MATCH Treatment Subprotocol Z1A: Binimetinib in Patients With Tumors (Other Than Melanoma) With NRAS Mutations
Phase: PHASE2
Conditions: Advanced Lymphoma, Advanced Malignant Solid Neoplasm, Hematopoietic and Lymphoid Cell Neoplasm, Refractory Lymphoma, Refractory Malignant Solid Neoplasm, Refractory Multiple Myeloma
Sponsor: National Cancer Institute (NCI)

EAY131-Z1A 
1 
Molecular Analysis for Therapy Choice (MATCH) 
MATCH Treatment Subprotocol Z1A: Binimetinib in 
Patients with Tumors (Other Than Melanoma) with NRAS 
Mutations 
BINIMETINIB TREATMENT SUBPROTOCOL 
CHAIR: 
James Cleary, MD, PhD 
BINIMETINIB TREATMENT SUBPROTOCOL CO-
CHAIR: 
Rebecca Heist, MD, MPH 
BINIMETINIB TRANSLATIONAL CHAIR: 
Scott Kopetz, MD, PhD, FACP 
Version Date:  May 16, 2018 
NOTE: This subprotocol (EAY131-Z1A) should 
be used in conjunction with the 
MATCH Master Protocol (EAY131). 
NOTE: As of 11/17, all protocol changes will be 
noted by addendum number. Please 
reference the activation memo for the 
addendum activation date. 
SUBPROTOCOL ACTIVATION DATE 
May 31, 2016 (incorporated in Addendum #3) 
Addendum #5 – 12/16 
Addendum #6 – 1/17 
Addendum #7 – 3/17 
Addendum #13 
Agent 
IND# 
NSC# 
Supply 
Binimetinib 
IND Sponsor: DCTD 
788187 
NCI Supplied 
Rev. Add13 

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Table of Contents 
Molecular Analysis for Therapy Choice (MATCH) ..................................................... 1 
MATCH Treatment Subprotocol Z1A: Binimetinib in Patients with Tumors (Other 
Than Melanoma) with NRAS Mutations ............................................................. 1 
Table of Contents ...................................................................................................... 2 
Schema ...................................................................................................................... 4 
1. Introduction ........................................................................................................ 5 
1.1 Binimetinib ................................................................................................ 5 
1.2 Supporting Preliminary Data ..................................................................... 5 
2. Selection of Patients ........................................................................................... 6 
2.1 Registration to Treatment ......................................................................... 6 
3. Binimetinib Treatment Plan ................................................................................ 8 
3.1 Administration Schedule ........................................................................... 8 
3.2 Adverse Event Reporting Requirements ................................................... 8 
3.3 Comprehensive Adverse Events and Potential Risks List (CAEPR) for 
Binimetinib (NSC 788187) ....................................................................... 11 
3.4 Dose Modifications ................................................................................. 14 
3.5 Supportive Care ....................................................................................... 22 
3.6 Duration of Agent-specific treatment ..................................................... 22 
3.7 Duration of Follow-Up ............................................................................. 23 
4. Study Parameters .............................................................................................. 24 
4.1 Therapeutic Parameters for Binimetinib Treatment .............................. 24 
5. Drug Formulation and Procurement ................................................................. 26 
5.1 Binimetinib (NSC #788187) ..................................................................... 27 
6. Translational Studies ......................................................................................... 29 
7. References ........................................................................................................ 29 
Appendix I  Patient Pill Calendar ............................................................................. 30 
Appendix II  Actionable Mutations for Sub-Protocol EAY131-Z1A .......................... 32 
Appendix III  Patient Drug Information Handout and Wallet Card ......................... 33 
 

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TREATMENT SUBPROTOCOL CHAIR 
James Cleary MD/PhD 
Dana-Farber Cancer Institute 
Dana Building, Room 1210L 
Boston MA 02215-5450 
Phone: (617) 632-6073 
Fax: (617) 632-5370 
E-mail: jcleary@partners.org 
 
 
TREATMENT SUBPROTOCOL CO-CHAIR  
Rebecca S. Heist MD MPH 
Massachusetts General Hospital 
32 Fruit Street, Yawkey 7B 
Boston MA 02114 
Phone: (617) 726-1838 
Fax: (617) 724-3166 
E-mail: rheist@partners.org 
 
TRANSLATIONAL CHAIR 
Scott Kopetz MD/PhD 
University of Texas, MD Anderson Cancer 
Center, 
1515 Holcombe Blvd, Unit 426 
Houston, TX 77584 
Phone: (713) 792-2828 
Fax: (713) 745-1163 
E-mail: skopetz@mdanderson.org 
 
 
 
 
 
 
 
 
 
 

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Schema 
 
Long-Term Follow-Up
Binimetinib 45 mg PO BID 
until progression or 
unacceptable toxicity
Cycle = 28 days
Accrual Goal: 70
 
Rev. 3/17 

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1. 
Introduction 
1.1 
Binimetinib 
Binimetinib (MEK162, ARRY-162) is a potent and selective oral inhibitor of MEK1 
and MEK2. It is a non-ATP-competitive allosteric inhibitor that has an 12 
nanomolar IC50 against purified MEK enzyme1. Preclinical studies demonstrated 
that binimetinib had significant activity, IC50 from 30 to 250 nanomolar,  in B-RAF 
and RAS mutated cell lines1.  A phase 1 trial demonstrated that binimetinib is well 
tolerated and has an MTD of 60mg twice daily2. However, because of retinal 
toxicity at 60mg twice daily, subsequent phase 2 and 3 trials have adapted a 
binimetinib dose of 45mg twice daily. The dose limiting toxicities of binimetinib 
were rash and central serous retinopathy2. Other common toxicities seen on the 
phase 1 include diarrhea, nausea, and peripheral edema 2. More rare toxicities 
include elevated CK and decreaesd left ventricular function. The half life of the 
drug was approximately 5 hours2. Skin biopsies performed on patients receiving 
binimetinib demonstrated decreased pERK activity2. 
1.2 
Supporting Preliminary Data  
RAS mutations result in upregulation of the mitogen-activated protein kinase 
(MAPK) pathway and are thought to be key driver mutations in many 
malignancies3.  The importance of RAS mutations is underscored by its high 
prevalence in human malignancies. Data from the COSMIC database indicates 
that RAS, which has three highly homologous isoforms KRAS, N-RAS, and H-
RAS, is mutated in approximately 30% of human malignancies4. Mutations in 
NRAS are found in approximately 8% of human cancers4. While most frequently 
seen in melanomas, NRAS mutations are seen in many other solid malignancies 
including colorectal, gastric, thyroid, uterine endometrial, lung, among others5-10. 
Despite enormous efforts from both academia and industry, successful targeting 
of RAS mutated malignancies has been an elusive goal11. Clinical trials testing 
numerous strategies, including farnesyl transferase inhibitors and combined 
MEK/PI3K inhibition, have failed to produce widespread, clinically meaningful 
results. Interestingly, preclinical testing demonstrates that NRAS mutated cell 
lines are more sensitive to MEK inhibitor than KRAS mutated cell lines12,13. For 
example, a study of lung cancer cell lines demonstrated that five of six NRAS-
mutant cell lines were sensitive to the MEK inhibitors 12.  
Consistent with in vitro observations,, the most successful effort in targeting RAS 
mutations has been seen in NRAS mutated melanoma. In an open label phase 2 
study, treatment of 117 patients with NRAS mutated melanoma with the MEK 
inhibitor binimetinib resulted in an overall response rate of 14.5% with PFS of 3.6 
months and OS of 12.2 months14. In a smaller phase 2 trial of binimetinib, six 
(20%; 95% CI 8-39%) of 30 patients with NRAS-mutated melanoma had a partial 
response15. An ongoing phase 3 study randomizes patients with NRAS mutated 
melanoma to binimetinib versus dacarbazine with a primary endpoint of PFS; 
enrollment is complete and results are awaited. Our trial will test the hypothesis 
that inhibition of MEK with binimetinib is an effective therapy in NRAS mutated 
malignancies.   
 

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2. 
Selection of Patients 
Each of the criteria in the checklist that follows must be met, along with the eligibility in 
the MATCH Master Protocol, in order for a patient to be considered eligible for this 
study. Use the checklist to confirm a patient’s eligibility. For each patient, this checklist 
must be photocopied, completed and maintained in the patient’s chart.  
In calculating days of tests and measurements, the day a test or measurement is 
done is considered Day 0. Therefore, if a test is done on a Monday, the Monday 
four weeks later would be considered Day 28.  
ECOG-ACRIN Patient No. ____________________________ 
Patient’s Initials (L, F, M) _______________________ 
Physician Signature and Date ___________________ 
NOTE: 
Policy does not allow for the issuance of waivers to any protocol specified 
criteria (http://ctep.cancer.gov/protocolDevelopment/policies_deviations.htm). 
Therefore, all eligibility criteria listed in Section 2 must be met, without 
exception. The registration of individuals who do not meet all criteria listed in 
Section 2 can result in the participant being censored from the analysis of the 
study, and the citation of a major protocol violation during an audit.  All 
questions regarding clarification of eligibility criteria must be directed to the 
Group's Executive Officer (EA.Execofficer@jimmy.harvard.edu) or the 
Group's Regulatory Officer (EA.RegOfficer@jimmy.harvard.edu). 
NOTE: 
Institutions may use the eligibility checklist as source documentation if it has 
been reviewed, signed, and dated prior to registration/randomization by the 
treating physician. 
NOTE: 
All patients must have signed the relevant treatment consent form 
2.1 
Registration to Treatment  
2.1.1 
Patients must fulfill all eligibility criteria outlined in Section 3.1 of 
MATCH Master Protocol (excluding Section 3.1.6) at the time of 
registration to treatment step (Step 1, 3, 5, 7). 
2.1.2 
Patients must have NRAS mutation in codon 12, 13, 61 as determined 
via the MATCH Master Protocol. See Appendix II for a list of the 
specific variants and corresponding Levels of Evidence. 
2.1.3 
Patients must have an electrocardiogram (ECG) within 8 weeks prior 
to treatment assignment and must have no clinically significant 
abnormalities in rhythm, conduction or morphology of resting ECG 
(e.g. complete left bundle branch block, third degree heart block). 
Date of ECG:  _______________ 
2.1.4 
Patients must have adequate bone marrow, organ function and 
laboratory parameters 
• 
Creatinine ≤ 1.5 mg/dL, or calculated creatinine clearance 
(determined as per Cockcroft-Gault) ≥ 50mL/min; 
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2.1.5 
Patients must have adequate cardiac function: 
• 
left ventricular ejection fraction (LVEF) ≥ 50% as determined by a 
multigated acquisition (MUGA) scan or echocardiogram, 
• 
QTc interval ≤ 480 ms 
2.1.6 
Patients must not have known hypersensitivity to binimetinib or 
compounds of similar chemical or biologic composition. 
2.1.7 
Patients with melanoma are excluded. 
2.1.8 
Patients must not have any active central nervous system (CNS) 
lesion (i.e., those with radiographically unstable, symptomatic lesions) 
and/or leptomeningeal metastases. 
NOTE: 
Patients treated with stereotactic radiotherapy or surgery 
are eligible if the patient remained without evidence of 
CNS disease progression ≥ 3 months. Patients must be off 
corticosteroid therapy for ≥ 3 weeks. 
2.1.9 
Patients must not have a history or current evidence of retinal vein 
occlusion (RVO) or predisposing factors to RVO (e.g. uncontrolled 
glaucoma or ocular hypertension, history of hyperviscosity or 
hypercoagulability syndromes). Please refer to Safety and Tolerability 
Assessments in Section 3.4 for more information. 
2.1.10 
Patients must not have a history of retinal degenerative disease. 
2.1.11 
Patients must not have a history of Gilbert’s syndrome. 
2.1.12 
Patients must not have uncontrolled arterial hypertension despite 
medical treatment. 
2.1.13 
Patients must not have active hepatitis B, and/or active hepatitis C 
infection. 
2.1.14 
Patients must not have neuromuscular disorders that are associated 
with elevated CK (e.g., inflammatory myopathies, muscular dystrophy, 
amyotrophic lateral sclerosis, spinal muscular atrophy). 
2.1.15 
Patients must not have impairment of gastrointestinal function or 
gastrointestinal disease (e.g., ulcerative disease, uncontrolled 
nausea, vomiting, diarrhea, malabsorption syndrome, small bowel 
resection). 
2.1.16 
Patients who have received prior MEK inhibitors are excluded. 
 
 
 
 
 
Physician Signature 
 
Date 
OPTIONAL: 
This signature line is provided for use by institutions wishing to 
use the eligibility checklist as source documentation. 
_____
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_____
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Rev. 12/16 

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3. 
Binimetinib Treatment Plan 
3.1 
Administration Schedule 
This is an open label single arm study testing binimetinib in patients with NRAS 
mutated malignancies. Each patient will be treated with orally administered 
binimetinib 45mg twice daily continuously throughout the trial. Patients will 
continue on the binimetinib until disease progression or unacceptable toxicity. A 
cycle is defined as 28 days. 
Each dose of binimetinib should be taken with a glass of water (with or without 
food). Missed or vomited doses of binimetinib will not be replaced. 
3.2 
Adverse Event Reporting Requirements 
The Adverse Event Reporting Requirements for all EAY131 subprotocols are 
outlined in the MATCH MASTER protocol.  Please refer to those guidelines when 
determining if an event qualifies as a Serious Adverse Event (SAE) and requires 
expedited reporting via CTEP’s Adverse Event Reporting System (CTEP-AERS). 
In addition, the following section outlines agent specific requirements and must 
be followed to ensure all reporting requirements are met. 
3.2.1 
Additional instructions, requirements and exceptions for protocol 
EAY131 – Subprotocol Z1A 
Additional Instructions 
For instructions on how to specifically report events that result in 
persistent or significant disability/incapacity, congenital anomaly, or 
birth defect events via CTEP-AERS, please contact the AEMD Help 
Desk at aemd@tech-res.com or 301-897-7497.  This will need to be 
discussed on a case-by-case basis. 
 
EAY131 – Subprotocol Z1A specific expedited reporting 
requirements: 
• 
Pregnancies:  Pregnancies and suspected pregnancies 
(including a positive or inconclusive pregnancy test, regardless of 
age or disease state) occurring while the subject is on 
binimetinib, or within 28 days of the subject’s last dose of 
binimetinib, are considered immediately reportable events. The 
pregnancy, suspected pregnancy, or positive/ inconclusive 
pregnancy test must be reported via CTEP-AERS within 24 hours 
of the Investigator’s knowledge.  Please refer to Appendix VIII in 
MATCH Master Protocol for detailed instructions on how to report 
the occurrence of a pregnancy as well as the outcome of all 
pregnancies. 
 

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EAY131 – Subprotocol Z1A specific expedited reporting 
exceptions: 
For Subprotocol Z1A, the adverse events listed below do not require 
expedited reporting via CTEP-AERS: 
• 
If an AE meets the reporting requirements of the protocol, and it 
is listed on the SPEER, it should ONLY be reported via CTEP-
AERS if the grade being reported exceeds the grade listed in the 
parentheses next to the event.  
3.2.2 
Second Primary Cancer Reporting Requirements 
All cases of second primary cancers, including acute myeloid 
leukemia (AML) and myelodysplastic syndrome (MDS), that occur 
following treatment on NCI-sponsored trials must be reported to 
ECOG-ACRIN using Medidata Rave 
• 
A second malignancy is a cancer that is UNRELATED to any 
prior anti-cancer treatment (including the treatment on this 
protocol).  Second malignancies require ONLY routine reporting 
as follows: 
1. Complete a Second Primary Form in Medidata Rave within 14 
days. 
2. Upload a copy of the pathology report to ECOG-ACRIN via 
Medidata Rave confirming the diagnosis. 
3. If the patient has been diagnosed with AML/MDS, upload a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
via Medidata Rave. 
• 
A secondary malignancy is a cancer CAUSED BY any prior anti-
cancer treatment (including the treatment on this protocol). 
Secondary malignancies require both routine and expedited 
reporting as follows: 
1. Complete a Second Primary Form in Medidata Rave within 14 
days 
2. Report the diagnosis via CTEP-AERS at http://ctep.cancer.gov  
Report under a.) leukemia secondary to oncology 
chemotherapy, b.) myelodysplastic syndrome, or c.) 
treatment related secondary malignancy 
3. Upload a copy of the pathology report to ECOG-ACRIN via 
Medidata Rave and submit a copy to NCI/CTEP confirming the 
diagnosis. 
4. If the patient has been diagnosed with AML/MDS, upload a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
via Medidata Rave and submit a copy to NCI/CTEP. 
NOTE: 
The Second Primary Form and the CTEP-AERS report 
should not be used to report recurrence or development of 
metastatic disease. 
NOTE: 
If a patient has been enrolled in more than one NCI-
sponsored study, the Second Primary Form must be 

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submitted for the most recent trial. ECOG-ACRIN must be 
provided with a copy of the form and the associated 
pathology report and cytogenetics report (if available) even 
if ECOG-ACRIN was not the patient's most recent trial. 
NOTE: 
Once data regarding survival and remission status are no 
longer required by the protocol, no follow-up data should 
be submitted via CTEP-AERS or by the Second Primary 
Form. 

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3.3 
Comprehensive Adverse Events and Potential Risks List (CAEPR) for Binimetinib 
(NSC 788187) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a 
single list of reported and/or potential adverse events (AE) associated with an 
agent using a uniform presentation of events by body system. In addition to the 
comprehensive list, a subset, the Specific Protocol Exceptions to Expedited 
Reporting (SPEER), appears in a separate column and is identified with bold and 
italicized text. This subset of AEs (SPEER) is a list of events that are protocol 
specific exceptions to expedited reporting to NCI (except as noted below).  Refer 
to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguide
lines.pdf for further clarification. Frequency is provided based on 662 patients. 
Below is the CAEPR for Binimetinib. 
NOTE: 
If an AE meets the reporting requirements of the protocol, and it is 
listed on the SPEER, it should ONLY be reported via CTEP-AERS if 
the grade being reported exceeds the grade listed in the parentheses 
next to the event in the SPEER. 
Version 2.0, March 2, 20161 
 
Adverse Events with Possible 
Relationship to Binimetinib 
(CTCAE 4.0 Term) 
[n= 662] 
 
 
Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER) 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia (Gr 2) 
CARDIAC DISORDERS 
  
 
 
 Heart failure 
  
EYE DISORDERS 
  
 
Blurred vision 
 
 Blurred vision (Gr 2) 
 
Eye disorders - Other 
(retinopathy)2  
 
  
 
 
 Eye disorders Other - 
(retinal vein occlusion) 
  
 
Eye disorders Other - 
(visual disorder)3 
 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 2) 
 
Constipation 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 2) 
 
Mucositis oral 
 
 Mucositis oral (Gr 2) 
Nausea 
 
 
 Nausea (Gr 2) 
 
Vomiting 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Edema face 
 
  
Edema limbs 
 
 
 Edema limbs (Gr 2) 
Fatigue 
 
 
 Fatigue (Gr 2) 

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INVESTIGATIONS 
  
 
Alanine 
aminotransferase 
increased 
 
 
Alanine 
aminotransferase 
increased (Gr 2) 
 
Aspartate 
aminotransferase 
increased 
 
 
Aspartate 
aminotransferase 
increased (Gr 2) 
CPK increased4 
 
 
 CPK increased4 (Gr 2) 
 
Ejection fraction 
decreased 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 2) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
 Arthralgia (Gr 2) 
 
Back pain 
 
 Back pain (Gr 2) 
 
Myalgia 
 
 Myalgia (Gr 2) 
 
 
Musculoskeletal and 
connective tissue disorders 
- Other (rhabdomyolysis) 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Dyspnea 
 
  
 
 
Pneumonitis 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
 Alopecia (Gr 2) 
 
Dry skin 
 
 Dry skin (Gr 2) 
 
Pruritus 
 
 Pruritus (Gr 2) 
Rash acneiform 
 
 
 Rash acneiform (Gr 2) 
Rash5  
 
 
 Rash5 (Gr 2) 
VASCULAR DISORDERS 
  
 
Hypertension 
 
 Hypertension (Gr 2) 
 
Hemorrhage6  
 
  
1 This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail 
2 Retinopathy may include chorioretinopathy, chorioretinitis, and retinal detachment. 
3 Visual disorders may include visual disturbance, blurred vision, visual acuity reduced, flashing light, and 
floaters. 
4 CPK increased may be associated with muscle pain and muscle weakness. 
5 Rash may include rash maculo-papular and erythematous rash. 
6 The majority of hemorrhage events were mild, although serious bleeding events in the eyes, GI tracts or 
lungs have rarely been reported. 
Adverse events reported on binimetinib trials, but for which there is insufficient evidence 
to suggest that there was a reasonable possibility that binimetinib caused the adverse 
event: 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Febrile neutropenia 
CARDIAC DISORDERS - Atrial fibrillation; Atrioventricular block complete; Cardiac disorders - 
Other (tachycardia); Myocardial infarction; Palpitations 
ENDOCRINE DISORDERS - Hypothyroidism 

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GASTROINTESTINAL DISORDERS - Ascites; Cheilitis; Dyspepsia; Gastritis; Gastrointestinal 
disorders - Other (gastroenteritis); Gastrointestinal disorders - Other (pneumatosis intestinalis); 
Ileus; Oral hemorrhage; Retroperitoneal hemorrhage; Small intestinal obstruction; Small 
intestinal perforation 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema trunk; 
Fever; Flu like symptoms; General disorders and administration site conditions - Other 
(generalized edema); Multi-organ failure 
HEPATOBILIARY DISORDERS - Hepatic failure 
INFECTIONS AND INFESTATIONS - Lung infection; Paronychia; Pharyngitis; Sepsis; Skin 
infection 
INVESTIGATIONS - Alkaline phosphatase increased; Blood bilirubin increased; Cardiac 
troponin I increased; Cardiac troponin T increased; Creatinine increased; Electrocardiogram QT 
corrected interval prolonged; GGT increased; INR increased; Lipase increased; Lymphocyte 
count decreased; Neutrophil count decreased; Platelet count decreased; Serum amylase 
increased; Weight loss 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hyperglycemia; 
Hypoalbuminemia; Hypoglycemia; Hypokalemia; Hyponatremia; Tumor lysis syndrome 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - 
Tumor pain 
NERVOUS SYSTEM DISORDERS - Akathisia; Dizziness; Headache; Intracranial hemorrhage; 
Nervous system disorders - Other (dropped head syndrome); Paresthesia; Somnolence; 
Syncope; Transient ischemic attacks 
PSYCHIATRIC DISORDERS - Insomnia; Suicide attempt 
RENAL AND URINARY DISORDERS - Acute kidney injury; Hematuria; Proteinuria 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Atelectasis; Cough; 
Epistaxis; Pleural effusion; Pneumothorax; Pulmonary hypertension; Respiratory failure; 
Wheezing 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Hyperhidrosis; Palmar-plantar 
erythrodysesthesia syndrome; Skin and subcutaneous tissue disorders - Other (skin burning 
sensation) 
VASCULAR DISORDERS - Hypotension; Venous thromboembolism 
NOTE: 
Binimetinib in combination with other agents could cause an exacerbation of any 
adverse event currently known to be caused by the other agent, or the combination 
may result in events never previously associated with either agent 
 

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3.4 
Dose Modifications  
The initial dose of each patient will be binimetinib 45mg twice daily. Patients who 
develop study drug related toxicity can reduce the dose of binimetinib to 30mg 
twice daily. Dose reductions below to binimetinib 30mg twice daily are not 
allowed. 
When the AE that resulted in a dose reduction improves to and remains stable at 
the patient’s Baseline for a minimum of 14 days, the dose can be re-escalated to 
the next dose level at the discretion of the Investigator, provided there are no 
other concomitant binimetinib-related toxicities that would prevent drug re-
escalation. There is no limit to the number of times the patient can have their 
dose reduced or re escalated (in 15 mg increments); however, no dose re 
escalation is allowed after a dose reduction due to LVEF dysfunction or any 
grade 4 toxicity. 
A dose reduction below 30 mg BID is not allowed. Patients requiring additional 
reductions must be discontinued from study treatment.  Dose interruptions of 
more than 21 days are not allowed. 
Recommended Dose Reductions for Binimetinib 
First Dose Reduction 
30 mg orally twice daily 
Subsequent Modification 
Effectiveness of binimetinib at doses below 30 mg twice 
daily has not been demonstrated. 
Dose Re-escalation 
Patients who have been dose reduced to 30 mg twice daily 
may re-escalate to 45 mg twice daily if the AE that resulted 
in a dose reduction improved to baseline and remained 
stable for 14 days provided there were no other 
concomitant BINIMETINIB-related toxicities that would 
prevent drug re-escalation. 
Do not re-escalate if the dose reduction is due to LVEF 
dysfunction or any grade 4 toxicity. 
Eye disorders should be graded according to CTCAE version 4.0 as described 
below in Table 1. 
Table 1 
CTCAE grading for eye disorders 
Grade 
Description 
1 
Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
2 
Moderate; minimal, local or noninvasive intervention indicated; limiting 
age appropriate instrumental ADL 
3 
Severe or medically significant but not immediately sight threatening; 
Hospitalization or prolongation of existing hospitalization indicated; 
disabling; limiting self-care ADL 
4 
Sight-threatening consequences; urgent intervention indicated; blindness 
(20/200 or worse) in the affected eye 
ADL= activities of daily living 
Retinal detachment should be graded according to the CTCAE version 4.0 as 
described below in Table 2. 
Rev. 12/16 

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Table 2 
CTCAE grading for retinal detachment 
Grade 
Description 
1 
Asymptomatic 
2 
Exudative and visual acuity 20/40 or better 
3 
Rhegmatogenous or exudative detachment; operative intervention 
indicated; decline in vision (worse than 20/40 but better than 20/200) 
4 
Blindness (20/200 or worse) in the affected eye 
Uveitis should be graded according to the CTCAE version 4.0 as described 
below in Table 3.  
Table 3 
CTCAE grading for uveitis 
Grade 
Description 
1 
Anterior uveitis; medical intervention indicated 
2 
Anterior uveitis; medical intervention indicated 
3 
Posterior or pan-uveitis 
4 
Blindness (20/200 or worse) in the affected eye 
Hand Foot Skin Reaction should be graded according to CTCAE version 4.0 as 
described below in Table 4. 
Table 4 
CTCAE grading of Hand foot skin reaction (HFSR)a 
Grade 
Descriptionb 
1 
Minimal skin changes or dermatitis (e.g., erythema, edema, numbness, 
dysesthesia, paresthesia, tingling or hyperkeratosis) without pain 
2 
Skin changes (e.g.,peeling, blisters, bleeding, edema, or hyperkeratosis) 
with pain; limiting instrumental ADL 
3 
Severe skin changes (e.g., peeling, ulceration, blisters, bleeding, edema, 
or hyperkeratosis) with pain; limiting self-care ADL 
ADL=activities of daily living 
aHFSR or palmar-plantar erythrodysaesthesia syndrome, a disorder characterized by 
redness, marked discomfort, swelling, and tingling in the palms of the hands or the 
soles of the feet; 
bMore specifics examples to grade 1 and grade 3 are added to facilitate proper grading 
[from the sorafenib package insert (West Haven, CT: Bayer Pharmaceuticals 
Corporation; 2007); Porta et al 2007]. 
Diarrhea should be graded according to CTCAE version 4.0 as described below 
in Table 5. 

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Table 5 
CTCAE grading of diarrhea 
Grade 
Description 
1 
Increase of < 4 stools per day over baseline; mild increase in ostomy 
output compared to baseline 
2 
Increase of 4-6 stools per day over baseline; moderate increase in 
ostomy output compared to baseline 
1-2 
Complicated  
Definition as above with the following complicating signs/symptoms: 
• 
Moderate to severe cramping 
• 
Grade ≥ 2 nausea/vomiting 
• 
Decreased performance status 
• 
Fever 
• 
Sepsis 
• 
Neutropenia 
• 
Frank bleeding 
• 
Dehydration 
• 
Unresolved diarrhea after 48 hours of treatment with loperamide 
(including high dose administration) and initiation of second-line 
treatment 
3 
Increase of ≥ 7 stools per day over baseline; hospitalization indicated; 
severe increase in ostomy output compared to baseline; limiting self-
care ADL 
4 
Life threatening consequences; urgent intervention indicated 
ADL=activities of daily living 
Recommended Dose Reductions for Binimetinib 
First Dose Reduction 
30 mg orally twice daily 
Subsequent Modification 
Effectiveness of binimetinib at doses below 30 mg twice 
daily has not been demonstrated. 
Dose Re-escalation 
Patients who have been dose reduced to 30 mg twice daily 
may re-escalate to 45 mg twice daily if the AE that resulted 
in a dose reduction improved to baseline and remained 
stable for 14 days provided there were no other 
concomitant BINIMETINIB-related toxicities that would 
prevent drug re-escalation. 
Do not re-escalate if the dose reduction is due to LVEF 
dysfunction or any grade 4 toxicity. 
Missed/skipped doses will not be made up (i.e. the patient should not double 
their dose if the previous dose was missed). When the toxicity that resulted in a 
dose reduction improves to and remains stable at the patient’s baseline for a 
minimum of 14 days, the dose can be re-escalated at the investigator’s discretion 
provided there are no other concomitant toxicities.  
No dose re-escalation is allowed after dose reduction due to left ventricular 
dysfunction or any grade 4 toxicity. 
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Dose reduction/interruption/discontinuation decisions should be based on the 
CTCAE grade of the toxicity and the guidelines provided below. All AEs should 
be followed weekly or as clinically appropriate until stabilization or resolution. 
Please refer to the tables below for dose adjustment recommendations for 
binimetinib induced toxicities.   
Binimetinib – Recommended dose modifications associated with treatment-related 
adverse events  
Severity of Adverse Reaction 
BINIMETINIB 
Cutaneous Reactions 
• 
Intolerable Grade 2 or 3 
• 
Grade 4 
Withhold BINIMETINIB or reduce dose. 
Permanently discontinue BINIMETINIB. 
Ocular 
• 
Symptomatic Retinal 
pigment epithelial 
detachments 
Withhold BINIMETINIB. 
• 
If improved to Grade 0 or 1, resume at same dose level. 
• 
If not improved, resume at the lower dose level or permanently 
discontinue. 
• 
Retinal Vein Occlusion 
Permanently discontinue BINIMETINIB. 
Cardiac 
• 
Asymptomatic, absolute 
decrease of > 10% in 
LVEF compared to 
baseline and the LVEF 
is below the institutional 
lower limit of normal 
(LLN) (e.g., a decrease 
of 60% to 48% is an 
absolute decrease of 
12%) 
 
• 
Symptomatic 
congestive heart  failure 
Withhold BINIMETINIB for 3 weeks: repeat LVEF. 
 
Resume BINIMETINIB at the lower dose level if all the following are 
present: 
• 
LVEF at or above the LLN and 
• 
Absolute decrease from baseline is 10% or less.   
If the LVEF does not recover within 3 weeks, permanently discontinue 
treatment. 
 
Permanently discontinue BINIMETINIB. 
Venous Thromboembolism 
• 
Uncomplicated DVT or 
PE 
Withhold BINIMETINIB for up to 3 weeks. 
• 
If improved to Grade 0 or 1, resume at reduced dose. 
• 
If not improved, permanently discontinue. 
• 
Life threatening PE 
Permanently discontinue BINIMETINIB. 
Liver Laboratory Abnormalities and Hepatotoxicity 
• 
First occurrence Grade 
4 
Withhold BINIMETINIB for up to 4 weeks. 
• 
If improved to Grade 0 or 1, or Grade ≤2 if liver metastasis, then 
resume at reduced dose. 
• 
If not improved to Grade 0 or 1 within 4 weeks, permanently 
discontinue. 
• 
Recurrent Grade 4 
Permanently discontinue BINIMETINIB. 
Other 
• 
Grade 2 (intolerable) 
adverse reactions 
• 
Consider dose reduction, or 
• 
Withhold BINIMETINIB for up to 3 weeks or until resolved to 
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Severity of Adverse Reaction 
BINIMETINIB 
Grade 0 or 1 and restart at a reduced dose. 
• 
Grade 3 or 4 
Withhold BINIMETINIB for up to 3 weeks. 
• 
If improved to Grade 0 or 1 or pretreatment/baseline level, resume 
at reduced dose. 
• 
If not improved, permanently discontinue. 
a National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 
 
SAFETY AND TOLERABILITY ASSESSMENTS 
At every four-week visit (±3 days), the following assessments should be 
performed (until study drug discontinuation) for safety purposes: physical 
examination, 12-lead ECG, weight, vital signs, laboratory assessments 
(hematology, chemistry, CPK), and urinalysis.  
• 
CPK will be performed at the same time points as the hematology collections. 
Follow up for total creatine kinase (CK) ≥ 3 X ULN will include weekly 
assessment of isoenzymes and myoglobin in blood/or urine, and troponin as 
applicable. 
MUGA/echocardiogram will be performed to determine cardiac ejection fraction 
at the end of the second cycle, and then every four cycles thereafter.  Whichever 
modality was used at baseline should be continued throughout the study. 
Patients will undergo ophthalmology exams performed by an ophthalmologist 
during screening and at the end of the first cycle. Following the first cycle, 
patients will then undergo eye exams every 2 cycles or sooner if they become 
symptomatic. These will be full ophthalmic examinations including slit lamp 
examination, visual acuity testing, visual field testing, intraocular pressure (IOP) 
and indirect fundoscopy with attention to retinal abnormalities, especially retinal 
pigment epithelial detachments (RPED) like events and RVO. 
For patients with clinical suspicion of retinal abnormalities (i.e. photopsia, 
metamorphopsia, impairment of visual acuity, etc.) or RVO, additional 
assessments of optical coherence tomography (for RPED) and fluorescein 
angiography (for RVO) should be mandatory. 
FOLLOW-UP FOR TOXICITIES 
Patients whose treatment is interrupted or permanently discontinued due to an 
adverse event 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 
will be provided. 
Monitoring of Hypertension 
Patients that receive binimetinib must monitor their blood pressure at home at 
Days 10 and 30 after treatment initiation if they meet the following criteria:  
• 
Patients with history of hypertension and/or 
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• 
Patient receiving antihypertensive drugs before onset of study treatment 
and/or 
• 
Patients with a screening systolic blood pressure ≥ 140 mmHg and/or  
• 
Patients with a screening diastolic blood pressure of ≥ 90 mmHg 
The investigator is to educate the patient on the signs and symptoms of 
hypertension and use of the home blood pressure monitor. More frequent 
assessments during the study drug treatment period may also be performed at 
the discretion of the investigator and if medically indicated.  
Measurements are to be taken at the same time on Study Days 10 and 30 after 
taking any hypertensive medications and after being at rest for 5 minutes in a 
sitting position. If SBP ≥160 mmHg, or DBP ≥ 100 mmHg, the patient should 
contact their investigator to have an unscheduled visit. At this unscheduled visit, 
the patient’s blood pressure should be assessed and these measurements must 
be documented in the patient record. Early initiation of treatment and aggressive 
management of emergent hypertension must be implemented after its diagnosis. 
For patients monitoring their blood pressure at home, it is suggested to develop a 
patient diary to record their self-assessed blood pressure measurements and 
present the collected data to the investigator for evaluation and appropriate 
management. This diary must be maintained in the patient’s source 
documentation 
Management of nausea and/or vomiting 
Because nausea and vomiting have been reported for 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. 
Clinical judgment and experience of the treating physician should guide the 
management plan of each patient. Patients experiencing nausea and/or vomiting 
CTCAE ≥ 1 will 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. 
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). 
Recommended Guidelines for the Management of binimetinib-induced Diarrhea 
Proactively investigate for occurrence of diarrhea and educate patients 
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 had symptoms, the patient should 
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be asked regarding the actions taken for these symptoms and re-instruct if 
indicated 
2. The patients should be instructed on dietary modifications and on early 
warning signs of diarrhea and potentially life-threatening illnesses (e.g. 
severe cramping might be a sign for severe diarrhea, fever with diarrhea 
might be a sign for infection, fever and dizziness on standing might be a sign 
for 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 Concomitant Medications section 
of the patient record. It is recommended that patients be provided loperamide 
tablets and are instructed on the use of loperamide at on the first day of 
binimetinib treatment. In addition to the binimetinib induced-diarrhea dosing 
guidelines, these instructions should be provided at each visit and the site should 
ensure that the patient understands the instructions. 
Explain the frequency of diarrhea and its relationship to NCI CTCAE grading. 
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 and Cryptosporidium species can lead to severe 
infections in immunosuppressed patients 
• 
Medication-induced diarrhea 
• 
Malabsorption/lactose intolerance 
• 
Fecal impaction, partial bowel obstruction 
For uncomplicated Grade 1/2 diarrhea 
• 
Stop all lactose-containing products, alcohol and eat frequent small meals 
that include bananas, rice, applesauce or toast) 
• 
Stop laxatives, bulk fiber (i.e. Metamucil®) and stool softeners (e.g. docusate 
sodium; Colace®) 
• 
Stop high-osmolar food supplements such as Ensure® Plus and Jevity® Plus 
(with fiber) 
• 
Drink 8 to 10 large glasses of clear liquids per day (e.g. water, Pedialyte®, 
Gatorade® or broth) 
• 
Consider administration of standard dose of loperamide: initial administration 
4 mg, then 2 mg every 4 hours (maximum of 16 mg/day) or after each 
unformed stool. 
• 
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• 
If uncomplicated Grade 1 to 2 diarrhea persists for more than 24 hours, 
escalate to high dose loperamide: 2 mg every 2 hours (max. 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 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 to 4 diarrhea 
• 
The patient must call the investigator immediately 
• 
If loperamide has not been initiated, 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 
dehydration, replace loperamide by octreotide. 
• 
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. 
Recommended Guidelines for the Management of Study Drug (binimetinib)-
induced Skin Toxicity  
Clinical judgment and experience of the treating physician should guide the 
management plan of each patient: 
• 
Prophylaxis of skin toxicity to be initiated 24 hours prior to the first treatment 
with study drug or later as needed 
• 
Application of topical agents to the most commonly affected skin areas such 
as face, scalp, neck, upper chest and upper back 
Topical agents include non-oily sunscreen (PABA free, SPF ≥ 30, UVA/UVB 
protection), topical steroids (preferably mometasone cream i.e. Elocon®) and 
topical erythromycin evening (i.e. Eryaknen® or topical pimocrolimus) 
NOTE: 
Topical agents should be applied on a daily basis starting on Day 1 of 
study treatment or 24 hours prior to the first dose, and more often as 
needed. 
• 
Possibly oral doxycycline (100 mg daily) for the first 2-3 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) 
• 
Consider prophylactic rash treatment if not already started 
• 
Topical or other topical corticosteroid (i.e. mometasone cream) and/or topical 
antibiotic (i.e. erythromycin 2%) are 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) 
• 
Use of topical erythromycin or clindamycin (1%) plus topical mometasone or 
pimecrolimus cream (1%) plus oral antibiotics such as: lymecycline (408 mg 
QD), doxycycline (100 mg BID) or minocycline (50 to 100 mg QD). 
• 
Although there has been no evidence of phototoxicity or photosensitivity in 
patients being 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) 
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 doses, i.e. 0.3 to 0.5 mg/kg) (Lacouture et 
al 2011) 
• 
Use of acitretin is not recommended 
CTCAE Grade 4 
• 
Immediately discontinue the patient from study drug and treat the patient with 
oral and topical medications (see recommendation CTCAE Grade 3). 
Symptomatic treatment: 
It is strongly recommended that patients who develop rash/skin toxicities receive 
symptomatic treatment: 
• 
For pruritic lesions, use cool compresses and oral antihistaminic agents 
• 
For fissuring, use Monsel’s solution, silver nitrate, or zinc oxide cream. If not 
sufficient use mild steroid ointments or combinations of steroids and 
antibiotics such as Fucicort® 
• 
For desquamation, use emollients with mild pH 5/neutral (best containing 
urea 10%) 
• 
For paronychia, antiseptic bath and local potent corticosteroids, use oral 
antibiotics and if no improvement is seen, refer to a dermatologist or surgeon 
• 
For infected lesions, obtain bacterial and fungal cultures and treat with topical 
or systemic antibiotics based on sensitivity of culture 
3.5 
Supportive Care  
All supportive measures consistent with optimal patient care will be given 
throughout the study. 
3.6 
Duration of Agent-specific treatment  
In the absence of treatment delays due to adverse event(s), treatment may 
continue until one of the following criteria applies: 
• 
Extraordinary Medical Circumstances: If at any time the constraints of this 
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discontinued. In this event submit forms according to the instructions in the 
MATCH Forms Packet. 
• 
Patient withdraws consent. 
• 
Patient experiences unacceptable toxicity. 
• 
Non-protocol therapies are administered. 
• 
Disease progression 
3.7 
Duration of Follow-Up 
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4. 
Study Parameters 
4.1 
Therapeutic Parameters for Binimetinib Treatment  
NOTE: 
In addition to the study parameters listed in the MATCH Master Protocol, the below parameters must also be 
performed for patients receiving binimetinib treatment. 
NOTE: 
All assessments required prior to registration to treatment should be done ≤ 4 weeks prior to registration to 
Steps 1, 3, 5, 7, excluding the radiologic evaluation and electrocardiogram (ECG). 
Test/Assessment 
Prior to 
Registration to 
Treatment 
Treatment 
End of 
Treatment 
Follow UpF 
Every Cycle, prior 
to treatment 
Every 2 Cycles 
H&P, Weight, Vital signsA 
X 
 XI 
 
 
X 
Performance status 
X 
 XI 
 
 
X 
CBC w/diff, pltsB 
X 
 XI 
 
 
X 
Serum chemistryB 
X 
 XI 
 
 
X 
Radiologic evaluationD 
X 
 
 XD 
 
 XF 
β-HCGC 
X 
 
 
 
 
Toxicity AssessmentG 
 
X 
 
X 
 XF 
Pill Count/DiaryH 
 
X 
 
X 
 
Ophthalmologic examination 
X 
XL 
 XL 
 
 
Echocardiogram or Nuclear StudyK 
X 
 
 XK 
 
 
ECG 
 XJ 
  XM 
 
 
 
Urinalysis 
 
XM 
 
 
 
Tumor biopsy and blood sample for MATCH Master ProtocolE 
 
 
X 
 XE 
 
A. History and physical, including vital signs and weight at the start of each cycle (up to 3 days before start of new cycle). 
B. Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, creatinine, glucose, phosphorus, potassium,  SGOT[AST], 
SGPT[ALT], creatine phosphokinase (CPK), sodium, magnesium and serum tumor markers (including LDH, PSA if appropriate).  For eligibility 
purposes, participants with creatinine levels above institutional normal, Cockcroft-Gault will be used to calculate creatinine clearance.  CBC 
w/diff, platelets and serum chemistries should be performed on cycle 1, day 1 (or up to 7 days prior), and at the start of each subsequent cycle 
(up to 3 days before start of new cycle).  CBC with differential will be performed more frequently in patients with grade 4 neutropenia or 
thrombocytopenia until resolution to ≤ grade 3. CBC and serum chemistries are only required in follow-up until values return to pre-treatment 
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levels or until progressive disease. Please refer to Safety and Tolerability Assessments in Section 3.4 for additional assessments if CPK ≥3 X 
ULN. 
C. Blood pregnancy test (women of childbearing potential) required prior to beginning treatment. 
D. Disease measurements are repeated every 2 cycles for the first 26 cycles, and every 3 cycles thereafter until PD or start of another MATCH 
treatment step. The baseline evaluation should be performed as closely as possible to the beginning of treatment and never more than 6 weeks 
before registration to treatment step. For multiple myeloma patients, please refer to Section 6.4 of the MATCH Master Protocol for additional 
information on myeloma response criteria and the required disease assessments. Documentation (radiologic) must be provided for patients 
removed from study for progressive disease. 
E. Additional blood specimens and/or biopsies are to be submitted from consenting patients per Section 9.3.2 of the MATCH Master Protocol. 
Submit at the following time points, as applicable: 
• 
Blood specimens are to be submitted at the end of Cycle 2 (prior to start of Cycle 3 treatment). If patient progresses or treatment is 
discontinued prior to Cycle 3, collect the blood at that time instead. On-treatment kits for blood sample collections will be automatically 
shipped to sites upon registration to the treatment step. 
• 
Screening biopsies for additional aMOI assessments after registration to appropriate screening step, if applicable (Step 2 or Step 4). 
• 
At end of all MATCH study treatments, blood specimens and/or research biopsy after consent and registration to Step 8 
Please refer to Section 4 of the MATCH Master Protocol to determine whether the patient proceeds to the next screening step or to follow-up 
(with a potential end of treatment biopsy for research purposes on Step 8). Samples are to be submitted as outlined in Section 9 of the MATCH 
Master Protocol. To order Step 2/4 Screening or Step 8 kits, complete the EAY131 Collection and Shipping Kit Order Form (See Appendix XII of 
the MATCH Master Protocol) and fax to 713-563-6506. 
F. Every 3 months if patient is < 2 years from study entry, and every 6 months for year 3. Toxicity assessments and radiologic evaluations are not 
required to be done during Follow Up if progression has been previously reported; however if an adverse event occurs post treatment that meets 
the SAE reporting requirements, it still must be reported via CTEP-AERS, even if progression has occurred. 
G. Site personnel should evaluate for toxicity and discuss treatment compliance with the patient in order to ensure the medication is taken correctly; 
this evaluation may be conducted by telephone or in person. The Toxicity Assessment is not required prior to Cycle 1, but is required every 
subsequent cycle. 
H. The pill calendar will be collected at the end of every cycle. The Pill Count/Diary is not required prior to Cycle 1, but is required every subsequent 
cycle. 
I. 
For Cycle 1, if the following tests/assessments occurred within 7 days of Day 1, they do not need to be repeated at this timepoint: H&P, Weight, 
Vital Signs; Performance Status; CBC w/diff, plts; Serum chemistry; Concomitant Medications.  
J. Within 8 weeks of treatment assignment. 
K. Echocardiogram or MUGA scan will be done at the end of the second cycle, and then every four cycles thereafter. 
L. Patients will undergo ophthalmology exams performed by an ophthalmologist during screening and at the end of the first cycle. Following the 
first cycle, patients will then undergo eye exams every 2 cycles or sooner if they become symptomatic. The ophthalmic exam should include slit 
lamp examination, visual acuity testing, visual field testing, intraocular pressure (IOP) and indirect fundoscopy with attention to retinal 
abnormalities, especially retinal pigment epithelial detachments (RPED) like events and retinal vein occlusion (RVO). 
M. Please refer to Safety and Tolerability Assessments in Section 3.4 for additional information. 
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5. 
Drug Formulation and Procurement 
This information has been prepared by the ECOG-ACRIN Pharmacy and Nursing 
Committees. 
Availability 
NO STARTER SUPPLIES MAY BE ORDERED. Subjects must be enrolled and assigned 
to the treatment subprotocol prior to submitting the clinical drug request to PMB. 
Drug Ordering: NCI supplied agents may be requested by eligible participating 
Investigators (or their authorized designee) at each participating institution. 
Pharmaceutical Management Branch (PMB) policy requires that drug be shipped directly 
to the institution where the patient is to be treated. PMB does not permit the transfer of 
agents between institutions (unless prior approval from PMB is obtained – see general 
information) The CTEP-assigned protocol number must be used for ordering all CTEP-
supplied investigational agents. The eligible participating investigators at each 
participating institution must be registered with CTEP, DCTD through an annual 
submission of FDA Form 1572 (Statement of Investigator), NCI Biosketch, Agent 
Shipment Form, and Financial Disclosure Form (FDF).  If there are several participating 
investigators at one institution, CTEP-supplied investigational agents for the study 
should be ordered under the name of one lead investigator at that institution. 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) 
application (https://ctepcore.nci.nih.gov/OAOP). Access to OAOP requires the 
establishment of a CTEP Identity and Access Management (IAM) account 
(https://ctepcore.nci.nih.gov/iam/) and the maintenance of an “active” account status, a 
“current” password, and an active person registration status. 
NCI Supplied Agent(s) – General Information 
Questions about drug orders, transfers, returns, or accountability should be 
addressed to the PMB by calling 240-276-6575 Monday through Friday between 
8:30 AM and 4:30 PM Eastern Time or email PMBAfterHours@mail.nih.gov 
anytime. 
Drug Returns: All undispensed drug supplies should be returned to the PMB. When it is 
necessary to return study drug (e.g., sealed bottles remaining when PMB sends a stock 
recovery letter), investigators should return the study drug to the PMB using the NCI 
Return Agent Form available on the NCI home page (http://ctep.cancer.gov). 
Drug Accountability: The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, disposition, and return of 
agent received from the PMB using the NCI Investigational Agent Accountability Record 
Form for Oral Agents available on the NCI home page (http://ctep.cancer.gov). Maintain 
separate NCI Investigational Agent Accountability Records for each agent, strength, 
formulation and ordering investigator. 
Investigator Brochure Availability: The current versions of the IBs for PMB-supplied 
agents will be accessible to site investigators and research staff through the PMB Online 
Agent Order Processing (OAOP) application.  Access to OAOP requires the 
establishment of a CTEP Identity and Access Management (IAM) account and the 
maintenance of an “active” account status, a “current” password, and active person 
registration status.  Questions about IB access may be directed to the PMB IB 
coordinator at IBCoordinator@mail.nih.gov. 
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5.1 
Binimetinib (NSC #788187) 
5.1.1 
Other Names  
MEK162, ARRY-438162 
5.1.2 
Classification  
MEK 1/2 inhibitor 
5.1.3 
Mode of Action  
Binimetinib is a potent, selective, allosteric small-molecule inhibitor of 
mitogen-activated protein (MAP) kinase kinase (MEK 1 and MEK 2) 
that is uncompetitive with adenosine triphosphate (ATP). 
5.1.4 
Storage and Stability  
Storage: Store below 25°C, protect from light 
If a storage temperature excursion is identified, promptly return 
binimetinib to room temperature and quarantine the supplies.  Provide 
a detailed report of the excursion (including documentation of 
temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
Stability: Stability studies are ongoing. Tablets should be dispensed 
in the original packaging. 
5.1.5 
Dose Specifics 
Each patient will be treated with binimetinib 45mg twice daily 
continuously throughout the trial. Each dose of binimetinib should be 
taken with a glass of water (with or without food). 
5.1.6 
How Supplied 
Array Biopharma supplies and CTEP, NCI, DCTD distributes 
binimetinib as 15 mg film-coated tablets in bottles containing 56 
tablets. The capsule-shaped tablets are yellow to dark yellow and the 
size is 0.2 x 0.48 inches. The film-coated tablets consist of binimetinib 
drug substance; colloidal silicon dioxide; croscarmellose sodium; 
lactose monohydrate; magnesium stearate; microcrystalline cellulose; 
and a commercial film coating. 
5.1.7 
Route of Administration  
Orally with or without food. Tablets should be swallowed whole. 
5.1.8 
Incompatibilities  
In vitro, binimetinib is metabolized primarily by glucuronidation mainly 
via UGT1A1 but also UGT1A3 and 1A9. Binimetinib is a substrate of 
CYP1A1, 1A2, 2C19, 3A4 in vitro but the potential for a clinical drug 
interaction is expected to be minimal. Binimetinib is also a substrate of 
P-gp and BCRP. Inhibitors or inducers of UGT1A1, P-gp, and BCRP 
should be co-administered with caution. 
In vitro, binimetinib showed relatively potent inhibitory effect on 
CYP2B6 and weak inhibition of CYP1A2 and 2C9.  Avoid co-
administration with agents that are substrates of CYP2B6.  It has little 
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or no inhibition of CYP2A6, 2C8, 2C19, 2D6, 2E1, and 3A4/5.  
Binimetinib is a weak inhibitor of UGT1A-mediated SN-38 conjugation 
in vitro. Binimetinib was not found to be an in vitro inhibitor of BCRP, 
P-gp, or OCT1 but is a weak inhibitor of OCT2. There is a low 
potential for binimetinib to cause a clinical drug interaction with 
substrates mainly cleared by OATP and OCT2.  
Binimetinib is an in vitro inducer of CYP3A4 but this was not 
confirmed clinically. Slight induction of CYP2C9 mRNA was also 
found but did not translate into induction of activity. 
Binimetinib is highly protein bound (97.2%).  Use caution in patients 
who are receiving concomitant medications that are also highly 
protein-bound. 
Drugs with a conditional, possible, or known risk to induce Torsades 
de Pointes or QT prolongation should be co-administered with 
caution. Patients that take these medications should be monitored 
frequently or according to protocol. 
5.1.9 
Side Effects  
See Section 3.3 for side effects. 
5.1.10 
Patient Care Implications 
There is some data that suggest binimetinib exposure may be 
associated with reproductive toxicity. Binimetinib must not be used in 
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6. 
Translational Studies 
Please refer to the MATCH Master Protocol for information on the Translational Studies.  
7. 
References 
1. Lee PA, Wallace E, Marlow A, et al: Abstract 2515: Preclinical Development of 
ARRY-162, A Potent and Selective MEK 1/2 Inhibitor. Cancer Research 70:2515, 
2010 
2. Bendell JC, Papadopoulos K, Jones SF, et al: Abstract B243: A phase I dose-
escalation study of MEK inhibitor MEK162 (ARRY-438162) in patients with advanced 
solid tumors. Molecular Cancer Therapeutics 10:B243, 2011 
3. Stephen Andrew G, Esposito D, Bagni Rachel K, et al: Dragging Ras Back in the 
Ring. Cancer Cell 25:272-281, 2014 
4. Prior IA, Lewis PD, Mattos C: A Comprehensive Survey of Ras Mutations in Cancer. 
Cancer Research 72:2457-2467, 2012 
5. Berger MF, Hodis E, Heffernan TP, et al: Melanoma genome sequencing reveals 
frequent PREX2 mutations. Nature 485:502-506, 2012 
6. The Cancer Genome Atlas Research N: Comprehensive molecular characterization 
of human colon and rectal cancer. Nature 487:330-337, 2012 
7. The Cancer Genome Atlas Research N: Comprehensive molecular characterization 
of gastric adenocarcinoma. Nature 513:202-209, 2014 
8. Agrawal N, Akbani R, Aksoy BA, et al: Integrated Genomic Characterization of 
Papillary Thyroid Carcinoma. Cell 159:676-690, 2014 
9. The Cancer Genome Atlas Research N: Integrated genomic characterization of 
endometrial carcinoma. Nature 497:67-73, 2013 
10. The Cancer Genome Atlas Research N: Comprehensive molecular profiling of lung 
adenocarcinoma. Nature 511:543-550, 2014 
11. Cox AD, Fesik SW, Kimmelman AC, et al: Drugging the undruggable RAS: Mission 
Possible? Nat Rev Drug Discov 13:828-851, 2014 
12. Ohashi K, Sequist LV, Arcila ME, et al: Characteristics of Lung Cancers Harboring 
NRAS Mutations. Clinical Cancer Research 19:2584-2591, 2013 
13. Solit DB, Garraway LA, Pratilas CA, et al: BRAF mutation predicts sensitivity to MEK 
inhibition. Nature 439:358-362, 2006 
14. van Herpen C, Agarwala SS, Hauschild A, et al: LBA35 Overall survival and 
biomarker results from a phase 2 study of mek1/2 inhibitor binimetinib (mek162) in 
patients with advanced nras-mutant melanoma. Annals of Oncology 25, 2014 
15. Ascierto PA, Schadendorf D, Berking C, et al: MEK162 for patients with advanced 
melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-
label phase 2 study. Lancet Oncol 14:249-256, 2013 

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Molecular Analysis for Therapy Choice (MATCH) 
MATCH Treatment Subprotocol Z1A: Binimetinib/NRAS 
Appendix I 
 
Patient Pill Calendar 
 
Pill Calendar Directions 
1. Take your scheduled dose by mouth twice daily. Each dose should be taken 
approximately 12 hours apart. 
2. Missed or vomited doses should not be replaced. 
3. If you forget, the missed tablets will not be taken later. 
4. Please bring the empty bottle or any leftover tablets and your pill calendar to your 
next clinic visit. 
5. Each dose of binimetinib should be taken with a glass of water (with or without food). 
6. Binimetinib tablets should be swallowed whole. 
7. Store binimetinib at room temperature. 
 
 

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Patient Pill Calendar 
This is a calendar on which you are to record the time and number of tablets you take 
each day.  You should take your scheduled dose of each tablet. Note the times and the 
number of tablets that you take each day. If you develop any side effects, please 
record them and anything you would like to tell the doctor in the space provided.  Bring 
any unused tablets and your completed pill calendar to your doctor’s visits. 
Binimetinib 
DAY  
Date 
Time tablets 
taken 
Number of 
tablets taken 
Use the space below to make notes 
about things you would like to tell the 
doctor (including unusual symptoms 
you experience, other medicine you 
have taken and anything else you think 
would be of interest.) 
Month 
Day 
Year 
AM 
PM 
AM 
PM 
1 
 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
 
8 
 
 
 
 
 
 
 
 
9 
 
 
 
 
 
 
 
 
10 
 
 
 
 
 
 
 
 
11 
 
 
 
 
 
 
 
 
12 
 
 
 
 
 
 
 
 
13 
 
 
 
 
 
 
 
 
14 
 
 
 
 
 
 
 
 
15 
 
 
 
 
 
 
 
 
16 
 
 
 
 
 
 
 
 
17 
 
 
 
 
 
 
 
 
18 
 
 
 
 
 
 
 
 
19 
 
 
 
 
 
 
 
 
20 
 
 
 
 
 
 
 
 
21 
 
 
 
 
 
 
 
 
22 
 
 
 
 
 
 
 
 
23 
 
 
 
 
 
 
 
 
24 
 
 
 
 
 
 
 
 
25 
 
 
 
 
 
 
 
 
26 
 
 
 
 
 
 
 
 
27 
 
 
 
 
 
 
 
 
28 
 
 
 
 
 
 
 
 
Patient Signature: __________________________________ Date: _____________

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Molecular Analysis for Therapy Choice (MATCH) 
MATCH Treatment Subprotocol Z1A: Binimetinib/NRAS 
Appendix II 
 
Actionable Mutations for Sub-Protocol EAY131-Z1A 
 
Gene 
Variant ID 
Variant Description 
Level of Evidence 
Code 
NRAS 
COSM585 
p.Q61H 
2 
NRAS 
COSM586 
p.Q61H 
2 
NRAS 
COSM583 
p.Q61L 
2 
NRAS 
COSM584 
p.Q61R 
2 
NRAS 
COSM582 
p.Q61P 
2 
NRAS 
COSM581 
p.Q61E 
2 
NRAS 
COSM580 
p.Q61K 
2 
NRAS 
COSM574 
p.G13V 
3 
NRAS 
COSM575 
p.G13A 
3 
NRAS 
COSM573 
p.G13D 
3 
NRAS 
COSM570 
p.G13C 
3 
NRAS 
COSM569 
p.G13R 
3 
NRAS 
COSM571 
p.G13S 
3 
NRAS 
COSM566 
p.G12V 
2 
NRAS 
COSM565 
p.G12A 
3 
NRAS 
COSM564 
p.G12D 
2 
NRAS 
COSM562 
p.G12C 
3 
NRAS 
COSM561 
p.G12R 
3 
NRAS 
COSM563 
p.G12S 
3 

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Molecular Analysis for Therapy Choice (MATCH) 
MATCH Treatment Subprotocol Z1A: Binimetinib/NRAS 
Appendix III 
 
Patient Drug Information Handout and Wallet Card 
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements 
The patient ____________________________ is enrolled on a clinical trial using the 
experimental study drug, binimetinib. This clinical trial is sponsored by the National Cancer 
Institute.  This form is addressed to the patient, but includes important information for others 
who care for this patient.  
These are the things that you as a healthcare provider need to know: 
Binimetinib interacts with certain specific enzymes in your liver and certain transport proteins 
that help move drugs in and out of cells. 
• 
The enzymes in question are UGT1A1 and CYP 2B6. Binimetinib is broken down by 
UGT1A1 and may be affected by other drugs that inhibit or induce this enzyme. Binimetinib 
is a strong inhibitor of CYP 2B6 and may affect other drugs that are broken down by this 
enzyme. 
• 
The transport proteins in question are P-gp and BCRP. Binimetinib is moved in and out of 
cells/organs by these transport proteins and may be affected by inhibitors or inducers of P-
gp and BCRP. 
• 
Binimetinib is highly protein bound (97.2%).  Patients receiving other medications that are 
also highly protein bound may need to be monitored more frequently. 
• 
Drugs that are known to or may cause Torsades de Pointes or prolong QT interval should 
be used with caution. Patients taking these medications should be monitored frequently. 
To the patient: Take this paper with you to your medical appointments and keep the 
attached information card in your wallet. 
Binimetinib may interact with other drugs which can cause side effects. For this reason, it is 
very important to tell your study doctors of any medicines you are taking before you enroll onto 
this clinical trial.  It is also very important to tell your doctors if you stop taking any regular 
medicines, or if you start taking a new medicine while you take part in this study.  When you talk 
about your current medications with your doctors, include medicine you buy without a 
prescription (over-the-counter remedy), or any herbal supplements such as St. John’s Wort.  It 
is helpful to bring your medication bottles or an updated medication list with you. 
Many health care providers can write prescriptions.  You must tell all of your health care 
providers (doctors, physician assistants, nurse practitioners, pharmacists) you are taking part in 
a clinical trial. 
These are the things that you and they need to know: 
Binimetinib must be used very carefully with other medicines that use certain liver enzymes or 
transport proteins to be effective or to be cleared from your system.  Before you enroll onto the 
clinical trial, your study doctor will work with your regular health care providers to review any 
medicines and herbal supplements that are considered “strong inducers/inhibitors of UGT1A1, 

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inhibitors and inducers of P-gp and BCRP. Binimetinib inhibits CYP 2B6 and may change how 
other medicines work in your body. 
• 
Please be very careful!  Over-the-counter drugs (including herbal supplements) may contain 
ingredients that could interact with your study drug.  Speak to your doctors or pharmacist to 
determine if there could be any side effects.  
• 
You may need to be monitored more frequently if you are receiving other medications that 
are also highly protein bound, are known to or may cause Torsades de Pointes, or prolong 
QT interval. 
• 
Your regular health care provider should check a frequently updated medical reference or 
call your study doctor before prescribing any new medicine or discontinuing any medicine.  
Your study doctor’s name is 
Your study doctor’s name is 
_____________________________________ 
and he or she can be contacted at: 
_____________________________________. 
 
 
 
 
 
 
 
 
Binimetinib interacts with specific liver enzymes called 
UGT1A1, CYP 2B6, and transport proteins P-gp and BCRP, 
and must be used very carefully with other medicines that 
interact with these enzymes and transporters.  
 Before you enroll onto the clinical trial, your study doctor will 
work with your regular health care providers to review any 
medicines and herbal supplements that are considered 
“strong inducers/inhibitors of UGT1A1, or inhibitors and 
inducers of transporters P-gp and BCRP. Binimetinib 
inhibits CYP 2B6 and may change how other medicines 
work in your body.” 
 Before prescribing new medicines, your regular health care 
providers should go to a frequently-updated medical 
reference for a list of drugs to avoid, or contact your study 
doctor.   
 Your study doctor’s name is 
_____________________________ and can be contacted 
at _________________________________.  
STUDY DRUG INFORMATION WALLET CARD   
You are enrolled on a clinical trial using the experimental study 
drug binimetinib. This clinical trial is sponsored by the NCI.  
Binimetinib may interact with drugs that are processed by your 
liver, or use certain transport proteins in your body.  Because of 
this, it is very important to: 
 Tell your doctors if you stop taking any medicines or if you 
start taking any new medicines. 
 Tell all of your health care providers (doctors, physician 
assistants, nurse practitioners, or pharmacists) that you are 
taking part in a clinical trial. 
 Check with your doctor or pharmacist whenever you need to 
use an over-the-counter medicine or herbal supplement. 
 You may need to be monitored more frequently if you are 
receiving other medications that are also highly protein 
bound, are known to or may cause Torsades de Pointes, or 
prolong QT interval.