reported (Blanchard and Sawers 1983). If a patient has quantifiable 
caffeine in their plasma sample predose, the most likely explanation is that they had improper 
intake of dietary caffeine during the washout period. For a typical half-life of caffeine of 5-6 
hours, a 2-day washout should be sufficient for caffeine concentrations to decrease below the 
LLOQ (25 ng/mL). However, if a patient has a longer half-life (e.g., 10 hours or longer), they 
may have detectable caffeine levels at baseline. Therefore, the following criterion has been 
proposed to identify patients that probably had dietary intake of caffeine: 
 
Predose caffeine concentration >150 ng/mL. The Cmax from about 2 cups of coffee 
(estimated 200-mg dose) is expected to be about 2700 ng/mL (based on dose- 
normalization from the observed 1335 ng/mL from a 100-mg dose) (Bosilkovska et al. 
2014). A patient with a t1/2 of about 11.5 hours (on the high end of t1/2 value range for 
caffeine) that drank 2 cups of coffee directly before the 48-hour washout period may 
have a predose caffeine plasma concentration of about 150 ng/mL (i.e., calculated as 
2700 × exp[-0.693 × 48 hours / 11.5 hours]). Therefore, a predose value >150 ng/mL 


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suggests the patient had improper dietary intake of caffeine during the 48-hour 
washout period. 
Data from a patient caffeine PK profile with a predose caffeine plasma 
concentration >150 ng/mL but <1000 ng/mL on any PK day will be flagged in the 
concentration listings but included in summarization with the PK Set. However, a 
 
caffeine and its metabolite paraxanthine data will be excluded from the Evaluable PK Set if 
their predose caffeine plasma concentration is >150 ng/mL on any PK day. 
3.4.1.2 
Plasma Pharmacokinetic Parameters 
For the calculation of PK parameters, all plasma concentrations that are BLQ prior to the first 
measurable concentration will be set to zero. The BLQ values that occur between measurable 
plasma concentrations or after Cmax will be set to missing. 
The following plasma PK parameters will be calculated on Days -7, 1, 14, and 21, as 
appropriate, by non-compartmental methods using Phoenix® WinNonlin® Version 8.0 or higher 
(Certara USA, Inc., Princeton, New Jersey). All calculations will be based on actual sampling 
times. 


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 Parameter Definition 
 
Cmax 
maximum observed plasma concentration 
AUClast 
area under the concentration time curve (AUC) from time zero to the time of 
last quantifiable concentration, calculated using the linear trapezoidal/linear 
interpolation method 
AUCinf 
AUC from time zero extrapolated to infinity (following single administration 
only) 
AUC%extrap 
percent of AUC extrapolated (following single administration only) 
Tmax 
time to reach maximum observed plasma concentration 
Kel 
apparent terminal elimination rate constant 
T1/2 
 terminal elimination half-life, calculated as: 
ln(2) / Kel 
Note: r2 
el and its related PK parameters, and Cmax 
must not be included in the calculation. 
CL/F 
apparent total body clearance of drug from the plasma (parent drugs only), 
calculated as: 
Dose / AUCinf (single administration) 
Dose / AUClast (repeated administration) 
Vz/F 
apparent volume of distribution during the terminal phase (parent drugs only), 
calculated as: 
CL/F / Kel 
MRAUClast 
ratio of AUClast values of the metabolite compared to parent, corrected for 
molecular weight (for 1-hydroxymidazolam/midazolam, 
paraxanthine/caffeine, 5-hydroxyomeprazole/omeprazole, 
bupropion/hydroxybupropion, LHY746/encorafenib, and 
AR00426032/binimetinib) 
MRAUCinf 
ratio of AUCinf values of the metabolite compared to parent, corrected for 
molecular weight (for 1-hydroxymidazolam/midazolam, 
paraxanthine/caffeine, 5-hydroxyomeprazole/omeprazole, 
bupropion/hydroxybupropion, LHY746/encorafenib, and 
AR00426032/binimetinib) 
MRCmax 
ratio of Cmax values of the metabolite compared to parent, corrected for 
molecular weight (for 1-hydroxymidazolam/midazolam, 
paraxanthine/caffeine, 5-hydroxyomeprazole/omeprazole, 
bupropion/hydroxybupropion, LHY746/encorafenib, and 
AR00426032/binimetinib) 
ARAUClast 
accumulation ratio for encorafenib and its metabolite LHY746, and 
binimetinib and its metabolite AR00426032, based on AUClast, calculated as: 
AUClast (Day 14) / AUClast (Day 1), for Arm 1 and Arm 2 only 


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ARCmax 
accumulation ratio for encorafenib and its metabolite LHY746, and 
binimetinib and its metabolite AR00426032, based on Cmax, calculated as: 
Cmax (Day 14) / Cmax (Day 1), for Arm 1 and Arm 2 only 
The PK parameters for each analyte will be presented in data listings and summarized by arm 
and study day using the following descriptive statistics: n, mean, SD, geometric mean, CV, 
geometric CV, median, minimum, and maximum. In addition, PK parameters of rosuvastatin, 
encorafenib and its metabolite (LHY746), and binimetinib and its metabolite (AR00426032) in 
Arm 2 will be summarized over study day by race (non-Asian and overall). For Tmax only n, 
median, minimum, and maximum will be presented. Dose normalization may be used where 
appropriate for summarization of PK parameters. If AUC%extrap is >20%, AUCinf will be listed 
but not be included in summary statistics or statistical analysis. 
If appropriate, PK parameters for encorafenib, LHY746, binimetinib, and AR00426032 in 
Arms 2 and 3 may be summarized by smoking status and presented in a table. 
3.4.1.2.1 
Caffeine Pharmacokinetic Parameters 
Due to the issues described in Section 3.4.1.1.1 relating to dietary caffeine intake, if a patient 
has a caffeine PK profile that meets the following criteria on any PK day, the affected profile 
will be flagged in the parameter listings and included in the summarization and statistical 
analysis of caffeine parameters with the PK Set: 
 
Predose caffeine plasma concentration >150 ng/mL but <1000 ng/mL 
If a patient has a caffeine PK profile that meets either criteria stated below on any PK day, PK 
parameters for that profile will be included the parameter listing; however, the affected profile 
of caffeine and its metabolite paraxanthine will be excluded from all data summarization and 
statistical analysis: 
 
Predose caffeine concentration >1000 ng/mL 
 
Caffeine Cmax that takes place at Tlast 
Additionally, PK parameters will also be calculated based on baseline-adjusted caffeine 
concentrations for all profiles, regardless of the predose level. Baseline-adjusted 
concentrations will be calculated as follows: 
Baseline adjusted concentration = measured concentration  [predose concentration * 
e-Kel*t], where Kel is terminal elimination rate constant based on actual measured 
concentration values for each profile and t is the actual sampling time. 
Where patients do not have a quantifiable caffeine predose concentration (i.e., 
predose = BLQ), unadjusted caffeine data will be carried over and used in baseline-adjusted 
tables, listings, and figures (TLFs), on the assumption that BLQ = zero; hence, baseline 
adjusting all concentrations by a factor of zero would be equivalent to the unadjusted data. For 
example, if a patient has a quantifiable predose value on only 1 or 2 of their PK days, and on 
the other day(s) the predose is BLQ, all 3 days will be used in the baseline-adjusted analysis. 


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Baseline-adjusted concentrations will be listed and summarized. If a patient has a caffeine PK 
profile that meets the criterion stated below on any PK day, baseline-adjusted parameters for 
that profile will be flagged in the listings; however, the patient will be excluded from all data 
summarization using Evaluable PK Set and PK Set. 
 
Caffeine Cmax that takes place at Tlast 
3.4.1.3 
Urine Concentration 
In Arm 1 only, urine samples will be collected predose and 0 to 8 hours after dosing on Days -7, 
1 and 14. The individual patient urine collection volume (Vol) from 0 to 8 hours on Days -7, 1 
and 14 and concentrations for losartan and its metabolite (E-3174), and dextromethorphan and 
its metabolite (dextrorphan), will be presented in listings. 
3.4.1.4 
Urine Pharmacokinetic Parameters 
PK parameters of losartan, E-3174, dextromethorphan and dextrorphan will be computed from 
the individual patient urine concentrations and collection volumes on Days -7, 1 and 14. 
PK parameters will be calculated as follows: 
Ae0-8 
amount excreted into the urine over the collection interval of 0 to 8 hours. Ae0- 
8 is equivalent to [CumA]e used in protocol 
MRAe0-8 
ratio of Ae0-8 values of the metabolite compared to parent, corrected for 
molecular weight (E-3174/losartan, and dextrorphan/dextromethorphan) 
Fe 
percentage of dose recovered in urine from 0 to 8 hours as parent or 
metabolite, calculated as Ae0-8 / dose × 100 (metabolite data will be adjusted to 
account for molecular weight) 
The individual urine PK parameters will be presented in listings and summarized separately 
using the following descriptive statistics for each study day: n, mean, SD, geometric mean, CV, 
geometric CV, median, minimum, and maximum. 
For losartan and its metabolite E-3174 only, dose normalized parameters will be calculated and 
reported as patients received 50 mg losartan per earlier versions of protocol (prior to Version 
5.0) but will receive 25 mg of losartan per protocol Version 5.0. and later versions. 
3.4.1.5 
Statistical Analysis of Plasma and Urine Pharmacokinetic Parameters 
For the primary analysis in Arms 1 and 2, an analysis of variance (ANOVA) will be performed 
on  the  natural  log  (ln)-transformed  Cmax,  AUClast,  and  AUCinf  of  midazolam, 
1-hydroxymidazolam, caffeine and baseline-adjusted caffeine, paraxanthine, omeprazole, 
5-hydroxyomeprazole, rosuvastatin, bupropion, and hydroxybupropion in plasma and 
performed on natural log (ln)-transformed Ae0-8 of of losartan, E-3174, dextromethorphan, and 
dextrorphan in urine (dose normalized parameters for losartan and E-3174). In addition, the 
analysis of variance (ANOVA) will be performed on the natural log (ln)-transformed Cmax, 
AUClast, and AUCinf PK parameters of rosuvastatin, encorafenib and its metabolite (LHY746), 
and binimetinib and its metabolite (AR00426032) in Arm 2 by race (non-Asian and overall). 
For the primary analysis in Arm 3, an ANOVA will be performed on the encorafenib, LHY746, 
binimetinib, and AR00426032 (ln)-transformed Cmax, AUClast, and AUCinf. The ANOVA model 
will include day as fixed effect and patient as the random effect. Each ANOVA will include 


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calculation of least squares means (LSM), the difference between LSM for each day, and the 
standard error associated with this difference. Ratios of LSM will be calculated using the 
exponentiation of the difference between treatment LSMs from the analyses on the (ln)- 
transformed parameters. In Arms 1 and 2, these ratios will be expressed as a percentage of Day 
1 (test) relative to Day -7 (reference), Day 14 (test) relative to Day 1 (reference), and Day 14 
(test) relative to Day -7 (reference). In Arm 3, these ratios will be expressed as a percentage of 
Day 21 (test) relative to Day 14 (reference). 
The statistical analysis will only include patients where each parameter of interest is available 
for all 3 PK occasions. 
Consistent with the 2 one-sided test, 90% confidence intervals (CIs) for the ratios will be 
derived by exponentiation of the CIs obtained for the difference between LSM resulting from 
the analyses on the (ln)-transformed parameters. 
Similarly, an ANOVA will be performed on the (ln)-transformed MRAUClast, MRAUCinf, and 
MRCmax calculated for 1-hydroxymidazolam/midazolam, paraxanthine/caffeine, 
5-hydroxyomeprazole/omeprazole, hydroxybupropion/bupropion, LHY746/encorafenib, and 
AR00426032/binimetinib, and MRAe0-8 for E-3174/losartan and 
dextrorphan/dextromethorphan. 
Geometric mean ratios and corresponding 90% CIs of PK parameters in plasma (Cmax, AUClast, 
and AUCinf, MRCmax, MRAUClast, and MRAUCinf for metabolites) and urine (Ae0-8) will be 
presented in forest plots to allow for an overview effect of encorafenib and binimetinib on CYP 
probe cocktail or rosuvastatin (Arms 1 and 2) or effect of modafinil on encorafenib and 
binimetinib (Arm 3). 
In addition, plots of individual PK parameters (Cmax, AUClast and AUCinf, Ae0-8) and, where 
applicable, metabolite to parent AUC and Cmax ratios combined with corresponding geometric 
means will be provided versus treatment for Arms 1 and 2 (probe substrates and metabolites) 
and Arm 3 (encorafenib, LHY746, binimetinib, and AR00426032). 
CCI  
 
 
3.5 
Other Analysis 
Interim analyses may be conducted after a sufficient number of patients have completed Day 
28 Visit (i.e., reached end of DDI phase) in each arm. A full analysis for Arm 2 will be 
conducted when all patients in this arm complete the DDI phase. This full analysis may be 
repeated for Arms 1 and 3 separately or combined, based on the timing of all patients in the 


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respective arms completing the DDI phase. A final analysis will be done when all patients have 
completed the study. 
After final database lock, another full database transfer, including all Study Data Tabulation 
Models (SDTM), Analysis Data Models (ADaM), PK, and safety TLFs will be performed. 
Furthermore, the individual lesion measurements and best overall response during treatment 
evaluated at the end of study will be listed and summarized by tumor type. 
 
4 
Data reported in the unscheduled visit forms of the eCRFs 
will be listed only in the final supplemental CSR for the Post- 
DDI Phase.Changes from the Analysis Described in the Protocol 
4.1 
Caffeine Dose 
Per protocol, patients enrolled in Arm 1 of the study were scheduled to receive a single dose of 
100 mg caffeine as a part of CYP probe cocktail on Days -7, 1 and 14; however, patients in the 
study received the salt form of caffeine (caffeine citrate), which equates to 50 mg caffeine in 
free-base form. The data from the first 3 patients who inadvertently received the lower dose of 
caffeine showed that there is adequate bioanalytical quantification at the 50 mg free-base dose 
level to support the evaluation of the primary objective of the study. The protocol was therefore 
updated to amend the caffeine dose to 50 mg free base in Arm 1 of the study in Amendment 5. 
All caffeine PK parameters will be based on 50 mg free-base dose level. 
 
5 
Changes to the Statistical Analysis Plan 
Version 2 is an update to Version 1.0 of SAP- Detailed Statistical Methodology. 
This incorporates the changes made as of Version 7 of the Protocol. Major changes in Version 
2.0 includes: 
 
Sample size of patient enrollment is included in description of Arms as per study design 
in Section 2.2.1. 
 
Details of subject exclusion criteria is added in Pharmacokinetic Section 2.4.2 of 
analysis sets. 
 
Added Section 2.9 for subgroup analyses. 
 
Section for Hydroxymidazolam Plasma Concentration is removed, and the 
corresponding text is moved to Plasma Concentration under Section 3.4.1.1. 
 
Added a sentence to clarify that Arm 2 will be summarized over scheduled time points 
by race (non-Asian and overall) under Section 3.4.1.1. 
 
Additional analysis of PK Parameter which includes Rosuvastatin, Encorafenib and its 
metabolite (LHY746), and Binimetinib and its metabolite (AR00426032) in Arm 2 will 
be analyzed by race under Section 3.4.1.2. 


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Dose normalization and analysis methodology for PK parameters is added in Section 
3.4.1.5. 
 
Updated details on interim analyses under Section 3.5. 
Version 3.0 is an update to Version 2.0 of SAP- Detailed Statistical Methodology. 
This incorporates the changes made as of Version 8.0 of the Protocol. Major changes in Version 
3.0 includes: 
 
The DDI Phase has been defined in Section 2.2.1; 
 
Derivations of dosing parameters have been revised in Sections 2.5.2 through 2.5.4; 
 
The dose reduction definition has been revised in Section 2.5.5; 
 
Added a summary of tumor types and stages in Section 3.2.5 and a summary for best 
overall responses in Section 3.5; 
 
Urinalysis shift tables have been removed from Tables 3-3 and 3-4; 
 
 The list of urinalysis results was updated in Section 3.3.7. 
A summary of major changes from Version 3.0 of the SAP to Version 4.0 include: 
 
All enrolled set has been added, it includes all patients who receive at least one dose of 
any study drug (Safety set as per Version 3.0). 
 
Safety set has been updated, it will include patients who receive at least one dose of 
encorafenib/binimetinib. 
 
Additional summary has been included for Arm 1 under Section 3.2.2. 
 
post-DDI phase hence it has been updated at all required places within SAP. 
 
TEAE derivation has been updated under Section 3.3.1. 
A summary of major changes from Version 4.0 of the SAP to Version 5.0 include: 
 
The definition of Study Day 1 in Section 3.1.1 was updated for cases when patients do 
not receive encorafenib/binimetinib. 
 
The lower limit for temperature in the Criteria for Notable Vital Sign Values table in 
Section 3.3.6 was revised from 36°C to 35°C for Arms 1 and 3 and 36°C for Arm 2. 
 
A statement in Section 3.5 was added to list data from unscheduled visits. 


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6 
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Stopfer P, Giessmann T, Hohl K, et al. Pharmacokinetic evaluation of a drug transporter cocktail 
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Nehlig A. Interindividual Differences in Caffeine Metabolism and Factors Driving Caffeine 
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Blanchard J and Sawers SJ. The absolute bioavailability of caffeine in man. Eur J Clin 
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