Phase 2 Trial of Fulvestrant and Binimetinib in Patients With Hormone Receptor-Positive Metastatic Breast Cancer With Inactivating or Inferred Inactivating NF1 Alterations: A ComboMATCH Treatment Trial
Phase: PHASE2
Conditions: Anatomic Stage IV Breast Cancer AJCC v8, Metastatic HER2-Negative Breast Carcinoma, Metastatic Hormone Receptor-Positive Breast Carcinoma
Sponsor: National Cancer Institute (NCI)

 
This protocol was designed and developed by NRG Oncology.  It is intended to be used only in 
conjunction with IRB approval for study entry.  No other use or reproduction is authorized by 
NRG Oncology nor does NRG Oncology assume any responsibility for unauthorized use of this 
protocol. 
 
EAY191-N2 
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NRG Oncology  
Four Penn Center 
1600 JFK BLVD Suite 1020  
Philadelphia, PA 19103 
Nrgoncology.org  
A ComboMATCH Treatment Trial  
EAY191-N2: PHASE 2 TRIAL OF FULVESTRANT AND BINIMETINIB IN 
PATIENTS WITH HORMONE RECEPTOR-POSITIVE METASTATIC 
BREAST CANCER WITH INACTIVATING OR INFERRED INACTIVATING 
NF1 ALTERATIONS 
ClinicalTrials.gov Identifier NCT05554354 
NCI Version Date: (February 12, 2024) 
 
Principal Investigator: 
Bora Lim, MD 
The University of Texas MD Anderson Cancer Center 
Department of Breast Medical Oncology 
1515 Holcombe Boulevard 
Unit 1354Houston, TX 77030 
713-792-2360 
Blim@mdanderson.org 
 
Participating Organizations 
ALLIANCE/Alliance for Clinical Trials in Oncology 
ECOG-ACRIN/ECOG-ACRIN Cancer Research Group 
SWOG/SWOG 
 
Participating Sites  
܈ U.S. 
܆ Canada  
܆ Approved International Member Sites 
܆ Limited Participation 
 
Protocol Agents: 
Agent 
Supply 
NSC# 
IND# 
IND Sponsor 
Binimetinib 
CTEP 
788187 
 
DCTD, NCI 
Fulvestrant 
Commercial 
719276 
N/A 
N/A 

 
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CANCER TRIALS SUPPORT UNIT CONTACT INFORMATION 
 
 
For regulatory requirements: 
For patient enrollments: 
For data submission: 
Regulatory documentation must 
be submitted to the Cancer 
Trials Support Unit (CTSU) via 
the Regulatory Submission 
Portal. 
(Sign in at 
https://www.ctsu.org, and select 
the Regulatory > Regulatory 
Submission.) 
Institutions with patients 
waiting that are unable to use 
the Portal should alert the 
CTSU Regulatory Office 
immediately by phone or email: 
1-866-651-CTSU(2878), or 
CTSURegHelp@coccg.org to 
receive further instruction and 
support. 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-CTSU 
(2878), or 
CTSURegHelp@coccg.org for 
regulatory assistance. 
Refer to the patient 
enrollment section of the 
protocol for instructions on 
using the Oncology Patient 
Enrollment Network 
(OPEN).  OPEN is accessed 
at https://www.ctsu.org/ 
OPEN_SYSTEM/ or 
https://OPEN.ctsu.org. 
Contact the CTSU Help 
Desk with any OPEN 
related questions by phone 
or e-mail: 1-888-823-5923, 
or ctsucontact@westat.com. 
Data collection for this study 
will be done exclusively 
through Medidata Rave.  
Refer to the data submission 
section of the protocol for 
further instructions. 
The most current version of the study protocol and all supporting documents must be 
downloaded from the protocol-specific page located on the CTSU members’ website 
(https://www.ctsu.org).   
Permission to view and download this protocol and its supporting documents is restricted and 
is based on person and site roster assignment housed in the Roster Maintenance application 
and in most cases viewable and manageable via the Roster Update Management System 
(RUMS) on the CTSU members’ website. 
For clinical questions (i.e., patient eligibility or treatment-related), contact the Clinical 
Coordinating Department at NRG Oncology at 1-800-477-7227 or by email at 
ccdPGH@NRGOncology.org. 
For non-clinical questions (i.e., unrelated to patient eligibility, treatment, or clinical data 
submission)  
Contact the CTSU Help Desk by phone or email: 
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com.  All calls and 
correspondence will be triaged to the appropriate CTSU representative. 

 
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TABLE OF CONTENTS 
Cancer Trials Support Unit Contact Information ..................................................................4 
 
1. 
OBJECTIVES ............................................................................................................................9 
1.1 
Primary Objective ....................................................................................................9 
1.2 
Secondary Objectives ...............................................................................................9 
1.3 
Exploratory Biomarker Objective ............................................................................9 
2. 
BACKGROUND .....................................................................................................................10 
2.1 
Hormone Receptor-Positive Metastatic Breast Cancers ........................................10 
2.2 
NF1 Loss Correlates with Poor Patient Outcome in ER+ Breast Cancer ..............10 
2.3 
NF1 Depletion Globally Enhances ER Transcriptional Activity, and the  
Survival Differs Between Types of Mutations ......................................................12 
2.4 
SERD Activity Against NF1 Loss HR+ Positive Breast Cancers and Synergistic 
Tumor Growth Inhibition of Combination Therapy (SERD + MEK inhibitor) ....14 
2.5 
Single-Agent Activity of Fulvestrant and Binimetinib ..........................................15 
3. 
ELIGIBILITY AND INELIGIBILITY CRITERIA ................................................................17 
3.1 
Eligibility Criteria ..................................................................................................17 
3.2 
Ineligibility Criteria ...............................................................................................18 
3.3 
Eligibility Criteria for Cohort 1, Treatment Regimen 2 Patients who Migrate  
to Cohort 2 .............................................................................................................19 
3.4 
Ineligibility Criteria for Cohort 1, Treatment Regimen 2 Patients who Migrate  
to Cohort 2 .............................................................................................................20 
3.5 
Inclusion of Women and Minorities ......................................................................20 
4. 
REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP ................21 
4.1 
Pre-Treatment Assessment .....................................................................................21 
4.2 
Assessments During Treatment .............................................................................23 
4.3 
Assessments in Follow-Up ....................................................................................25 
5. 
TREATMENT PLAN/REGIMEN DESCRIPTION ................................................................26 
5.1 
Fulvestrant/Binimetinib Therapy ...........................................................................26 
5.2 
General Concomitant Medication and Supportive Care Guidelines ......................27 
5.3 
Duration of Therapy ...............................................................................................28 
6. 
TREATMENT MODIFICATIONS/MANAGEMENT ...........................................................29 
6.1 
Dose Modifications ................................................................................................29 
6.2 
Management of Binimetinib Treatment-Related Events .......................................30 
6.3 
Management of Fulvestrant Treatment-Related Events ........................................32 
7. 
ADVERSE EVENTS REPORTING REQUIREMENTS .......................................................33 
7.1 
Protocol Agents ......................................................................................................33 
7.2 
Adverse Event Reporting Requirements ................................................................33 
7.3 
Adverse Events and Serious Adverse Events ........................................................33 
7.4 
Comprehensive Adverse Events and Potential Risks (CAEPR) List for 
Binimetinib (NSC 788187) ....................................................................................34 
7.5 
Adverse Events for Commercial Study Agent (Fulvestrant) .................................38 
7.6 
Expedited Reporting of Adverse Events ................................................................38 
7.7 
Routine Reporting Requirements for Adverse Events ...........................................41 
7.8 
Pregnancy ...............................................................................................................41 
8. 
REGISTRATION AND STUDY ENTRY PROCEDURES ...................................................43 

 
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8.1 
Cancer Trials Support Unit Registration Procedures .............................................44 
8.2 
Patient Enrollment .................................................................................................46 
9. 
DRUG INFORMATION .........................................................................................................49 
9.1 
Investigational Study Agent: Binimetinib (MEK162, ARRY-438162) (NSC# 
788187, IND
) ...........................................................................................49 
9.2 
Commercial Agent: Fulvestrant .............................................................................52 
10. PATHOLOGY/BIOSPECIMEN .............................................................................................53 
10.1 
Biomarker Testing .................................................................................................53 
10.2 
Specimen collection and submission .....................................................................55 
10.3 
Kit information for collections ...............................................................................56 
11. SPECIAL STUDIES (NON-TISSUE) NOT APPLICABLE ..................................................57 
12. CENTRAL QUALITY/ENDPOINT REVIEWS NOT APPLICABLE ..................................57 
13. ASSESSMENT OF DISEASE STATUS ................................................................................58 
13.1 
Definition ...............................................................................................................58 
13.2 
Disease Parameters ................................................................................................58 
13.3 
Response Criteria ...................................................................................................60 
13.4 
Evaluation of Best Overall Response ....................................................................61 
13.5 
Symptomatic Deterioration ....................................................................................62 
13.6 
Duration of Response .............................................................................................62 
13.7 
Progression-Free Survival ......................................................................................63 
14. DATA AND RECORDS .........................................................................................................64 
14.1 
Data Management/Collection ................................................................................64 
14.2 
Summary of Data Submission ...............................................................................65 
14.3 
Rave-CTEP-AERS Integration ..............................................................................65 
14.4 
Data Quality Portal ................................................................................................66 
14.5 
Global Reporting/Monitoring ................................................................................67 
15. STATISTICAL CONSIDERATIONS.....................................................................................68 
15.1 
Abstract ..................................................................................................................68 
15.2 
Primary Endpoints .................................................................................................68 
15.3 
Secondary Endpoints .............................................................................................68 
15.4 
Randomization and Stratification ..........................................................................68 
15.5 
Patient Population for Analysis .............................................................................69 
15.6 
Primary Endpoint(s), Sample Size, and Analysis Plan ..........................................69 
15.7 
Analysis Plan .........................................................................................................70 
15.8 
Monitoring/Oversight Committee ..........................................................................71 
15.9 
Project Optimus Contingency ................................................................................73 
15.10 
Gender/Ethnicity/Race Distribution .......................................................................73 
16. REFERENCES ........................................................................................................................74 
Appendix A 
Assessment of Performance Status and Activities of Daily Living .......................76 
Appendix B 
CTEP Collaborative Agreements Language ..........................................................77 
Appendix C 
Exploratory Biospecimen Research .......................................................................79 
Appendix D 
Research Biospecimen Submission Guidelines .....................................................82 
Appendix E 
Medication Diary ...................................................................................................86 
Appendix F 
Patient Clinical Trial Wallet Card ..........................................................................90 
 

 
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A ComboMATCH Treatment Trial EAY191-N2 Schema ................................................................8 
Figure 1. 
NF1 loss promotes tamoxifen agonism and E2 hypersensitivity leading  
to poor patient outcome in HR+ breast cancer ......................................................11 
Figure 2. 
NF1 depletion globally enhances ER transcriptional activity ................................13 
Figure 3. 
NF1 Loss of Function Mutations Drive Poor Outcomes. ......................................14 
Figure 4. 
Co-targeting Ras and ER to treat NF1-Deficient ER+ Breast Cancer. ..................15 
 
Table 1. 
Pre-treatment assessments .....................................................................................21 
Table 2. 
Assessments during treatment ................................................................................23 
Table 3. 
Dose levels for binimetinib (Cohort 1, Treatment Regimen 1 or Cohort 2) ..........29 
Table 4. 
Dose modifications for binimetinib .......................................................................30 
Table 5. 
Comprehensive Adverse Events And Potential Risks (CAEPR) List for 
Binimetinib ............................................................................................................34 
Table 6. 
Late Phase 2 and Phase 3 Studies: Expedited reporting requirements for  
adverse events that occur on studies under an IND within 30 days of the last 
administration of the investigational agent (binimetinib) and/or commercial  
agent (fulvestrant) ..................................................................................................40 
Table 7. 
Biomarker table ......................................................................................................53 
Table 8. 
Specimen collection ...............................................................................................56 
Table 9. 
Time point response: patients with target (r non-target) disease ..........................62 
Table 10. 
Time point response: patients with non-target disease only ..................................62 
 
 
 

 
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A ComboMATCH Treatment Trial EAY191-N2 SCHEMA 
 
 
 
 
For Cohort 1, randomization is 1:1. 
 
Table of Abbreviations 
NF1 
 
 
Neurofibromin type 1 
 
 

 
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1. 
OBJECTIVES 
1.1 
Primary Objective 
Cohort 1: To determine whether the combination of fulvestrant and binimetinib improves 
progression-free survival (PFS) compared to treatment with fulvestrant alone in patients 
not previously treated with fulvestrant. 
Cohort 2: To determine whether overall response rate (ORR) within 4 months in patients 
who have previously progressed on a fulvestrant-containing regimen is greater than 10%, 
as a historical comparison, when these patients receive combination fulvestrant and 
binimetinib therapy.  
1.2 
Secondary Objectives 
1.2.1 To estimate ORR at any time after the start of the treatment for Cohort 2 and separately 
for the two arms in Cohort 1. 
1.2.2 To estimate PFS distribution in Cohort 2. 
1.2.3 To estimate clinical benefit rate separately for the two arms in Cohort 1 and Cohort 2. 
1.2.4 To determine the safety and toxicity profile in both cohorts. 
1.2.5 To estimate the overall survival (OS) in both cohorts. 
1.2.6 Collect tissue and provide it to the ComboMATCH Registration Protocol to assess 
concordance between the diagnostic tumor mutation profile generated by the Designated 
Laboratories, the pre-treatment biopsy mutation profile, and the pre-treatment ctDNA 
mutation profile from plasma, as described in ComboMATCH Registration Protocol.  For 
this treatment substudy, the outcome objective will be to report the proportion of cases 
providing sufficient tissue for that integrated scientific activity in the ComboMATCH 
Registration Protocol. 
1.3 
Exploratory Biomarker Objective 
1.3.1 To analyze the cfDNA at progression to determine the changes in cfDNA profile in order 
to understand blood-based mutation dynamics. 
1.3.2 To analyze RNAseq at progression to determine potential pathways that are altered that 
may contribute to the sensitivity/resistance. 
1.3.3 To discover/detect novel biomarkers using microscaled proteogenomics by analyzing the 
proteins and phosphor-proteins along with genomics to determine potential pathways that 
may correlate with the response to the combination treatment. 
1.3.4 To detect the loss of NF1, using immunohistochemistry staining to precisely measure the 
level of the NF1 protein. 
1.3.5 To determine the variant allele frequency (VAF) of mutant NF1 measuring by using 
droplet digital polymerase chain reaction (ddPCR) for the targeted NF1 gene level. 
 
 

 
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2. 
BACKGROUND 
2.1 
Hormone Receptor-Positive Metastatic Breast Cancers 
Approximately 80% of breast cancers are positive for estrogen receptor-α (ER+), a 
ligand-dependent transcription factor that is activated by estradiol (E2) (Feng 2014).  The 
E2-liganded ER recruits co-activators (such as steroid-receptor co-activators, SRC-1-3) to 
estrogen-responsive elements (EREs) in ER-regulated genes.  Tamoxifen, a selective ER 
modulator (SERM), is predominantly antagonistic in breast cancer cells, hence its 
therapeutic effect.  When tamoxifen binds to ER, co-activators are displaced by 
corepressors in the ER- ERE complex (Shang 2000).  Established ER corepressors bind 
ER via their leucine/isoleucine-rich motifs, and substitutions of L or I with an A can 
disrupt binding (Hu 1999).  Interactions are also mediated by electrostatic interactions 
(Heldring 2007, Shiau 1998).  Despite the development of novel therapeutics such as 
CDK 4/6 inhibitors, cancers eventually develop resistance to endocrine therapy, leading 
to breast-cancer-caused mortality.  There is a great need for novel ways to target this 
emerging resistance to endocrine therapy. 
2.2 
NF1 Loss Correlates with Poor Patient Outcome in ER+ Breast Cancer 
While NF1 mutation frequencies are low in primary ER+ breast cancer (2% in TCGA 
[TCGA, 2014], as shown in Figure 1A, and 4% in the patient cohort investigated by the 
Baylor College of Medicine [BCM] researchers [Griffith 2018]), NF1 mutation frequency 
is higher in metastatic ER+ breast cancer patients (n = 535) (Lanman 2015, Zill 2018).  
Neurofibromin (NF), a tumor suppressor and Ras-GAP (GTPase-activating protein), is 
also an estrogen receptor-α (ER) transcriptional corepressor through leucine/isoleucine-
rich motifs that are functionally independent of GAP activity.  However, GAP activity, in 
turn, does not affect ER binding of NF1.  Similar enrichment of NF1 mutations in 
metastatic hormone receptor (HR)-positive breast cancer has been reported by others 
(TCGA 2014, Bertucci 2019, Meric-Bernstam 2014, Pearson 2020, Razavi 2018).  These 
observations suggest that somatic NF1 events are an essential class of mutations causing 
breast cancer progression. 
To investigate the consequences of NF1 depletion on ER+ breast cancer, MCF-7 ER+ 
breast cancer cells were engineered to harbor lentiviruses expressing one of two 
doxycycline (DOX)-inducible small hairpin RNA (shRNA) clones (C5 and C6).  Upon 
DOX addition (+DOX), NF1 protein levels were reduced by ~70% as detected by a 
monoclonal antibody (mAb) raised by BCM investigators.  Remarkably, when NF1 
expression was suppressed (+DOX) in MCF-7 cells as well as in two more ER+ breast 
cancer cell lines—ZR-75B and T47D—in vitro growth was consistently stimulated by  
4-hydroxy-tamoxifen (4-OHT) under E2-deprived conditions (charcoal-stripped serum) 
(Figure 1D), in comparison with the non-silenced control (–DOX) or the scrambled 
shRNA +DOX control, indicating an NF1-loss-mediated transition from 4-OHT 
antagonism to agonism.  Furthermore, NF1-silenced cells proliferated at lower 
concentrations of E2 than controls, and higher E2 concentrations paradoxically inhibited 
cell growth, indicating E2 hypersensitivity (Figure 1E).  Two pools of NF1 ‘‘knockout’’ 
(KO) MCF-7 cells were independently created by CRISPR-Cas9 with results similar to 
the shRNA data (Figures 1D and 1E). 

 
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MDA-MB-231 cells are ER–, and NF1 expression is barely detectable (Sokol 2019) due 
to a frameshift mutation (NF1-T467fs) (Ogata 2001).  These NF1 low cells were 
unresponsive to 4-OHT or E2, which was validated by 4-OHT agonism in an MCF-7-
based xenograft mouse model, when NF1 is silenced (Figure 1F, left).  Interestingly, 
these tumors grew better than control tumors even at a lower dose of E2 (0.05 mg dose) 
(Figure 1F, right). 
Figure 1.  NF1 loss promotes tamoxifen agonism and E2 hypersensitivity leading to 
poor patient outcome in HR+ breast cancer 
 
Figure1. NF1LossPromotesTamoxifenAgonism andE2HypersensitivityLeadingtoPoorPatient
OutcomeinHR+BreastCancer
(A) The percentages of ER+ primary versus metastatic breast cancers carrying NF1 mutations were analyzed by Fisher’s exact test.
NS and FS stand for nonsense and frameshift, respectively. The number of patients carrying a particular type of NF1 mutation is 
shown at the upper left side of each column. (B) Boxplot analysis of NF1 mRNA levels in ER+ breast tumors carrying different NF1
mutations in the RNA-seq database of TCGA. p value by Wilcoxon rank-sum test. The line in the middle of the box is the median. 
The box edges are the 25th and 75th percentiles and the whiskers denote 1.5 times the interquartile range. (C) Patient samples 
were stratified by NF1 mRNA levels according to TCGA definitions of high versus low expression (mean, 1.5 3 SD). The boxplot 
analysis was similarly performed as in (B) to compare multigene proliferation score (MGPS) in tumors before treatment (BT) and 
on treatment (OT) with AI. The differences in MGPS before and during treatment in each NF1 group were analyzed by the 
Wilcoxon signed-rank test. The differences in MGPS as a result of treatment between the two NF1 groups were further analyzed 
by Wilcoxon rank-sum test. (D) DOX-inducible gene silencing using NF1 shRNA clone C5 and CRISPR-mediated NF1-KO were 
performed in MCF-7 cells. These cells were seeded in E2- deprived medium, to which 4-OHT was added, and cultured for 6 days. 
Cell numbers relative to vehicle control are plotted. Experiments were conducted as biological triplicates (n = 3 experiments), 
except for MCF-7 cells carrying NF1 shRNA C5 (n = 8 experiments). (E) Cell growth in response to E2 was similarly analyzed as in
(D). n = 3 experiments, except for MCF-7 cells carrying NF1 shRNA C5 (n = 8 experiments). (F) MCF-7 cells carrying DOX-inducible
NF1 shRNA were transplanted into the mammary fat pads of ovariectomized nude mice, supplemented by an E2 capsule. When 
tumors appeared, the original E2 capsule was removed, and the resulting mice were randomized, DOX or vehicle treated. Each set 
was then treated by either tamoxifen (5 mg/mouse, left), or E2 (at two doses, middle). For NF1+ (–DOX) tumors, n = 10, 12, 12, 
and 8 mice per group for treatment of vehicle, 0.05 mg E2, 0.5 mg E2, and tamoxifen; for NF1KD (+DOX) tumors, n = 10, 13, 11,
and 8 mice per group. The inset shows NF1-silencing validation by qPCR 2 weeks post-DOX addition. On the far right, ‘‘D tumor 
volumes’’ between vehicle and either tamoxifen or E2 treated were analyzed by boxplot as in (C). Data are reported as mean ±
SEM. *p < 0.05, **p < 0.01 by pairwise two-tailed Student’s t test, unless otherwise indicated.

 
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2.3 
NF1 Depletion Globally Enhances ER Transcriptional Activity, and the Survival 
Differs Between Types of Mutations 
Because the abnormal E2 and tamoxifen responses observed in NF1-depleted cells are 
ER dependent, BCM researchers investigated whether NF1 depletion affects ER-
dependent transcription.  To examine the effects of NF1 on gene expression in a genome-
wide fashion, RNA sequencing (RNA-seq) experiments were performed in control  
(–DOX) and NF1 knockdown (+DOX, KD) MCF-7 cells with and without E2 
stimulation.  Overall, E2 altered expression from 540 genes in the control NF1+ cells and 
955 genes in NF1KD cells (Figure 2A).  Aside from a predominance of additional E2-
regulated genes, a K-Ras-dependent gene expression signature was also observed (Figure 
2A).  To determine whether the E2-induced gene expression patterns shown in Figure 2A 
could be replicated in patient samples, differentially expressed genes according to NF1 
status (with or without NF1 nonsense/frameshift mutation) METABRIC and TCGA ER+ 
datasets were identified, and pathway enrichments were similarly assessed.  The results 
were compared with the two MCF-7 E2-regulons described above.  Supporting the 
conclusion that NF1 depletion dramatically affects the expression of E2-responsive genes 
in clinical ER+ specimens, E2-responsive pathway terms were most significantly 
modulated by NF1 mutation status, followed by the K-Ras signature (Figure 2B).  Next, 
it was determined that neurofibromin can interact with ER via an ER-binding motif that is 
independent of Ras/GAP activity.  The Ras-Raf signaling was not critical for estrogen-
sensitive HR+ breast cancer cells or the ER-dependent gene expressions.  Among two 
commonly clinically observed corepressor motifs, I417M (coexisted with NF1 nonsense 
mutation as the biallelic event) and R1362Q (located in GAP domain, increased NF1 gain 
of expression by mutation), the I417M motif mutation increased the level of estrogen-
responsive genes, regardless of Ras-Raf inhibition by MEK inhibitor treatments but not 
R1362Q (Figure 2A).  This finding suggested that the estrogen hypersensitivity mediated 
by NF1 is not dependent on the interaction with GAP.  In light of all of this, NF1 loss 
should be considered an attractive therapeutic target in ER+ breast cancer—always 
keeping in mind, however, that not all the mutations are the same.   
 
 

 
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Figure 2.  NF1 depletion globally enhances ER transcriptional activity 
Previously, BCM researchers showed the survival data from the patient samples using the 
UBC-TAM study (Griffith 2018) that only nonsense/frameshift mutation without 
interaction with GAP but causing the loss of NF1 activity, was associated with worse 
survival outcomes (Figure 3).  
 
Figure2. NF1depletiongloballyenhancesERtranscriptionalactivity
(A) RNA-seq was performed on NF1+ or NF1KD MCF-7 cells treated with E2 or vehicle. A 
Venn diagram depicts the number of E2-mediated differentially expressed genes in 
NF1+ (red), NF1KD cells (blue), and those that overlap (common E2-regulon, purple). The 
common E2-regulon genes identified in NF1+ and NF1KD cells were ranked by (Log2) fold-
change in gene expression, and enrichment for Hallmark Pathways by GSEA is shown to the 
right (red line marks a false discovery rate cutoff at 0.05). GSEA analysis was also performed 
to examine Hallmark Pathways selectively enriched in NF1KD cells (“NF1KD unique E2-
regulon”). (B) Genes identified in (A) were examined in the TCGA and METABRIC ER+ breast 
cancer cases to identify those genes that are differentially expressed between tumors with 
wild-type NF1 and NF1 frameshift/nonsense mutations. The enriched Hallmark Pathways in 
the patient data are presented along with the results of the two E2-regulons identified in 
MCF-7 cells.

 
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Taken together, BCM researchers designed this exciting finding into a Phase 2 Trial of 
Fulvestrant and Binimetinib in Patients with HR-Positive Metastatic Breast Cancer with 
inactivating or inferred inactivating NF1 alterations.  
The benefiting target patients will be determined by identifying the mutation of NF1 that 
leads to the loss of the function of NF1.  This novel fulvestrant and binimetinib 
combination will be studied in patients with metastatic HR positive breast cancer, with 
known/confirmed neurofibromin loss by inactivating or inferred inactivating NF1 
alterations. 
 
 

 
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3. 
ELIGIBILITY AND INELIGIBILITY CRITERIA 
Notes: Per NCI guidelines, exceptions to inclusion and exclusion criteria are not 
permitted.  For questions concerning eligibility, please contact the Clinical Coordinating 
Department (CCD). 
Patients who meet the eligibility and ineligibility criteria and are fulvestrant-naïve will 
be randomized after registration to receive either fulvestrant and binimetinib or 
fulvestrant alone. 
3.1 
Eligibility Criteria 
A patient cannot be considered eligible for this study unless ALL of the following 
conditions are met. 
A ComboMATCH Treatment Trial EAY191 Eligibility Criteria 
3.1.1 The patient must be enrolled on the ComboMATCH Master Registration Trial EAY191. 
Note: Patients must fulfill all eligibility criteria outlined in Section 3 of the 
ComboMATCH Registration Trial EAY191 at the time of registration to EAY191-N2.  
This includes submission of NGS data from one of the NCI credentialed Designated 
laboratories for all potential patients prior to treatment trial assignment.  Copy number 
and allele frequency cutoff as per the Registration Protocol. 
3.1.2 Patients must have disease that can be safely biopsied and agree to a pre-treatment biopsy 
or, if disease cannot be safely biopsied, have archival tissue available from within 12 
months prior to the date of registration on the ComboMATCH Registration Trial 
(EAY191). 
Please note the current actionable marker of interest (aMOI)/actionable alteration list for this 
treatment trial can be found on the CTSU ComboMATCH Registration Protocol page. 
Please note novel/Dynamic aMOI can be submitted for review per the process described in the 
ComboMATCH Registration Protocol. 
A ComboMATCH Treatment Trial EAY191-N2 Eligibility Criteria 
3.1.3 The patient or a legally authorized representative must provide study-specific informed 
consent prior to study entry and, for patients treated in the U.S., authorization permitting 
release of personal health information. 
3.1.4 Age ≥ 18. 
3.1.5 ECOG performance status 0-2 (see Appendix A). 
3.1.6 Histologically or cytologically confirmed invasive breast carcinoma. 
3.1.7 Confirmed metastatic disease by either imaging or tissue diagnosis. 
3.1.8 Measurable disease by RECIST 1.1 and one additional lesion that can be biopsied 
(primary, metastatic both allowed). 
3.1.9 Patients must have inactivating or inferred inactivating NF1 alterations detected in tumor 
as determined by the ComboMATCH screening assessment. 

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3.1.10 The tumor must have been determined to be ER and/or PgR positive assessed by current 
ASCO/CAP Guideline Recommendations for hormone receptor testing.  Patients with 
≥1% ER or PgR staining by IHC are considered positive.
3.1.11 The tumor must have been determined to be HER2-negative by current ASCO/CAP 
guidelines.
3.1.12 Prior therapy:
x
Prior use of CDK4/6i is required.
x
Prior use of fulvestrant regardless of duration.is allowed and will determine treatment 
assignment.  
x
Up to one line of chemotherapy in metastatic setting is allowed.
3.1.13 Adequate hematologic function defined as follows:
x
Absolute neutrophil count ≥1,500/mm3
x
Platelet count ≥100,000/ mm3
x
Hemoglobin level ≥10 g/dL
3.1.14 Adequate renal function defined as:
Creatinine clearance (CrCL) of ≥30 mL/min by the Cockcroft-Gault formula.
CrCl (mL/min) = 
[140 – age (years)] x weight (kg)
{x 0.85 for female patients}
72 x creatinine (mg / dL)
3.1.15 Adequate hepatic function defined as follows:
x
Total bilirubin level ≤institutional upper limit of normal.
x
AST and ALT must be ≤5.0 x ULN.
3.1.16 For patients who will be assigned to Cohort 2 (fulvestrant-resistant), a LVEF assessment 
must be performed within 12 weeks prior to registration.  The LVEF must be ≥ 50% 
regardless of the cardiac imaging facility’s lower limit of normal. (LVEF assessment 
performed by echocardiogram is preferred; however, MUGA scan may be substituted 
based on institutional/situational preferences.)  
3.1.17 Patients with a prior or concurrent malignancy whose natural history or treatment does 
not have the potential to interfere with the safety or efficacy assessment of the 
investigational regimen are eligible for this trial.
3.1.18 HIV-infected patients on effective anti-retroviral therapy with undetectable viral load 
within 6 months of registration are eligible for this trial.
3.2
Ineligibility Criteria
Patients with any of the following conditions are NOT eligible for this study.
3.2.1
Concurrent anticancer therapy.
3.2.2
Active autoimmune disease requiring systemic treatment within the past 3 months, 
documented history of clinically severe autoimmune disease, or a syndrome that requires 
systemic steroids or immunosuppressive agents. 

 
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3.2.3 Active brain metastasis.  Brain metastases that have been stable for at least 1 month after 
completion of treatment are not an exclusion criterion. 
3.2.4 History of or evidence of retinal pathology on ophthalmologic examination that is 
considered a risk factor for neurosensory retinal detachment/central serous, 
chorioretinopathy (CSCR), retinal vein occlusion (RVO), or neovascular macular 
degeneration. 
3.2.5 Patients will be excluded if they currently have the following risk factors for RVO that 
are documented prior to the enrollment: 
x Known uncontrolled glaucoma with intra-ocular pressures ≥ 21 mmHg. 
x Known serum cholesterol ≥ Grade 2. 
x Known hypertriglyceridemia ≥ Grade 2. 
x Known hyperglycemia (fasting) ≥ Grade 2. 
3.2.6 Cardiac history: 
x Patients with baseline QTc > 500 ms, either induced by medication or congenital long 
QT syndrome will be excluded due to known side effects of binimetinib. 
x Patients with known history or current symptoms of cardiac disease, or history of 
treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac 
function using the New York Heart Association Functional Classification.  To be 
eligible for this trial, patients should be class 2B or better. 
3.2.7 Nervous system disorder (paresthesia, peripheral motor neuropathy, or peripheral sensory 
neuropathy) ≥ Grade 2. 
3.2.8 Any other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that 
contraindicates the use of an investigational drug or that may affect the interpretation of 
the results or render the patient at high risk from treatment complications. 
3.2.9 Other conditions that, in the opinion of the investigator, would preclude the patient from 
meeting the study requirements or interfere with interpretation of study results. 
3.2.10 Pregnancy or lactation at the time of registration or intention to become pregnant during 
the study.  (Note: Pregnancy testing according to institutional standards for patients of 
childbearing potential.) 
x For binimetinib, highly effective contraception should be used for at least 30 days 
after the last dose, and patients should not breastfeed for 3 days after the last dose. 
x For fulvestrant, highly effective contraception should be used for 1 year after the last 
dose, and patients should not breastfeed for 1 year after the last dose. 
3.2.11 Use of any investigational product within 30 days prior to study entry. 
3.3 
Eligibility Criteria for Cohort 1, Treatment Regimen 2 Patients who Migrate to 
Cohort 2 
Cohort Migration 
Patients treated with control treatment fulvestrant who experience disease progression 

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may be eligible to migrate to Cohort 2 and receive combination treatment with 
binimetinib and fulvestrant.  Patients who choose to do so must meet laboratory values 
and performance status requirements below and should begin treatment within 28 days.
3.3.1
Patient’s willingness to migrate to Cohort 2 affirmed.
3.3.2
The patient must have an ECOG performance status of 0-2 (see Appendix A).
3.3.3
Adequate hematologic function defined as follows:
x
Absolute neutrophil count ≥1,500/mm3
x
Platelet count ≥100,000/ mm3
x
Hemoglobin level ≥10 g/dL
3.3.4
Adequate hepatic function  defined as follows:
x
Total bilirubin level ≤institutional upper limit of normal (ULN).
x
AST and ALT must be ≤5.0 x ULN.
3.3.5
Adequate renal function defined as:
Creatinine clearance (CrCL) of ≥30 mL/min by the Cockcroft-Gault formula.
CrCl (mL/min) =
[140 – age (years)] x weight (kg)
{x 0.85 for female patients}
72 x creatinine (mg / dL)
3.3.6
A LVEF performed within the last 3 months must be ≥ 50% regardless of the cardiac 
imaging facility’s lower limit of normal.  (LVEF assessment performed by 
echocardiogram is preferred; however, MUGA scan may be substituted based on 
institutional/situational preferences.).  
3.3.7
Pregnancy test according to institutional standards must be negative (for patients of 
childbearing potential only).
3.4
Ineligibility Criteria for Cohort 1, Treatment Regimen 2 Patients who Migrate to 
Cohort 2
3.4.1
Not a candidate for binimetinib in the opinion of the treating investigator.
3.5
Inclusion of Women and Minorities
NIH policy requires that women and members of minority groups and their 
subpopulations be included in all NIH-supported biomedical and behavioral research 
projects involving NIH-defined clinical research unless a clear and compelling rationale 
and justification establishes to the satisfaction of the funding Institute & Center (IC) 
Director that inclusion is inappropriate with respect to the health of the subjects or the 
purpose of the research.  Exclusion under other circumstances must be designated by the 
Director, NIH, upon the recommendation of an IC Director based on a compelling 
rationale and justification.  Cost is not an acceptable reason for exclusion except when 
the study would duplicate data from other sources.  Women of childbearing potential 
should not be routinely excluded from participation in clinical research.  Please see 
http://grants.nih.gov/grants/funding/phs398/phs398.pdf.

 
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4. 
REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP 
4.1 
Pre-Treatment Assessment 
Table 1.  Pre-treatment assessments 
Assessments 
See Section 10 for Biospecimen 
Submission Information 
Prior to Registration on 
EAY191-N2 
Prior to Treatment 
(within 3 calendar 
days) 
(Cycle 1, Day 1) 
Consent form signed by the patient 
X 
 
Central NF1 testing results 
(determined by ComboMATCH 
screening assessment) 
X 
 
Confirm any known documentation of 
risk factors for RVO (see 3.2.4)a 
X 
 
History and physical examb 
X 
Within 4 weeks 
X 
Performance status (see Appendix A)l 
X 
 
Height and weight 
X 
 
Assessment of BP  
X 
X 
Assessment of concomitant 
medicationsc 
X 
X 
CBC/differential/platelet countl 
X 
Within 14 days 
X 
Total bilirubin/AST/ALT/alkaline 
phosphatasel 
X 
X 
Calcium, fasting blood glucose, 
albumin, sodium, potassiuml 
X 
X 
Tumor markersd 
X 
X 
Creatinine clearance l 
X 
X 
Pregnancy teste,j 
X 
X 
Echocardiogram (or MUGA scan)f,l 
X 
X 
Within 12 weeks 
for patients in 
Cohort 2 
X 
Within 12 weeks for 
patients in Cohort 1, 
Treatment Regimen 1) 
12-Lead ECG (if clinically indicated)g 
X 
Within 12 weeks 
 
Imaging of chest/abdomen/pelvish  
X 
Within 5 weeks 
 
Bone scani 
X 
 
Neuroimagingj 
X 
 
Table continued on next page. 
 

 
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Table 1.  Pre-treatment assessments (continued) 
Assessments 
See Section 10 for Biospecimen 
Submission Information 
Prior to Registration on 
EAY191-N2 
Prior to Treatment 
(within 3 calendar days) 
(Cycle 1, Day 1) 
Submission of fresh tumor core 
biopsy OR archival FFPE if within 
12 months of registration on the 
ComboMATCH Registration Trial 
(EAY191)k 
 
X 
(if submitting fresh tumor 
core biopsy 
Submission of whole blood for 
cfDNA, WES, and NF1 VAFk 
 
X 
(After registration before 
treatment begins) 
a While the known risk factors of RVO including previously documented glaucoma are exclusion 
criteria, eye exams and blood tests to identify risk factors for RVO will be conducted as clinically 
indicated (physician discretion) and are not required by the study. 
b History and physical by a physician or other healthcare professional. 
c 
Include all prescribed and over-the-counter medications, supplements, herbal therapies (see Section 
5.2.1). 
d Tumor marker testing is not a study requirement.  The results of tumor markers (e.g., CA15-3, 
CEA, CA27.29) will be collected if they are ordered as part of standard care. 
e 
For patients of childbearing potential: Pregnancy testing should be performed according to 
institutional standards prior to registration. 
f 
Patients in Cohort 2 must have a LVEF ≥ 50% as stated in the binimetinib package insert prior to 
registration.  Patients in Cohort 1 who are randomized to Treatment Regimen 1 must have a LVEF 
≥ 50% as stated in the binimetinib package insert prior to starting treatment.  Echocardiogram is 
the preferred method for assessment of LVEF.  However, LVEF assessment by MUGA scan is 
permitted.  All subsequent LVEF assessments should be performed by the same method 
(echocardiogram or MUGA scan) that was performed at baseline. 
g ECGs will be conducted as clinically indicated and are not mandated. 
h The same method (CT or MRI) used for baseline tumor measurements should be used at all other 
tumor measurement time points.  If patient is unable to receive CT contrast, an MRI of the 
abdomen/pelvis and non-contrast chest CT should be performed.  PET/CT is not an acceptable 
alternative contrast enhanced imaging method. 
i 
If PET/CT was previously performed within the 5 weeks prior to registration and demonstrated no 
evidence of bone metastases, baseline bone scan is recommended but not required. 
j 
MRI of the brain (or contrast CT scan of the brain if patients are unable to undergo MRI) is 
required if symptoms suggest possible CNS metastatic disease.  However, neuroimaging is also 
recommended in asymptomatic patients. 
k Samples are to be collected and submitted as outlined in Section 10 and Appendix D.  Kits are 
available for the collection and shipment of blood specimens (see Section 10.3 for kit information).  
To order kits, complete the EAY191 Collection and Shipping Kit Order Form (see Appendix D).   
l 
These assessments must be completed prior to registration to Cohort 2 for patients in Cohort 1, 
Treatment Regimen 2 who progress on fulvestrant alone.  Patient’s willingness to migrate to Cohort 
2 must be affirmed. 
 
 

 
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4.2 
Assessments During Treatment 
Table 2.  Assessments during treatment 
Assessments 
(See footnotes a, b, and c) 
Time Points 
C1D1 C1D15 C2D1 
Day 1 of each cycle 
until off study 
therapy 
(from registration) 
30 days 
after last 
dose of 
binimetinib 
History & physical examd 
(≤ 3 days) 
X 
X 
X 
X 
 
Vital signs (≤ 3 days) 
X 
X 
X 
X 
 
Adverse event assessment 
(≤ 3 days) 
X 
X 
X 
X 
X 
Concomitant medication 
assessmentf (≤ 3 days) 
X 
X 
X 
X 
 
CBC/differential/platelet 
countg (≤ 3 days) 
X 
X 
X 
X 
 
Total 
bilirubin/AST/ALT/alkaline 
phosphatase (≤ 3 days) 
X 
X 
X 
X 
 
Creatinine, calcium, 
glucose, albumin, sodium, 
potassium (≤ 3 days) 
X 
X 
X 
X 
 
Tumor markersh  
X 
 
X 
X 
 
Imaging of 
chest/abdomen/pelvis for 
disease assessmenti,j 
(+/- 7 days) 
X 
(every 8 weeks) 
 
Echocardiogram (or 
MUGA scan)k 
(+/- 14 days) 
 
 
 
X 
(every 3 cycles starting 
at Cycle 4 Day 1) 
 
12-Lead ECG 
X 
(as clinically indicated) 
 
Eye examl 
X 
(as clinically indicated) 
 
Bone scan 
(+/- 28 days) 
X 
(every 6 months from registration) 
Table continued on next page. 
 

 
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Table 2.  Assessments during treatment (continued) 
Assessments 
(See footnotes a, b, and c) 
Time Points 
C1D1 
C1D15 
C2D1 
Day 1 of each 
cycle until off 
study therapy 
(from registration) 
30 days 
after last 
dose of 
binimetinib 
Optional submission of 
whole blood for cfDNA 
and NF1 VAF  
 
X 
X 
 
X 
(at progression or end of treatment) 
Optional submission of 
FFPE sections for WES, 
RNAseq, and microscaled 
proteogenomicsm 
X 
(at progression or end of treatment) 
a 
History and physical, blood tests, x-rays, scans, and other testing may be performed more 
frequently at the discretion of the investigator. 
b 
See Section 4.3 for required assessments in follow-up.  See Section 6.1 for treatment 
management and modifications.   
c 
While tests, exams, and assessments, are not required following disease progression, 
survival status continues to be required every 6 months for 5 years.  (See Section 7 for 
adverse event reporting requirements.) 
d 
History and physical with exams (by physician or other healthcare professional) 
appropriate for therapy-related assessments and follow-up evaluations. 
e 
See Section 7 for instructions regarding adverse event reporting. 
f 
Include all prescribed and over-the-counter medications, supplements, herbal therapies 
(see Section 5.2.1). 
g 
CBC/differential/platelet count may be checked more frequently per institutional policy. 
h 
Tumor marker testing is not a study requirement.  The results of tumor markers (e.g., 
CA15-3, CEA, CA27.29) will be collected if they are ordered as part of standard care. 
i 
The same method (CT or MRI) used for baseline tumor measurements should be used at 
all other tumor measurement time points.  Scans may be performed within 14 days of the 
scheduled scan. 
j 
At the time of progression, patients should have imaging of the chest/abdomen/pelvis, 
preferably with a CT scan, and a bone scan performed to document extent of disease. 
Note: In the event of declining renal function or dye allergy, chest CT may be performed 
without contrast and MRI of abdomen and pelvis may be substituted for CT scan. 
k 
Due to the known cardiac effect of binimetinib, patients in Cohort 1, Treatment Regimen 
1 and patients in Cohort 2 will have an echocardiogram performed every 3 cycles.  
Patients in Cohort 1, Treatment Regimen 2 may have an echocardiogram or MUGA 
performed if clinically indicated.  Echocardiogram is the preferred method for assessment 
of LVEF.  However, LVEF assessment by MUGA scan is permitted.  All LVEF 
assessments should be performed by the same method (echocardiogram or MUGA scan) 
that was performed at baseline. 
Table continued on next page. 
 

 
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Table 2.  Assessments during treatment (continued) 
l 
While the risk factor of RVO including previously documented glaucoma are exclusion 
criteria, eye exams will be conducted as clinically indicated and not mandated. 
m A new biopsy will not be required for migration, but the optional biopsy at disease 
progression should be encouraged. 
4.3 
Assessments in Follow-Up 
Patients who discontinue protocol therapy for reasons other than disease progression 
should continue tumor assessments and tissue and blood sample submissions outlined on 
Table 2 until progression is documented or non-protocol therapy initiated.  The frequency 
of imaging will be at the investigator’s discretion until progression is documented or non-
protocol therapy initiated.  
Following disease progression, protocol-specified tests, exams, and assessments, are not 
required, and survival status should continue every 6 months for 5 years.  (See Section 7 
for adverse event reporting requirements.) 
 
 

 
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5. 
TREATMENT PLAN/REGIMEN DESCRIPTION 
5.1 
Fulvestrant/Binimetinib Therapy 
Study treatment should begin within 2 weeks after registration.  The first dose of 
fulvestrant can be administered while waiting for the PMB-supplied binimetinib to be 
received at the site.  
Treatment will continue in the absence of progression or toxicity. 
5.1.1 Cohort 1 (fulvestrant-naïve): Patients are randomized 1:1 between fulvestrant + 
binimetinib (Treatment Regimen 1) and fulvestrant alone (Treatment Regimen 2).   
x Fulvestrant will be administered intramuscularly (500 mg intramuscularly into gluteal 
area slowly [1-2 minutes per injection] as two 5 mL injections) on Day 1 and Day 15 
of Cycle 1 and Day 1 of each 28-day cycle afterwards.   
x Binimetinib 45 mg (3 tablets) is taken twice daily on Days 15-28 of Cycle 1 and then 
twice daily for 28 days starting with Cycle 2 and beyond.  A cycle is 28 days.  
Binimetinib will be administered orally twice daily on a fixed schedule unless the 
side effects warrant dose reduction.  The use of a binimetinib medication diary is 
recommended (see Appendix E). 
For patients with known metastasis in the liver and have a baseline grade 1 or 
grade 2 liver enzymes abnormality (AST, ALT), patients are required to start with 
the dosage of 30 mg (2 tablets) orally taken twice daily.  If patients have known 
liver metastasis but have normal liver function test, they will start with the normal 
dose. 
x Patients in Cohort 1, Treatment Regimen 2 who progress on fulvestrant alone may 
migrate to Cohort 2 if they meet the EAY191-N2 eligibility/ineligibility criteria in 
Sections 3.3 and 3.4.  Migration to Cohort 2 should take place within one month of 
progression, with no non-protocol intervening anti-cancer therapy given.  Patients not 
willing to migrate to Cohort 2 will have further therapy at the investigator’s 
discretion. 
Cohort Migration 
Patients receiving fulvestrant who experience disease progression may be eligible to 
migrate to Cohort 2 and receive combination treatment with binimetinib and fulvestrant 
upon documentation of disease progression. 
A new biopsy will not be required for migration, but the optional biopsy at disease 
progression should be encouraged. 
5.1.2 Cohort 2 (fulvestrant-resistant): Patients will receive fulvestrant + binimetinib. 
x Fulvestrant will be administered intramuscularly (500 mg intramuscularly into gluteal 
area slowly [1-2 minutes per injection] as two 5 mL injections) on Day 1 of Cycle 1 
and Day 1 of each 28-day cycle afterwards.   
Note: If a fulvestrant-containing regimen was not administered immediately prior to 

 
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enrolling on this study, reload fulvestrant on Day 1 and Day 15 of Cycle 1.  If the 
patient has progressed on fulvestrant and the EAY191-N2 treatment is the next line of 
therapy, or if patients receiving fulvestrant alone in Cohort 1, Treatment Regimen 2 
progress, the Day 15 loading dose of fulvestrant will be omitted, while the study visits 
and labs will still be conducted.  
x Binimetinib 45 mg (3 tablets) is taken twice daily on Days 15-28 of Cycle 1 and then 
twice daily for 28 days starting with Cycle 2 and beyond.  A cycle is 28 days.  
Binimetinib will be administered orally twice daily on a fixed schedule unless the 
side effects warrant dose reduction.  The use of a binimetinib medication diary is 
recommended (see Appendix E). 
For patients with known metastasis in the liver and have a grade 1 or grade 2 liver 
enzymes abnormality (AST, ALT), patients are required to start with the dosage of 
30 mg (2 tablets) orally taken twice daily.  If patients have known liver metastasis 
but have normal liver function test, they will start with the normal dose. 
5.1.3 Route of Administration of Binimetinib 
Binimetinib can be taken orally with or without food.  Tablets should be swallowed 
whole.  If a dose of binimetinib is missed, take it if there is > 6 hours until the next dose.  
If it is within 6 hours of the next scheduled dose, skip this dose and take the next dose at 
the scheduled time.  Do not make up for the missed dose.  If a dose is vomited, skip the 
dose.  Take the next dose at the scheduled time. 
5.2 
General Concomitant Medication and Supportive Care Guidelines 
5.2.1 Supportive Ancillary Care and Concomitant Medications 
All supportive therapy for optimal medical care will be given during the study period at 
the discretion of the attending physician(s) within the parameters of the protocol and 
documented on each site’s source documents as concomitant medication. 
Herbal and Nutritional Supplement 
The concomitant use of herbal therapies is generally not recommended, as their 
pharmacokinetics, safety profiles, and potential drug-drug interactions are generally 
unknown.  However, the use of general nutritional foundation supplements including 
calcium with vitamin D and/or minerals, Omega3s (fish oil), Vitamin B6, Vitamin B12, 
basic multivitamins, L-glutamine, or probiotics oral supplements will be permitted either 
at or below the recommended dosing by a healthcare provider.  Herbal-based 
multivitamins are not allowed. 
Concomitant therapy includes any prescription medications or over the counter 
preparations used by a patient between the 7 days preceding registration and the 
treatment discontinuation visit.  If the patient is taking any prohibited medications as of 
the day of consent, they will be instructed to discontinue the drug and alternatives will be 
discussed with the patients. 
See Section 9.1 for potential drug interactions with binimetinib.  See Appendix F for a 
Patient Clinical Trial Wallet Card. 

 
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5.2.2 Participation in Other Trials 
Patients are not to participate in other therapeutic trials.  However, trials that do not add 
experimental agents are allowed (e.g., imaging trials, quality of life, etc.). 
5.3 
Duration of Therapy 
Treatment may continue as specified in the above treatment modality sections or until 
one of the following criteria applies: 
x Disease progression (see Section 13), 
x Intercurrent illness that prevents further administration of treatment, 
x Unacceptable adverse event(s), as described in Section 6, 
x Patient decides to withdraw consent for participation in the study,  
x General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator, or 
x Death 
x Pregnancy 
- 
All women of childbearing potential should be instructed to contact the 
investigator immediately if they suspect they might be pregnant (e.g., missed or 
late menstrual period) at any time during study participation. 
- 
The investigator must immediately notify CTEP in the event of a confirmed 
pregnancy in a female patient or the partner of a male patient participating in the 
study. 
Note:  
 Patient has the right to refuse further treatment, but that does not necessitate 
withdrawing consent for participation in the study (e.g., follow-up) (See Section 
8.2.2 regarding study consent withdrawal) 
 See Section 6 to determine if individual treatment components can be stopped 
independently. 
 If all protocol treatment is discontinued, follow-up and data collection will 
continue as specified in the protocol. 
 

 
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6. 
TREATMENT MODIFICATIONS/MANAGEMENT 
6.1 
Dose Modifications 
x The CTCAE v5.0 must be used to grade the severity of AEs.  Refer to 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
x Dose reductions for binimetinib must be based on the AE requiring the greatest 
modification. 
x Binimetinib doses that have been reduced may be escalated at investigator discretion. 
x There are no dose reductions for fulvestrant. 
x Binimetinib cannot be given as single agent therapy. 
x If binimetinib is discontinued due to toxicity and in the absence of progression in 
Cohort 1, Treatment Regimen 1 or Cohort 2 patients, fulvestrant doses should be 
continued until progression if the patient is benefitting from the fulvestrant. 
x Patients in Cohort 1, Treatment Regimen 2 who progress may migrate to Cohort 2 
(see Section 3.3) as long as the accrual of Cohort 2 is not finished. 
x Binimetinib and fulvestrant must be discontinued at the time of progression for 
patients in Cohort 1, Treatment Regimen 1 or Cohort 2 patients.   
x If necessary, the timing of fulvestrant in both cohorts may be adjusted to 2 days 
earlier or 2 days later than the scheduled date of treatment. 
x Dosing interruptions are permitted in the case of medical/surgical events or logistical 
reasons not related to study therapy (e.g., elective surgery, unrelated medical events, 
patient vacation, and/or holidays).  Patients should be placed back on study therapy 
within 28 days of the scheduled interruption.  The reason for interruption should be 
documented in the patient's study record. 
x When rescheduling study therapy for non-medical adjustments, refer to the memo 
posted under Supplemental Documents on the protocol-specific page located on the 
CTSU members’ website (https://www.ctsu.org) for information regarding treatment 
over holidays/vacations and other non-medical delays (e.g., physician or patient 
schedules).  This memo is updated annually.   
Table 3.  Dose levels for binimetinib (Cohort 1, Treatment Regimen 1 or Cohort 2) 
 
Dose Level 0 
Starting Dose 
Dose Level -1 
Dose Level -2 
Binimetinib 
45 mg orally 
twice daily 
30 mg orally twice daily 
Permanently discontinue if 
unable to tolerate 
binimetinib 30 mg orally 
twice daily 
Binimetinib 
(For patients 
with known 
metastasis of the 
liver) 
30 mg orally 
twice daily 
Permanently discontinue 
if unable to tolerate 
binimetinib 30 mg orally 
twice daily 
N/A 
 
 

 
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7. 
ADVERSE EVENTS REPORTING REQUIREMENTS 
7.1 
Protocol Agents 
Investigational Agents 
The investigational agent (binimetinib) administered in EAY191-N2, which is being 
made available under an IND sponsored by the NCI, CTEP.  For patients receiving 
binimetinib, determination of whether an adverse event meets expedited reporting 
criteria, see the reporting table in Section 7.6.2. 
Commercial Agents 
The commercial agent in EAY191-N2 is fulvestrant.  For patients receiving fulvestrant, 
determination of whether an adverse event meets expedited reporting criteria, see the 
reporting table in Section 7.6.2. 
7.2 
Adverse Event Reporting Requirements 
Complications associated with the prior to start of treatment or end-of-
treatment/progression research biopsy will be reported and tracked as protocol-related 
AEs within Medidata Rave on the relevant ComboMATCH Treatment Trial.  No AE 
reporting will be reported via the ComboMATCH Registration Trial. 
7.3 
Adverse Events and Serious Adverse Events 
7.3.1 Adverse Event Characteristics 
This study will utilize the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0 for CTEP-AERS (CTEP Adverse Event Reporting System) CAERs 
reporting of adverse events (AEs), located on the CTEP web site, 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  All 
appropriate treatment areas should have access to a copy of the CTCAE version 5.0. 
7.3.2 Definition of an Adverse Event (AE) 
Any untoward medical occurrence associated with the use of a drug in humans, whether 
or not considered drug related.  Therefore, an AE can be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not 
considered related to the medicinal (investigational) product (attribution of unrelated, 
unlikely, possible, probable, or definite). (International Conference on Harmonisation 
[ICH], E2A, E6).  
For multi-modality trials, adverse event reporting encompasses all aspects of protocol 
treatment including radiation therapy, surgery, device, and drug. 
Due to the risk of intrauterine exposure of a fetus to potentially teratogenic agents, the 
pregnancy of a study patient must be reported via CTEP-AERS in an expedited manner. 

 
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- Other (subretinal fluid); Glaucoma; Vision decreased. 
GASTROINTESTINAL DISORDERS - Abdominal distension; Ascites; Cheilitis; 
Colitis; Dry mouth; Duodenal perforation; Dyspepsia; Dysphagia; Esophagitis; 
Flatulence; Gastric ulcer; Gastritis; Gastrointestinal disorders - Other (anorectal 
discomfort); Gastrointestinal disorders - Other (gastroenteritis); Gastrointestinal disorders 
- Other (hematochezia); Gastrointestinal disorders - Other (intestinal obstruction); 
Gastrointestinal disorders - Other (pneumatosis intestinalis); Hemorrhoids; Ileus; 
Pancreatitis; Small intestinal obstruction; Small intestinal perforation 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; 
Death NOS; Edema face; Edema trunk; Flu like symptoms; General disorders and 
administration site conditions - Other (axillary pain); General disorders and 
administration site conditions - Other (hemorrhagic cyst); General disorders and 
administration site conditions - Other (ulcer hemorrhage); Malaise; Multi-organ failure 
HEPATOBILIARY DISORDERS - Hepatobiliary disorders - Other (biliary colic); 
Hepatobiliary disorders - Other (cholestasis); Hepatobiliary disorders - Other (hepatic 
function abnormal) 
INFECTIONS AND INFESTATIONS - Bacteremia; Bronchial infection; Kidney 
infection; Lung infection; Paronychia; Peritoneal infection; Sepsis; Shingles; Soft tissue 
infection; Upper respiratory infection; Urinary tract infection; Viremia 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS – Bruising; 
Injury, poisoning and procedural complications - Other (toxic skin eruption) 
INVESTIGATIONS - Alkaline phosphatase increased; Blood bilirubin increased; Blood 
lactate dehydrogenase increased; Cardiac troponin I increased; Cardiac troponin T 
increased; Creatinine increased; Electrocardiogram QT corrected interval prolonged; 
GGT increased; INR increased; Investigations - Other (C-reactive protein increased); 
Investigations - Other (electrocardiogram change); Investigations - Other (haptoglobin 
increased); Lipase increased; Lymphocyte count decreased; Neutrophil count decreased; 
Platelet count decreased; Serum amylase increased; Weight gain; Weight loss 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypercalcemia; 
Hyperglycemia; Hyperkalemia; Hyperuricemia; Hypoalbuminemia; Hypocalcemia; 
Hypoglycemia; Hypokalemia; Hypomagnesemia; Hyponatremia; Hypophosphatemia; 
Metabolism and nutrition disorders - Other (diabetes mellitus); Metabolism and nutrition 
disorders - Other (hypoproteinemia); Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; 
Flank pain; Muscle cramp; Myositis; Neck pain; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) - Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other 
(skin papilloma, papilloma); Treatment related secondary malignancy; Tumor pain 
NERVOUS SYSTEM DISORDERS - Akathisia; Dysgeusia; Headache; Nervous 
system disorders - Other (dropped head syndrome); Nervous system disorders - Other 
(myasthenic syndrome); Paresthesia; Presyncope; Somnolence; Spinal cord compression; 
Syncope; Transient ischemic attacks 
PSYCHIATRIC DISORDERS - Confusion; Hallucinations; Insomnia; Psychiatric 
disorders - Other (abnormal behavior); Suicide attempt 
RENAL AND URINARY DISORDERS - Acute kidney injury; Hematuria; Proteinuria 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Menorrhagia; 

 
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Reproductive system and breast disorders - Other (polymenorrhea); Reproductive system 
and breast disorders - Other (metrorrhagia); Reproductive system and breast disorders - 
Other (hematospermia); Reproductive system and breast disorders - Other (uterine 
hemorrhage) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Aspiration; 
Atelectasis; Cough; Hypoxia; Oropharyngeal pain; Pharyngolaryngeal pain; Pleural 
effusion; Pneumothorax; Pulmonary hypertension; Respiratory failure; Respiratory, 
thoracic and mediastinal disorders - Other (asthma); Wheezing 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Eczema; Erythema 
multiforme; Erythroderma; Hyperhidrosis; Nail discoloration; Palmar-plantar 
erythrodysesthesia syndrome; Photosensitivity; Skin and subcutaneous tissue disorders - 
Other (excoriation); Skin and subcutaneous tissue disorders - Other (panniculitis and 
erythema nodosum); Skin and subcutaneous tissue disorders - Other (psoriasis); Skin and 
subcutaneous tissue disorders - Other (rosacea); Skin and subcutaneous tissue disorders - 
Other (skin burning sensation); Urticaria 
VASCULAR DISORDERS - Hypotension; Lymphedema; Superficial thrombophlebitis; 
Vascular disorders - Other (aortic dilatation) 
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. 
7.5 
Adverse Events for Commercial Study Agent (Fulvestrant) 
Refer to the current FDA-approved package insert for detailed pharmacologic and safety 
information for fulvestrant. 
Common adverse events (> 20%) include: cough; infection; anemia; thrombocytopenia; 
constipation, diarrhea, nausea, vomiting, anorexia; pain, fatigue; flushing; headache 
Occasional events (<= 20%) include: arrhythmia; peripheral edema; dyspnea; 
thromboembolic event; alanine aminotransferase increased, aspartate aminotransferase 
increased; allergic reaction 
Rare but serious events (< 3%) none. 
7.6 
Expedited Reporting of Adverse Events 
For studies that utilize the Rave-CTEP-AERS integration, expedited reports are initiated 
via Rave; see Section 14.3 for important operational details/information about Rave-
CTEP-AERS Integration and how to obtain the CTSU Expedited Safety Reporting 
Rules Evaluation User Guide. 
Submitting a report via CTEP-AERS serves as notification to NRG Oncology and 
satisfies NRG Oncology requirements for expedited adverse event reporting. 
7.6.1 Expedited Reporting Methods 
x Per CTEP NCI Guidelines for Adverse Events Reporting, a CTEP-AERS-24-hour 
notification must be submitted within 24 hours of learning of the AE.  Each CTEP-

 
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AERS 24-hour notification must be followed by a complete report within 5 calendar 
days. 
x CTEP-AERS 10 Calendar Day Report requires that a complete report is 
electronically submitted within 10 calendar days of learning of the AE (see Table 6). 
x Supporting source documentation is requested by CTEP and by NRG as needed to 
complete adverse event review.  Deidentified supporting source documentation 
should be uploaded to the CTSU Source Document Portal via the CTEP-AERS 
integration. 
x A serious adverse event that meets expedited reporting criteria outlined in the AE 
Reporting Tables but is assessed by the CTEP-AERS as “an action not 
recommended” must still be reported to fulfill NRG safety reporting obligations.  
Sites must bypass the “NOT recommended” assessment; the CTEP-AERS allows 
submission of all reports regardless of the results of the assessment. 
 
 

 
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7.6.3 Reporting to the Site IRB 
Investigators will report unanticipated problems to the NCI CIRB according to the NCI 
CIRB SOPs.  In addition, investigators must report serious adverse events to the local 
Institutional Review Board (IRB) responsible for the oversight of the patient if required 
by institutional policy. 
7.6.4 Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy).  A 
secondary malignancy is not considered a metastasis of the initial neoplasm.  
CTEP requires all secondary malignancies that occur during or subsequent to treatment 
with an agent under an NCI IND/IDE be reported via CTEP-AERS.  In addition, 
secondary malignancies following radiation therapy must be reported via CTEP-AERS.  
Three options are available to describe the event: 
x Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
x Myelodysplastic syndrome (MDS) 
x Treatment-related secondary malignancy 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also 
be reported via the routine reporting mechanisms outlined Section 7.7.  
7.6.5 Second Malignancy  
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT 
a metastasis from the initial malignancy).  Second malignancies require ONLY routine 
AE reporting unless otherwise specified. 
7.7 
Routine Reporting Requirements for Adverse Events 
All Adverse Events must be reported in routine study data submissions.  AEs reported 
expeditiously through CTEP-AERS must also be reported in routine study data 
submissions. 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of patients enrolled in the studies as well as those who 
will enroll in future studies using similar agents.  AEs are reported in a routine manner at 
scheduled times during the trial using Medidata Rave.  For this trial the Adverse Event 
CRF is used for routine AE reporting in Rave. 
7.8 
Pregnancy 
Although not an adverse event in and of itself, pregnancy as well as its outcome must be 
documented via CTEP-AERS.  In addition, the Pregnancy Information Form included 
within the NCI Guidelines for Adverse Event Reporting Requirements must be 
completed and submitted to CTEP.  Any pregnancy occurring in a patient or patient’s 

 
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partner from the time of consent to 30 days after the last dose of binimetinib or one year 
after the last dose of fulvestrant must be reported and then followed for outcome.  
Newborn infants should be followed until 30 days old.  Please see the “NCI Guidelines 
for Investigators: Adverse Event Reporting Requirements for DCTD (CTEP and CIP) 
and DCP INDs and IDEs” (at 
http://ctep.cancer.gov/protocolDevelopment/adverse effects.htm) for more details on 
how to report pregnancy and its outcome to CTEP. 
 
 

 
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Boards (IRBs) covering their practice sites in RCR to allow the following: 
x Addition to a site roster; 
x Selection as the treating, credit, or consenting person in OPEN; 
x Ability to be named as the site-protocol Principal Investigator (PI) on the IRB 
approval; and 
x Assignment of the Clinical Investigator (CI) task on the Delegation of Tasks Log 
(DTL). 
In addition, all investigators acting as the Site-Protocol PI (investigator listed on the IRB 
approval), consenting or treating investigator in OPEN, or as the CI on the DTL must be 
rostered at the enrolling site with a participating organization.  Note that NINTs may only 
participate on studies flagged for NINT participation and cannot hold any active task on a 
DTL. 
Refer to the NCI RCR page on the CTEP website for additional information.  For 
questions, please contact the RCR Help Desk by email at RCRHelpDesk@nih.gov. 
8.1 
Cancer Trials Support Unit Registration Procedures 
Permission to view and download this protocol and its supporting documents is restricted 
and is based on the person and site roster assignment housed in the Roster Maintenance 
application and in most cases viewable and manageable via the Roster Update 
Management System (RUMS) on the Cancer Trials Support Unit (CTSU) members’ 
website. 
This study is supported by the NCI CTSU. 
IRB Approval  
As of March 1, 2019, all U.S.-based sites must be members of the NCI Central 
Institutional Review Board (NCI CIRB) in order to participate in Cancer Therapy 
Evaluation Program (CTEP) and Division of Cancer Prevention (DCP) studies open to 
the National Clinical Trials Network (NCTN) and NCI Community Oncology Research 
Program (NCORP) Research Bases.  In addition, U.S.-based sites must accept the NCI 
CIRB review to activate new studies at the site after March 1, 2019.  Local IRB review 
will continue to be accepted for studies that are not reviewed by the CIRB, or if the study 
was previously open at the site under the local IRB.  
Sites participating through the NCI CIRB must submit the Study Specific Worksheet 
(SSW) for Local Context to the CIRB using IRBManager to indicate their intent to open 
the study locally.  The NCI CIRB’s approval of the SSW is automatically communicated 
to the CTSU Regulatory Office, but sites are required to contact the CTSU Regulatory 
Office at CTSURegPref@ctsu.coccg.org to establish site preferences for applying NCI 
CIRB approvals across their Signatory Network.  Site preferences can be set at the 
network or protocol level.  Questions about establishing site preferences can be addressed 
to the CTSU Regulatory Office by email (CTSURegPref@ctsu.coccg.org) or calling 1-
888-651-CTSU (2878). 
In addition, the Site-Protocol Principal Investigator (PI) (i.e., the investigator on the IRB 

 
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approval) must meet the following criteria for the site to be able to have an Approved 
status following processing of the IRB approval record: 
x 
Have an active CTEP status; 
x 
Have active status at the site(s) on the IRB approval on at least one participating 
organization’s roster; 
x 
If using NCI CIRB, be active on the NCI CIRB roster under the applicable 
CIRB Signatory institution(s) record; 
x 
Include the IRB number of the IRB providing approval in the Form FDA 1572 
in the RCR profile;  
x 
List all sites on the IRB approval as Practice Sites in the Form FDA 1572 in the 
RCR profile; and 
x 
Have the appropriate CTEP registration type for the protocol.  
Additional Requirements  
Additional site requirements to obtain an approved site registration status include: 
x 
An active Federal Wide Assurance (FWA) number; 
x 
An active roster affiliation with the Lead Protocol Organization (LPO) or a 
Participating Organization (PO);  
x 
An active roster affiliation with the NCI CIRB roster under at least one CIRB 
Signatory Institution (US sites only); and 
x 
Compliance with all applicable protocol-specific requirements (PSRs). 
Downloading Site Registration Documents: 
Download the site registration forms from the protocol-specific page located on the 
CTSU members’ website.  Permission to view and download this protocol and its 
supporting documents is restricted to institutions and their associated investigators and 
staff on a participating roster.  To view/download site registration forms: 
x Log in to the CTSU members’ website (https://www.ctsu.org); 
x Click on Protocols in the upper left of the screen: 
o Enter the protocol number in the search field at the top of the protocol tree, or 
o Click on the By Lead Organization folder to expand, then select NRG and 
protocol number [EAY191-N2]. 
x Click on Documents, Protocol Related Documents, and use the Document Type 
filter and select Site Registration to download and complete the forms provided.  
(Note: For sites under the CIRB, IRB data will load automatically to the CTSU.) 
Submitting Regulatory Documents: 
Submit required forms and documents to the CTSU Regulatory Office using the 
Regulatory Submission Portal on the CTSU members’ website.  
To access the Regulatory Submission Portal log in to the CTSU members’ website, go to 
the Regulatory section and select Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal 
should alert the CTSU Regulatory Office immediately at by phone or email: 1-866-651-

 
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CTSU (2878), or CTSURegHelp@coccg.org to receive further instruction and support. 
Checking Site’s Registration Status: 
Site registration status may be verified on the CTSU members’ website.  
x Click on Regulatory at the top of the screen; 
x Click on Site Registration; and 
x Enter the site’s 5-character CTEP Institution Code and click on Go: 
o Additional filters are available to sort by Protocol, Registration Status, 
Protocol Status, and/or IRB Type. 
Note: The status shown only reflects institutional compliance with site registration 
requirements as outlined within the protocol.  It does not reflect compliance with protocol 
requirements for individuals participating on the protocol or the enrolling investigator’s 
status with NCI or their affiliated networks.  
Delegation of Tasks Log (DTL)  
Each site must complete a protocol-specific Delegation of Tasks Log (DTL) using the 
DTL application in the Delegation Log section on the CTSU members’ website.  The 
Clinical Investigator (CI) is required to review and electronically sign the DTL prior to 
the site receiving an approved site registration status and enrolling patients to the study.  
To maintain an approved site registration status the CI must re-sign the DTL at least 
annually and when a new version of the DTL is released; and to activate new task 
assignments requiring CI sign-off.  Any individual at the enrolling site on a participating 
roster may initiate the site DTL.  Once the DTL is submitted for CI approval, only the 
designated DTL Administrators or the CI may update the DTL.  Instructions on 
completing the DTL are available in the Help Topics button in the DTL application and 
describe DTL task assignments, CI signature, and CTEP registration requirements, as 
well as include a Master Task List.  Persons with Non-Investigational New Drug/Non-
Treatment (NINT) registration type cannot be assigned any task on the DTL. 
8.2 
Patient Enrollment 
Patient registration can occur only after evaluation for eligibility is complete, eligibility 
criteria have been met, and the study site is listed as ‘approved’ in the CTSU RSS.  
Patients must have signed and dated all applicable consents and authorization forms.   
8.2.1 Oncology Patient Enrollment Network (OPEN) 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system 
available on a 24/7 basis.  OPEN is integrated with CTSU regulatory and roster data and 
with the LPOs’ registration/randomization systems or the Theradex Interactive Web 
Response System (IWRS) for retrieval of patient registration/randomization assignment.  
OPEN will populate the patient enrollment data in NCI’s clinical data management 
system, Medidata Rave. 
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x Active CTEP registration with the credentials necessary to access secure 
NCI/CTSU IT systems; 
x To perform enrollments or request slot reservations: Must be on an LPO roster, 
ETCTN corresponding roster, or participating organization roster with the role of 
Registrar.  Registrars must hold a minimum of an Associate Plus (AP) registration 
type; 
x If a Delegation of Tasks Log (DTL) is required for the study; the registrars must 
hold the OPEN Registrar task on the DTL for the site; and 
x Have an approved site registration for the protocol prior to patient enrollment. 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient 
transfer in OPEN, the IVR or NPIVR must list the Institutional Review Board (IRB) 
number used on the site’s IRB approval on their Form Food and Drug Administration 
(FDA) 1572 in the Registration and Credential Repository (RCR).  If a DTL is required 
for the study; the IVR or NPIVR must be assigned the appropriate OPEN-related tasks on 
the DTL. 
To assign a Non-Investigational New Drug (IND)/Non-Treatment (NINT) as the treating, 
crediting, consenting, or receiving investigator for a patient transfer in OPEN, NINTs 
must list all clinical practice sites, Institutional Review Boards, and labs covering their 
practice sites on the NINT Investigator Acceptance Form in RCR.  NINTs may only 
participate on studies flagged for NINT participation. 
Prior to accessing OPEN, site staff should verify the following: 
x Patient has met all eligibility criteria within the protocol stated timeframes; and  
x All patients have signed an appropriate consent form and Health Insurance 
Portability and Accountability Act (HIPAA) authorization form (if applicable). 
Note:  The OPEN system will provide the site with a printable confirmation of 
registration and treatment information.  You may print this confirmation for your records.  
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ 
website.  Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org.  For any additional questions, contact the 
CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
8.2.2 Cohort Migration Registration Procedure 
Patients receiving fulvestrant who experience disease progression may be eligible to 
migrate to Cohort 2 and receive combination treatment with binimetinib and fulvestrant 
(see Section 5.1.2).  Cohort migration can be requested by initiating Step 2 registration on 
the treatment trial in OPEN.   
Click “Request” to confirm the patient is eligible for and determine whether a slot is 
available for the patients to migrate; click “Cancel” to withdraw a request.  Determination 
of slot availability might be delayed < 24 hours for review if trial eligibility criteria has 
changed since the patient’s initial enrollment. 

 
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Patient Migration steps: 
x Log into the Treatment Trial in the OPEN registration system and select the 
appropriate patient.  
x Cohort migration can be requested by initiating a Step 2 registration on the treatment 
trial in OPEN.  Complete Cohort/Stratum Migration Request question in OPEN by 
clicking “Request.” 
x Once a slot in Cohort 2 has been confirmed, the patient can be migrated to Cohort 2. 
x Once a patient is assigned to Cohort 2 via migration, they must be enrolled within 14 
days, or the slot will be automatically released, and the process must be repeated to 
request a new slot on Cohort 2 for this patient. 
x Cohort Migration is dependent on slot availability.  
x If the patient opts not to migrate after the request has been made, the request can be 
cancelled in OPEN by clicking “cancel.” 
x Please note: Once the patient has been registered to Cohort 2, they must start 
treatment within 14 days – therefore total time from migration request to start of 
treatment is a maximum of 28 days. 
x A new biopsy will not be required for migration, but the optional biopsy at disease 
progression should be encouraged. 
x If assistance is needed with this process, contact the ComboMATCH Help Desk. 
8.2.3 Patient-Initiated Consent Withdrawal from the Study 
If a patient chooses to have no further interaction regarding the study (i.e., allow no 
future follow up data to be submitted to NRG Oncology), the study applicable form 
should be completed in Medidata Rave to report the patient’s consent withdrawal.  
NOTE: This should not be done if the patient has only chosen to stop protocol treatment 
and is willing to still be followed (see Section 5.3). 
 
 

 
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9. 
DRUG INFORMATION 
General Patient Care Implications 
Patients must use highly effective contraception because the study treatment may be 
teratogenic.  Highly effective contraception is defined as hormonal contraceptives (oral 
contraceptives, Nuvaring, Depo Provera), intrauterine device, true abstinence, two barrier 
methods of birth control including condoms with cervical cap or diaphragm, patient has 
received surgical sterilization, patient is monogamous with a post-menopausal partner. 
9.1 
Investigational Study Agent: Binimetinib (MEK162, ARRY-438162) (NSC# 788187, 
IND#
 
Chemical Name or Amino Acid Sequence: 5-[(4-bromo-2-fluorophenyl)amino]-4-
fluoro-N-(2-hydroxyethoxy)-1-methyl-1Hbenzimidazole-6-carboxamide 
Other Names: MEK162, ARRY-438162 
Classification: MEK 1/2 inhibitor 
CAS Registry Number: 606143-89-9 
Molecular Formula: C17H15BrF2N4O3 
M.W.: 441.23 
Approximate Solubility: Binimetinib’s solubility is pH dependent.  At pH 1 solubility is 
0.993 mg/mL.  At pH 7.4 solubility is 0.012 mg/mL. 
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). 
How Supplied: Array Biopharma Inc., a wholly owned subsidiary of Pfizer Inc.  supplies 
and CTEP, NCI, DCTD distributes binimetinib as 15 mg film-coated tablets in bottles 
containing 180 tablets.  The tablets are yellow to dark yellow, unscored biconvex oval 
shaped and the size is 0.2 x 0.48 inches.  The tablets are debossed with a stylized “A” on 
one side and “15” on the other side.  The film-coated tablets consist of binimetinib drug 
substance; colloidal silicon dioxide; croscarmellose sodium; lactose monohydrate; 
magnesium stearate; microcrystalline cellulose; polyvinyl alcohol, polyethylene glycol, 
titanium dioxide, talc, ferric oxide yellow, and ferrosoferric oxide. 
Storage: Store at 20°C - 25°C, excursions permitted between 15°C and 30°C, protect 
from light. 
If a storage temperature excursion is identified, promptly return binimetinib to 
controlled 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: Refer to label for shelf life dating.  Tablets should be dispensed in the original 
packaging. 
Route and Method of Administration: Orally with or without food.  Tablets should be 
swallowed whole.  If a dose of binimetinib is missed, take it if there is > 6 hours until the 
next dose.  If it is within 6 hours of the next scheduled dose, skip this dose and take the 
next dose at the scheduled time.  Do not make up for the missed dose.  If a dose is 

 
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vomited, skip the dose.  Take the next dose at the scheduled time. 
Potential Drug Interactions: 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.  
Binimetinib is not a substrate of OATP1B1, 1B3, 2B1, or OCT1.  Inhibitors or inducers 
of UGT1A1, P-gp, and BCRP should be co-administered with caution.   
In vitro, binimetinib reversibly inhibited CYP2B6 and is a weak inhibitor of CYP1A2 
and 2C9.  However in vivo no clinically significant inhibition is expected with CYP2B6.  
Binimetinib is not a time-dependent inhibitor of CYP1A2, 2C9, 2D6, and 3A4/5.  It has 
little 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. 
Patient Care Implications: There is some data that suggest binimetinib exposure may be 
associated with reproductive toxicity.  Binimetinib must not be used in pregnant women 
during treatment and for 30 days after last dose.  Women should not breastfeed during 
treatment and for 3 days after last dose. 
9.1.1 Procurement of binimetinib 
x Binimetinib will be supplied free of charge by Array Biopharma Inc., a wholly owned 
subsidiary of Pfizer Inc., and will be distributed by the Pharmaceutical Management 
Branch (PMB), Cancer Therapy Evaluation Program (CTEP), Division of Cancer 
Treatment and Diagnosis (DCTD), National Cancer Institute (NCI).   
x NCI-supplied agents may be requested by eligible participating Investigators (or their 
authorized designee) at each participating institution.  The CTEP-assigned protocol 
number must be used for ordering all CTEP-supplied investigational agents.  The 
eligible participating investigator 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. 
x No starter supplies will be provided for this study.  Orders can be placed after 

 
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enrollment and randomization and include the patient ID# when placing the order.  
Submit binimetinib requests through the PMB online agent order processing 
(AURORA) application (https://ctepcore.nci.nih.gov/aurora).  Access to AURORA 
requires the establishment of a CTEP Identity and Access Management (IAM) 
account (https://ctepcore.nci.nih.gov/iam/index.jsp) and the maintenance of an 
“active” account status, a “current” password, and active person registration status 
x For questions about drug orders, transfers, returns, or accountability call or email 
PMB any time.  Refer to the PMB’s website for specific policies and guidelines 
related to agent management. 
9.1.2 PMB Useful Links and Contacts 
x CTEP Forms, Templates, Documents: http://ctep.cancer.gov/forms/  
x NCI CTEP Investigator Registration: RCRHelpDesk@nih.gov  
x PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
x PMB online agent order processing (AURORA) application: 
https://ctepcore.nci.nih.gov/aurora  
x CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/index.jsp  
x CTEP IAM account help: ctepreghelp@ctep.nci.nih.gov  
x IB Coordinator: IBCoordinator@mail.nih.gov  
x PMB email: PMBAfterHours@mail.nih.gov  
x PMB phone and hours of service: (240) 276-6575 Monday through Friday between 
8:30 am and 4:30 pm (ET)  
9.1.3 Agent Inventory Records 
The investigator, or a responsible party designated by the investigator, must maintain a 
careful record of the receipt, dispensing and final disposition of all agents received from 
the PMB using the appropriate NCI Investigational Agent (Drug) Accountability Record 
(DARF) available on the CTEP forms page.  Store and maintain separate NCI 
Investigational Agent Accountability Records for each agent, strength, formulation and 
ordering investigator on this protocol. 
Product Quality Complaint (PQC): A product quality complaint is defined as any 
suspicion of a product defect related to a potential quality issue during manufacturing, 
packaging, release testing, stability monitoring, dose preparation, storage or distribution 
of the product, or delivery system.  Not all PQCs involve a study subject.  Lot or batch 
numbers are of high significance and need to be provided where and when possible. PQC 
must be reported to the PMB as soon as the PQC is identified.  Report PQC to PMB at 
PMBAfterHours@mail.nih.gov or by using the dialog function in AURORA to 
communicate with PMB staff. 
9.1.4 Investigator Brochure Availability 
The current version of the binimetinib IB will be accessible to site investigators and 
research staff through the PMB AURORA application.  Access to AURORA requires the 

 
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establishment of a CTEP 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 via email. 
9.1.5 Material Safety Data Sheets 
The current versions of the material safety data sheets (MSDS or SDS) for PMB-
distributed agents will be accessible to site investigators and research staff through the 
PMB AURORA application. Questions about MSDS access may be directed to the PMB 
at PMBAfterHours@mail.nih.gov or by using the dialog function in AURORA to 
communicate with PMB staff. 
9.2 
Commercial Agent: Fulvestrant 
Sites must refer to the FDA package insert for detailed pharmacologic and safety 
information. 
Product description: FASLODEX is supplied as two 5 mL clear neutral glass (Type 1) 
barrels, each containing 250 mg/5 mL of FASLODEX solution for intramuscular 
injection and fitted with a tamper evident closure.  The single-dose prefilled syringes are 
presented in a tray with polystyrene plunger rod and safety needles (SafetyGlide™) for 
connection to the barrel. 
Solution preparation:  Refer to the current FDA-approved package insert for 'standard' 
preparation instructions, handling, and storage.   
Route of administration: The recommended dose of FASLODEX is 500 mg to be 
administered intramuscularly into the buttocks (gluteal area) slowly (1-2 minutes per 
injection) as two 5 mL injections, one in each buttock.  Discard each syringe after use.   
Agent Ordering: Fulvestrant is commercially available. 
 
 

 
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10. 
PATHOLOGY/BIOSPECIMEN 
10.1 
Biomarker Testing 
Table 7.  Biomarker Table 
Priority Biomarker 
Name a 
Assay 
(CLIA: Y/N) 
Use in the 
Trial 
(Integral, 
Integrated, 
or 
Exploratory) 
AND 
Purpose b 
Specimens 
Tested 
Collection 
Time 
Points 
Mandatory 
or Optional Assay 
Laboratory and 
Lab PI c 
Funding 
Source(s) d 
Tissue-based Biomarkers 
1 
Whole Exome  
(REQUIRED) 
Whole 
Exome 
Sequencing 
CLIA: No 
 
Integrated  
 
To compare 
with 
Designated 
Laboratory 
assay 
 
To identify 
markers of 
response 
and 
resistance to 
binimetinib 
and 
fulvestrant 
Fresh 
tumor core 
biopsy 
(preferred) 
or archival 
paraffin-
embedded 
tumor 
tissue  
Pre-
treatment 
and at 
progression 
or end of 
treatment  
Pre-
treatment 
Mandatory  
 
Post 
treatment 
Optional 
 
 
 
 
MoCha 
Laboratory 
(FNLCR) 
 
P. Mickey 
Williams  
Molecular 
Diagnostic 
Network 
(MDNet) 
Contract 
(Lyndsay 
Harris, NCI 
Contact) 
2 
Whole 
Transcriptome 
(RNAseq) 
(REQUIRED) 
RNA 
sequencing 
CLIA: No 
Exploratory 
To identify 
markers of 
response 
and 
resistance to 
binimetinib 
and 
fulvestrant. 
Fresh 
tumor core 
biopsy 
(preferred) 
or archival 
paraffin-
embedded 
tumor 
tissue  
Pre-
treatment 
and at 
progression 
or end of 
treatment  
Pre-
treatment 
Mandatory  
Post-
treatment 
Optional 
MoCha 
Laboratory 
(FNLCR)  
P. Mickey 
Williams 
Molecular 
Diagnostic 
Network 
(MDNet) 
Contract 
(Lyndsay 
Harris, NCI 
Contact) 
3 
NF1 protein 
 
IHC 
CLIA: No 
Exploratory  
To identify 
markers of 
response 
and 
resistance to 
binimetinib 
and 
fulvestrant, 
by comparing 
with baseline 
Fresh 
tumor core 
biopsy or 
archival 
paraffin-
embedded 
tumor 
tissue  
Pre-
treatment 
Optional 
 
Baylor College of 
Medicine (BCM) 
Laboratory 
George Miles 
BCM 
SPORE 
4 
NF1 protein 
and related 
biomarkers  
Microscaled 
proteogeno-
mic assay 
CLIA: No 
 
Exploratory 
To identify 
markers of 
response 
and 
resistance to 
binimetinib 
and 
fulvestrant  
Fresh 
tumor core 
biopsy, 
frozen  
Pre-
treatment 
and at 
progression 
or end of 
treatment  
Optional 
Baylor College of 
Medicine (BCM) 
Laboratory 
Eric Chang 
BCM 
SPORE 
Table continued on next page. 
 

 
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Table 7.  Biomarker Table (continued) 
Priority Biomarker 
Name a 
Assay 
(CLIA: Y/N) 
Use in the 
Trial 
(Integral, 
Integrated, 
or 
Exploratory) 
AND 
Purpose b 
Specimens 
Tested 
Collection 
Time 
Points 
Mandatory 
or Optional 
Assay 
Laboratory and 
Lab PI c 
Funding 
Source(s) d 
Blood-based Biomarkers 
1 
Germline 
Whole Exome  
(REQUIRED) 
Whole 
Exome 
Sequencing 
(WES)  
CLIA: No 
Integrated 
Germline 
genomic 
control for 
tissue WES 
Whole 
blood 
Pre-
treatment  
Mandatory 
MoCha 
Laboratory 
(FNLCR) 
P. Mickey 
Williams 
Molecular 
Diagnostic 
Network 
(MDNet) 
Contract 
(Lyndsay 
Harris, NCI 
Contact) 
2 
Cell-free DNA 
(REQUIRED) 
TSO500® for 
cfDNA 
CLIA: No 
Integrated 
To compare 
with WES 
and 
Designated 
Laboratory 
assay  
Exploratory 
To explore 
serial 
changes in 
cfDNA 
alterations 
over course 
of treatment 
Plasma  
Pre-
treatment, 
C1D15, 
C2D1, and 
at 
progression 
or end of 
treatment  
 
Pre-
treatment 
Mandatory  
Progression 
Optional 
 
MoCha 
Laboratory 
(FNLCR)  
P. Mickey 
Williams 
 
 
 
 
 
Molecular 
Diagnostic 
Network 
(MDNet) 
Contract 
(Lyndsay 
Harris, NCI 
Contact) 
 
BCM 
SPORE 
3 
NF1 VAF 
ddPCR 
CLIA: No 
Exploratory 
To detect 
Variant Allele 
Fraction 
(VAF) of NF1 
and co-
mutations 
Plasma 
Pre-
treatment, 
C1D15, 
C2D1, and 
at 
progression 
or end of 
treatment  
Optional 
Baylor College of 
Medicine (BCM) 
Laboratory  
George Miles 
BCM 
SPORE 
 
10.1.1 
Integrated Biomarkers 
Integrated and exploratory molecular profiling assays will be performed within the 
research setting in the Molecular Diagnostics Network (MDNet) laboratories. 
Integrated whole exome sequencing and exploratory sequencing of RNA and ctDNA 
will use massively parallel sequencing (next generation sequencing) on an Illumina 
sequencer. 
10.1.1.1 Whole Exome 
Whole exome sequencing analyzing tissue samples collected prior to start of therapy 
will be performed in order to assess the concordance of the central molecular 
characterization of the pre-treatment biopsy samples with the genetic readouts from the 

 
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designated outside laboratories (dOLs).  Whole blood will also be sequenced to 
compare to tumor sequence.  
Please refer to the ComboMATCH registration protocol for further information. 
10.1.1.2 Pre-Treatment Circulating Tumor DNA (ctDNA) 
DNA sequencing will be performed at MDNet laboratories on circulating tumor DNA 
in blood samples collected prior to start of therapy in order to assess how the 
registration diagnostic tumor mutation profile and pre-treatment biopsy profile compare 
to the ctDNA mutation profile from plasma.  
Please refer to the ComboMATCH registration protocol for further information. 
10.1.2 
Exploratory Biomarkers 
10.1.2.1 Whole Transcriptome 
RNA sequencing will be performed on tumor tissue samples collected prior to start of 
therapy in order to investigate molecular features that may have influence on response 
or lack of response to the treatment.  Tumor RNA and DNA sequences obtained at 
progression or end of treatment will be assessed for potential resistance mechanisms. 
Please refer to the ComboMATCH registration protocol for further information. 
10.1.2.2 NF1 Protein and Related Biomarkers 
Immunohistochemical (IHC) staining will be performed to measure the level of NF1 
protein loss.  Microscaled proteogenomics assays will be performed to determine the 
phosphoproteome of ER+ NF1-depleted tumors.  See Appendix C for further 
information. 
10.1.2.3 Digital Droplet PCR 
Digital Droplet PCR (ddPCR) will be used to assess longitudinal changes in the Variant 
Allele Fraction (VAF) of NF1 and co-mutations in ctDNA.  See Appendix C for further 
information. 
10.2 
Specimen collection and submission 
Samples are to be submitted as outlined in Appendix D.  Tissue and blood will be 
collected at the time points listed below. 
 

 
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Table 8.  Specimen Collection 
Specimen 
Type 
Intended 
Assay(s) 
Archival 
Baseline 
On Study Progression1 
Ship to: 
Fresh 
tumor 
core 
biopsy 
WES 
RNAseq 
IHC 
N/A 
Two cores in 
formalin for 
paraffin 
embedding2 
(Mandatory)3 
N/A 
Two cores in 
formalin for 
paraffin 
embedding 
(Optional) 
Central 
Biorepository 
and 
Pathology 
Facility 
Fresh 
tumor 
core 
biopsy 
Microscaled 
proteogenomics 
N/A 
Two cores in 
OCT 
(Optional) 
N/A 
Two cores in 
OCT 
(Optional) 
FFPE 
tumor 
WES 
RNAseq 
IHC 
FFPE block 
or unstained 
slides 
(Mandatory)3 
N/A 
N/A 
N/A 
Whole 
blood4 
WES germline 
control, 
ctDNA 
N/A 
4 Streck 
tubes 
(Mandatory) 
4 Streck 
tubes 
C1D15, 
C2D1 
(Optional) 
4 Streck 
tubes 
(Optional) 
1. 
Collect samples at progression or end of treatment only if patient has been on study 
therapy for 6 months or more. 
2. 
It is requested that two core biopsies 16-18 gauge in diameter and at least 1 cm in 
length are obtained.  Note that for the prior to start of treatment submissions, FFPE 
tissue collected within 12 months prior to registration to the EAY191 Registration 
Trial may be an acceptable alternative submission based on treatment status of the 
patient.  See Appendix D for specific instructions. 
3. 
Per Section 3.1.2, “Patients must have disease that can be safely biopsied and agree to 
a pre-treatment biopsy or have archival tissue available from within 12 months prior 
to registration.” 
4. 
Collect blood prior to start of treatment, on C1D15, on C2D1, and at 
end/discontinuation of ComboMATCH treatment (or progression, whichever is 
earlier) 
 
10.3 
Kit information for collections 
Samples are to be submitted as outlined in Appendix D.  Kits are available for the 
collection and shipment of blood specimens.  To order kits, complete the EAY191 
Collection and Shipping Kit Order Form (see CTSU website) and fax to 713-563-6506.  
All samples submitted on the ComboMATCH Treatment Trials must follow the same 
logging and tracking process.  ComboMATCH will initially leverage a manual paper-
based process.  The paper-based process will subsequently be replaced with the Precision 
Medicine Specimen Tracking Forms within Rave and submitted with a Rave generated 

 
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shipment manifest and local pathology group information.  Sample tracking and biopsy 
collection procedures are described in Appendix D.  For pathology materials it is strongly 
recommended that full patient names be provided. 
11. 
SPECIAL STUDIES (NON-TISSUE) NOT APPLICABLE 
12. 
CENTRAL QUALITY/ENDPOINT REVIEWS NOT APPLICABLE 
 
 

 
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13. 
ASSESSMENT OF DISEASE STATUS 
Tumor response and progression will be evaluated in this study using the Response 
Evaluation Criteria in Solid Tumors (RECIST) 1.1 (Eisenhauer 2009) except in the 
documentation of progressive disease (PD).   
13.1 
Definition 
13.1.1 Evaluable Toxicity 
All patients will be evaluable for toxicity from the time of their first administration of 
protocol therapy. 
13.1.2 Evaluable for Objective Response 
Patients who have measurable disease present at baseline and have had their disease re-
evaluated will be considered evaluable for response.  These patients will have their 
response classified according to the definitions stated below.  (Note: Patients who exhibit 
objective disease progression prior to the end of the first 3 weeks of treatment will also be 
considered evaluable.) 
13.2 
Disease Parameters 
13.2.1 Measurable Disease 
Measurable lesions are defined as those that can be accurately measured in at least one 
dimension (longest diameter to be recorded) ≥ 10 mm by CT scan with slice thickness no 
greater than 5 mm, MRI, or calipers in clinical exam.  All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters).  The same method (CT or 
MRI) used at baseline should be used at all other tumor measurement time points. 
In rare instances in which none of the metastatic sites can be used as a measurable lesion, 
the breast primary, if intact, can be used as a measurable lesion.  If it meets the criterion 
of ≥ 10 mm, it can be monitored on serial chest CT or on breast imaging techniques (e.g., 
mammography, ultrasound).  The breast primary should not be used as a site of 
measurable disease if other sites of measurable disease have been identified.  This should 
only be done when resection of the breast primary is not anticipated. 
13.2.2 Malignant Lymph Nodes 
To be considered pathologically enlarged and measurable, a lymph node must be  
t 15 mm in short axis when assessed by CT scan (CT scan thickness recommended to be 
no greater than 5 mm).  At baseline and in follow-up, only the short axis will be 
measured and followed. 
13.2.3 Non-Measurable Disease 
All other lesions (or sites of disease), including small lesions (longest diameter < 10 mm 

 
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or pathological lymph nodes with ≥ 10 to < 15 mm short axis), are considered non-
measurable disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pneumonitis, inflammatory breast disease, and abdominal 
masses (not followed by CT or MRI), are considered as non-measurable. 
13.2.4 Special Considerations Regarding Tumor Measurability 
x Bone lesion measurability 
When evaluating bone lesions, the following should be considered: 
 Bone 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 or MRI can be considered as measurable lesions if the soft tissue component 
meets the definition of measurability described above. 
 Blastic bone lesions are non-measurable. 
x 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 metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above.  
However, if non-cystic lesions are presented in the same patient, these are 
preferred for selection as target lesions.  
x Tumors with prior local treatment 
 Tumor 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. 
13.2.5 Target Lesions 
Up to a maximum of five measurable lesions (maximum 2 lesions per organ), should be 
identified as target lesions and recorded and measured at baseline.  Target lesions should 
be selected on the basis of their size (lesions with the longest diameter), be representative 
of all involved organs, and lend themselves reproducible repeated measurements by CT 
scan or MRI.  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.  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 only the short axis is added into the sum.  The baseline sum diameters will be used 
as reference by to further characterize any objective tumor regression in the measurable 
dimension of the disease. 

 
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13.2.6 Non-target Lesions 
All other lesions (or sites of disease) including pathological lymph nodes which are not 
used as target lesions should be identified as non-target lesions and should also be 
recorded at baseline.  All sites of non-target lesions must be assessed along with the 
target lesions.  Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted throughout follow-up. 
13.2.7 Lesions 
If new lesions appear and there is clinical doubt as to whether a lesion is new or an 
inflammatory change, follow-up scans are required in no less than 6 weeks.  If the new 
lesion is confirmed as unequivocal (i.e., not attributable to differences in scanning 
technique, change in imaging modality or findings thought to be something other than the 
tumor by a scan obtained at least 6 weeks after the initial scan), the date of progression is 
taken to be the date on which the new lesion was first detected.  If a lesion reappears after 
disappearing in a patient previously declared to have a CR, PD is declared.  However, if 
such a lesion behaves in this manner in a patient with SD or PR, confirmation as stated 
above defines the response or progression. 
13.2.8 Pseudoprogression 
Delayed responses after a tumor flare have been reported in patients who have received 
immune-based therapy.  Caution must be exercised not to confuse a possible tumor flare 
with PD.  In scenarios where pseudoprogression of previously targeted or not-targeted 
lesions is suspected, follow-up scans are required in 4 to 6 weeks.  Based on that 
repeating imaging, if there is confirmatory evidence of tumor progression, the date of PD 
will be documented as the initial evaluation.  However, if subsequent response is 
confirmed, no progression is documented, and the imaging schedule reverts to that 
otherwise stated in the protocol. 
13.3 
Response Criteria 
13.3.1 Evaluation of Target Lesions 
x 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). 
x Partial response (PR) 
At least a 30% decrease in the sum of diameters of target lesions, taking as reference 
the baseline sum diameters. 
x 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 

 
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study).  In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm.  (Note: The appearance of one or more new 
lesions is also considered progression.) 
x 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. 
13.3.2 Evaluation of Non-Measurable/Non-Target Lesions 
x Complete response (CR): Disappearance of all non-target lesions.  All lymph nodes 
must be non-pathological in size ( 10 mm short axis). 
x Non-CR/Non-PD: Persistence of one or more non-target lesion(s).   
x Progressive disease (PD): Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression 
should not normally trump target lesion status.  It must be representative of overall 
disease status change, not a single lesion increase. 
13.4 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best response 
assignment will depend on the achievement of both measurement and confirmation 
criteria.   
Refer to Table 9 and Table 10 for a summary of the criteria that contribute to the 
determination of response. 
 

 
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Table 9.  Time point response: patients with target (r 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-CR/Non-PD or 
not all evaluated 
No 
SD 
Not all 
evaluated 
Non-PD 
No 
Inevaluable 
PD 
Any 
Yes or No 
PD 
Any 
PD** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* See RECIST 1.1 manuscript for further details on what is evidence of 
a new lesion (Eisenhauer 2009). 
** In exceptional circumstances, unequivocal progression in non-target 
lesions may be accepted as disease progression. 
 
Table 10.  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-PD* 
Not all evaluated 
No 
Inevaluable 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target 
disease since SD is increasingly used as an endpoint for assessment of 
efficacy in some trials so to assign this category when no lesions can be 
measured is not advised 
 
13.5 
Symptomatic Deterioration 
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 protocol therapy. 
13.6 
Duration of Response 
13.6.1 Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are met 

 
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for CR or PR (whichever is first recorded) until the first date that recurrent or progressive 
disease is objectively documented (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started). 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively documented. 
13.6.2 Duration of Stable Disease 
Stable disease is measured from the start of the treatment until the criteria for progression 
are met, taking as reference the smallest measurements recorded since the treatment 
started, including the baseline measurements. 
13.7 
Progression-Free Survival 
Progression-free survival is defined as the time from randomization to the first 
documented progressive disease, as determined using the current RECIST 1.1 criteria, or 
death from any causes, whichever occurs first. 
 
 

 
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14. 
DATA AND RECORDS 
14.1 
Data Management/Collection 
Medidata Rave is the clinical data management system being used for data collection for 
this trial/study.  Access to the trial in Rave is controlled through the CTEP-IAM system 
and role assignments. 
Requirements to access Rave via iMedidata: 
x  Active CTEP registration with the credentials necessary to access secure 
NCI/CTSU IT systems; and  
x Assigned a Rave role on the LPO or PO roster at the enrolling site of: Rave CRA, 
Rave Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.  
Rave role requirements: 
x Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an Associate 
Plus (AP) registration type; 
x Rave Investigator role must be registered as a Non-Investigational New Drug 
(IND)/Non-Treatment (NINT), NonPhysician Investigator (NPIVR), or Investigator 
(IVR); and 
x Rave Read Only or Rave SLA role must have at a minimum an Associates (A) 
registration type. 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types 
and documentation required.  NINTs will only have write access in Rave for studies 
flagged for NINT participation. 
This study has a Delegation of Tasks Log (DTL).  Therefore, those individuals requiring 
write access to Rave must also be assigned the appropriate Rave tasks on the DTL. 
Upon initial site registration approval for the study in the Regulatory application, all 
persons with Rave roles assigned on the appropriate roster will be sent a study invitation 
email from iMedidata.  No action will be required; each study invitation will be 
automatically accepted and study access in Rave will be automatically granted.  Site staff 
will not be able to access the study in Rave until all required Medidata and study-specific 
trainings are completed.  Trainings will be in the form of electronic learnings 
(eLearnings) and can be accessed by clicking on the eLearning link in the Tasks pane 
located in the upper right corner of the iMedidata screen.  If an eLearning is required for 
a study and has not yet been taken, the link to the eLearning will appear under the study 
name in the Studies pane located in the center of the iMedidata screen; once the 
successful completion of the eLearning has been recorded, access to the study in Rave 
will be granted, and a Rave EDC link will replace the eLearning link under the study 
name.  
No action will be required by site staff (to activate their account) who have not 
previously activated their iMedidata/Rave account at the time of initial site registration 
approval for the study in the Regulatory application.  Pending study invitations 
(previously sent but not accepted or declined by a site user) will be automatically 
accepted and study access in Rave will be automatically granted for the site user.  

 
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Account activation instructions are located on the CTSU website in the Data 
Management section under the Data Management Help Topics > Rave resource materials 
(Medidata Account Activation and Study Invitation).  Additional information on 
iMedidata/Rave is available on the CTSU members’ website in the Data Management > 
Rave section or by contacting the CTSU Help Desk at 1-888-823-5923 or by email at 
ctsucontact@westat.com. 
14.2 
Summary of Data Submission 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of patients enrolled in the studies as well as those who 
will enroll in future studies using similar agents.  Adverse events are reported in a routine 
manner at scheduled times during the trial using Medidata Rave®.  Additionally, certain 
adverse events must be reported in an expedited manner for more timely monitoring of 
patient safety and care.  See Sections 7.6 and 7.7 for information about expedited and 
routine reporting.   
14.3 
Rave-CTEP-AERS Integration 
The Rave Cancer Therapy Evaluation Program Adverse Event Reporting System (CTEP-
AERS) Integration enables evaluation of Adverse Events (AE) entered in Rave to 
determine whether they require expedited reporting and facilitates entry in CTEP-AERS 
for those AEs requiring expedited reporting.  Sites must initiate all AEs for this study 
in Medidata Rave. 
Treatment emergent AEs: All AEs that occur after start of treatment are collected in 
Medidata Rave using the Adverse Event form, which is available for entry at each 
treatment course or reporting period and is used to collect AEs that start during the period 
or persist from the previous reporting period.  AEs that occur 30 days after the last 
administration of the investigational study agent/intervention are collected using the Late 
Adverse Event Form. 
Prior to sending AEs through the rules evaluation process, site staff should verify the 
following on the Adverse Event form in Rave: 
x 
The reporting period (course/cycle) is correct; and  
x 
AEs are recorded and complete (no missing fields) and the form is query-free. 
The CRA reports AEs in Rave at the time the Investigator learns of the event.  If the CRA 
modifies an AE, it must be re-submitted for rules evaluation. 
Upon completion of AE entry in Medidata Rave, the CRA submits the AE for rules 
evaluation by completing the Expedited Reporting Evaluation form (i.e., checking the 
box Send All AEs for Evaluation and save the form).  Both NCI and protocol-specific 
reporting rules evaluate the AEs submitted for expedited reporting.  A report is initiated 
in CTEP-AERS using information entered in Medidata Rave for AEs that meet reporting 
requirements.  The CRA completes the report by accessing CTEP-AERS via a direct link 
on the Medidata Rave Expedited Reporting Evaluation form.  Contact the CTSU Help 
Desk at 1-888-823-5923 or by email at ctsucontact@westatctsucontact@westat.com.com 
if you have any issues submitting an expedited report in CTEP-AERS. 

 
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In the rare occurrence that internet connectivity is lost, a 24-hour notification is to be 
made to CTEP by telephone at 301-897-7497.  Once internet connectivity is restored, the 
24-hour notification that was phoned in must be entered immediately into CTEP-AERS 
using the direct link from Medidata Rave. 
Additional information about the CTEP-AERS integration is available on the CTSU 
members’ website: 
x Study specific documents: Protocols > Documents > Protocol Related 
Documents > Adverse Event Reporting; and   
x Additional resources: Resources > CTSU Operations Information > User 
Guides & Help Topics. 
NCI requirements for SAE reporting are available on the CTEP website:  
x NCI Guidelines for Investigators: Adverse Event Reporting Requirements is 
available at 
https://ctep.cancer.gov/protocolDevelopment/electronic applications/docs/aeg
uidelines.pdf. 
14.4 
Data Quality Portal 
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, 
generate reports, and review metrics.  
The DQP is located on the CTSU members’ website under Data Management.  The Rave 
Home section displays a table providing summary counts of Total Delinquencies and 
Total Queries.  DQP Queries, DQP Delinquent Forms, DQP Form Status and the DQP 
Reports modules are available to access details and reports of unanswered queries, 
delinquent forms, forms with current status, and timeliness reports.  Site staff should 
review the DQP modules on a regular basis to manage specified queries and delinquent 
forms. 
The DQP is accessible by site staff who are rostered to a site and have access to the 
CTSU website.  Staff who have Rave study access can access the Rave study data via 
direct links available in the DQP modules. 
CTSU Delinquency Notification emails are sent to primary contacts at sites twice a 
month.  These notifications serve as alerts that queries and/or delinquent forms require 
site review, providing a summary count of queries and delinquent forms for each Rave 
study that a site is participating in.  Additional site staff can subscribe and unsubscribe to 
these notifications using the CTSU Report and Information Subscription Portal on the 
CTSU members’ website. 
To learn more about DQP use and access, click on the Help Topics button displayed on 
the Rave Home, DQP Queries, DQP Delinquent Forms, DQP Form Status, and DQP 
Reports modules. 
 

 
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14.5 
Global Reporting/Monitoring 
DMU Light monitoring: 
Data for this study will be submitted via the Data Mapping Utility (DMU).  Cumulative 
protocol- and patient-specific data will be submitted weekly to CTEP electronically via 
the DMU.  DMU Light reporting consists of Patient Demographics, On/Off Treatment 
Status, Abbreviated Treatment and Course information, and Adverse Events as 
applicable. 
Note:  All adverse events (both routine and serious) that meet the protocol mandatory 
reporting requirements must be reported via DMU in addition to expedited reporting of 
serious adverse events via CTEP-AERS.   
 

 
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15. 
STATISTICAL CONSIDERATIONS 
15.1 
Abstract 
This is a phase II study of binimetinib in combination with fulvestrant in patients with 
metastatic hormone receptor positive HER2 negative breast cancers with a non-functional 
mutation (inactivation or inferred inactivation) in NF1.  This trial includes two cohorts: 
the fulvestrant naïve cohort (Cohort 1: randomized) and the fulvestrant resistant cohort 
(Cohort 2: single arm). 
15.2 
Primary Endpoints 
15.2.1 Cohort 1 
Progression free survival (PFS) defined as the duration between randomization and 
progression or death from all cause, whichever happens first. 
15.2.2 Cohort 2 
Overall response rate (ORR) within 4 months defined as the percentage of patients who 
reaches a complete or partial response (defined by RECIST v1.1) within 4 months of the 
start of the treatment. 
15.3 
Secondary Endpoints 
x ORR for each study arm of Cohort 1.  ORR is defined as the percentage of patients 
who reach a complete or partial response (defined by RECIST v1.1) any time after 
the start of the treatment. 
x ORR for Cohort 2 is defined as the percentage of patients who reach a complete or 
partial response (defined by RECIST v1.1) any time after the start of the treatment. 
x Clinical benefit rate, defined as proportion of patients who achieved a CR, PR, or 
stable disease (SD) defined by RECIST criteria any time after the start of the 
treatment. 
x PFS for patients of Cohort 2.  PFS as defined in Section 15.2.1. 
x Overall survival (OS) defined as the duration between randomization and death of all 
causes. 
x Toxicity by study arm for Cohort 1 and toxicity for Cohort 2. 
15.4 
Randomization and Stratification 
Cohort 1 patients will be randomized in 1:1 ratio to fulvestrant + binimetinib or 
fulvestrant only arm by permuted block randomization.  Block size 4, 6, and 8 will be 
used.  No stratification will be considered. 
 

 
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15.5 
Patient Population for Analysis 
15.5.1 Per Protocol Population 
The per protocol (PP) population includes all patients who completed the study according 
to the protocol.  For Cohort 1, the PP analysis will be performed for the primary 
endpoints.  For Cohort 2, all patients who have started the experimental therapy will be 
analyzed for the primary outcomes. 
15.5.2 Safety Population 
For both study cohorts, patients who received at least one dose of the study regiment will 
be included in the safety population.  Safety population will be used for the analysis of 
safety endpoints.  Patients will be analyzed according to the treatment received. 
15.6 
Primary Endpoint(s), Sample Size, and Analysis Plan 
15.6.1 Sample Size and Power Calculations 
Cohort 1  
A total of 70 fulvestrant naïve patients will be randomized in a 1:1 ratio to receive either 
fulvestrant + binimetinib or fulvestrant only.  Patients who progressed on the fulvestrant 
only arm will have the choice to consent to join the Cohort 2 study.  The primary 
endpoint for Cohort 1 is progression-free survival (PFS).  It is estimated that the median 
PFS for the patients on the fulvestrant alone arm will be around 6 months (H0).  A HR of 
0.5 or smaller (HA) is considered worth further investigation of the regimen, which will 
require a total number of 55 events to reach 90% power with a 1-sided log rank test 
(α=0.1).  The estimated monthly accrual for this cohort is 1.5/month, thus the accrual will 
be finished in 47 months.  The average lost to follow-up rate is 1% per year.  With the 
above assumptions, we will need to follow up the patients for an additional 6 months to 
reach the number of events needed.  The total study time after the first patient is 
randomized on the trial will be 53 months.  
One interim analysis for futility will be performed when 28 events are obtained (about  
31 months after the first patient is randomized on the trial).  If the PFS hazard ratio at the 
interim is in the wrong direction (favoring control arm), then the study will be stopped for 
futility (Wieand 1994), this rule is binding.  The probability of stopping the trial for 
futility under the null is 0.5 and under the alternative is 0.033.  The overall power for the 
definitive analysis is 89%.  
Cohort 2 (n=16 or 25) 
This is the cohort for fulvestrant exposed patients (as single agent or combination).  The 
primary endpoint of this cohort is ORR (best response rate within 4 months).  Our 
targeted rate is 30% or higher (HA), as compared to the expected 10% for the patients 
eligible for the study (H0).  We base our study size based on a Simon 2-stage mini-max 
design in which 16 patients will be treated initially.  If 2 or more patients responded, an 

 
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additional 9 patients (total n=25) will be treated.  If 5 or more patients responded by the 
end of the second stage, we will consider the regimen to be potentially worthy of further 
investigation.  The type I and type II errors of the study are both set at 10%.   
That is, if the true rate is 30% or higher, we will have over 90% power to declare the 
regimen effective.  If the response rate is 10%, the probability of stopping at the first 
stage is 51%, and the overall probability of false positive is controlled at 10%.  The 
expected sample size under null is 20.37.   
Accrual/Study Duration 
Cohort 1: The estimated monthly accrue for Cohort 1 is 1.5 patients/month, thus the 
accrue will be finished in 47 months. 
Cohort 2: We expect the accrual rate for Cohort 2 to be approximately 1 patient per 
month.  Accounting for a potential up to a 4-month hiatus between the two stages, we 
will finish the accrual of 25 patients in 29 months. 
Stopping guideline for insufficient accrual for both cohorts: 
Monitoring will be done separately for each cohort. 
If at one year after activation, the accrual is less than 35% of what was projected in the 
protocol for one year of accrual, consideration will be given to amendment of the 
statistical section or terminating that cohort of insufficient accrual. 
If at two years after activation, the accrual is less than 50% of what was projected in the 
protocol for two years of accrual, consideration will be given to amendment of the 
statistical section or terminating that cohort of insufficient accrual. 
15.7 
Analysis Plan 
15.7.1 Analysis of Primary Endpoints 
Cohort 1: PFS of the two study arms will be compared by log-rank test (1-sided, α=0.1).  
Kaplan-Meir plot will be provided.  HR and the corresponding 95% confidence interval 
(CI) will be estimated by Cox proportional model using treatment as covariate.  The 
primary analysis will be based on PP population.   
Cohort 2: ORR will be calculated as the proportion of patients achieved PR or CR within 
4 months after the initiation of the treatment.  ORR will be reported with corresponding 
95% exact CI.  Patients who have withdrawn from the study before starting the 
experimental therapy will be considered non-evaluable for clinical response and hence 
replaced. 
15.7.2 Analysis of Secondary Efficacy Endpoints 
x ORR in Cohort 1: ORR for each study arm will be calculated with corresponding 
95% exact CI.  Fisher exact test will be used to compare the ORR of the two study 
arms. 
x PFS in Cohort 2: PFS for Cohort 2 will be summarized using the Kaplan-Meir’s 

 
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method.  Median PFS with corresponding 95% CI will be provided.  
x Clinical benefit rate will be analyzed for each arm of Cohort 1 and Cohort 2 as 
described for ORR above.  
x OS: OS for Cohort 1 will be analyzed as described for PFS in Cohort 1 in Section 
15.6.1.  OS for Cohort 2 will be analyzed as described for PFS in Cohort 2 above. 
15.7.3 Analysis of Safety Endpoints 
The grade of toxicity measurement will follow CTCAE version 5.0.  The distribution by 
treatment group of the highest grade of each CTCAEs experienced by each patient 
categorized will be tabulated.  The tabulations will also be reviewed on a semi-annual 
basis by the Data Monitoring Committee (DMC).  These tabulations will include 
summaries by system organ class and summaries by term under each system organ class.   
15.7.4 Analysis of Integrated and Exploratory Biomarkers 
A separate Statistical Analysis Plan (SAP) will be developed for the integrated and 
exploratory biomarker analysis. 
Concordance of diagnostic tumor mutation profile generated by the Designated 
Laboratory, the pre-treatment biopsy mutation profile, and the pre-treatment ctDNA 
mutation profile will be assessed.  Details are provided in the statistical plan of the 
ComboMATCH Registration Protocol. 
15.8 
Monitoring/Oversight Committee 
NRG Oncology Data Monitoring Committee (DMC) 
The NRG Oncology DMC will review the study twice a year with respect to patient 
accrual and AEs.  The DMC also will review the study for protocol-specified interim 
analyses and on an “as needed” basis.   
NRG Oncology Early Phase Oversight Committee 
Study reports focusing on accrual, adverse event, and DLT data will be prepared 
regularly, and the PI/NRG study team will have regular conference calls (biweekly) to 
review the accrual/safety data, which will be summarized by the study chair.  Summaries 
from these calls will be reviewed quarterly by the NRG Oncology Early Phase Oversight 
Committee. 
Safety monitoring 
The grade of toxicity measurement will follow CTCAE v5.0.  Dose limiting toxicity 
(DLT) are defined as hematologic toxicity grade 3 or 4; Grade 4 neutropenia or 
thrombocytopenia > 7 days, Grade 3 thrombocytopenia with bleeding; non-hematologic 
toxicity grade ≥ 2 that, in the judgement of the investigator, was dose limiting; rash grade 
≥ 3 requiring dose reduction; treatment delay of ≥ 14 days because of unresolved toxicity. 
≥Grade 3 electrolyte abnormality that lasts >72 hours, unless the patient has clinical 

 
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symptoms, in which case all ≥ Grade 3 electrolyte abnormality regardless of duration 
should count as a DLT.   For patients with hepatic metastases, AST or ALT > 8 x ULN or 
AST or ALT > 5 x ULN for ≥ 14 days is considered a DLT.  Non-hematologic DLT will 
be defined as a treatment-related grade 3 or greater nonhematologic toxic effect other 
than nausea, vomiting, or fatigue; a drug-related grade 3 or greater clinically significant 
laboratory abnormality including CBC determined by the site PI (and discussion with the 
study PI if there is a consult needed), liver and kidney function, electrolyte that does not 
return to grade 1 or less or baseline within 1 week; grade 3 nausea/vomiting or diarrhea 
related to study drug treatment that is not controlled after > 72 hours with adequate 
antiemetic and other supportive care ; or ≥ Grade 3 fatigue ≥ 1 week related to study drug 
treatment.  A drug-related grade 2 toxicity persistent over 2 weeks requiring a dose 
reduction will be considered a DLT if the treating physician and the PI concur.  The 
threshold for allowable Grade 3 events is < 72 hours.  A previously reported DLT of 
binimetinib, including cardiac issues or retinal issues, will be further investigated for its 
effect on cardiac complication and will be considered a DLT as it is even if no other 
cardiac sequels are detected on investigation.  The observation period of the DLT is 1 
cycle.  
Bayesian analysis will be used by the study investigators to monitor the DLT rate in the 
first 15 patients of the combination arm in Cohort 1 and Cohort 2 to ensure that the 
underlying DLT rate does not exceed 20%.  For this purpose, a posterior probability (PPr) 
will be calculated from the study’s accumulating data on DLT or absence thereof, and a 
weak prior distribution of a beta distribution with parameters α= 0.5 and β= 0.5 is used.  
If PPr (DLT rate>0.2) > 0.90, i.e., there is a 90% or higher chance that more than 20% of 
patients will experience serious adverse events, then enrollment will be suspended 
pending a review of both the data and the study’s implementation.   
The enrollment suspension rule using the Bayesian analysis mentioned above can be 
represented as a table of possible outcomes for DLTs, as shown below. 
Bayesian rule for suspending enrollment 
Suspend accrual if > =n patients 
experience a DLT 
in N patients treated 
2 
2-4 
3 
5-7 
4 
8-11 
5 
12-14 
6 
15 
The operating characteristics of this study design can be expressed in terms of probability 
of early suspending the enrollment for a study arm under the assumptions of various true 
rates of DLT.  The following table calculated these probabilities for a single dose level 
based on the simulation of 10,000 hypothetical trials.  Simulations are done using the web 
tool provided at https://www.trialdesign.org/one-page-shell.html#BTOX. 
 

 
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16. 
REFERENCES 
Bertucci F, Ng CKY, Patsouris A, et al.  Genomic characterization of metastatic breast 
cancers.  Nature 2019; 569(7757):560-564. 
Ellis MJ, Llombart-Cussac A, Feltl D, et al.  Fulvestrant 500 mg versus anastrozole 1 mg 
for the first-line treatment of advanced breast cancer: overall survival analysis from the 
phase II FIRST study.  J Clin Oncol 2015; 33(32):3781-3787. 
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):228-247. 
Feng Q, O'Malley BW.  Nuclear receptor modulation--role of coregulators in selective 
estrogen receptor modulator (SERM) actions.  Steroids 2014; 90:39-43. 
Griffith OL, Spies NC, Anurag M, et al.  The prognostic effects of somatic mutations in 
ER-positive breast cancer.  Nat Commun 2018; 9(1):3476. 
Heldring N, Pawson T, McDonnell D, et al.  Structural insights into corepressor 
recognition by antagonist-bound estrogen receptors.  J Biol Chem 2007; 282(14):10449-
10455. 
Hu X, Lazar MA.  The CoRNR motif controls the recruitment of corepressors by nuclear 
hormone receptors.  Nature 1999; 402(6757):93-96. 
Lanman RB, Mortimer SA, Zill OA, et al.  Analytical and clinical validation of a digital 
sequencing panel for quantitative, highly accurate evaluation of cell-free circulating 
tumor DNA.  PLoS One 2015; 10(10):e0140712. 
Meric-Bernstam F, Frampton GM, Ferrer-Lozano J, et al.  Concordance of genomic 
alterations between primary and recurrent breast cancer.  Mol Cancer Ther 2014; 
13(5):1382-1389. 
Neve R, Chin K, Fridlyand J, et al.  A collection of breast cancer cell lines for the study 
of functionally distinct cancer subtypes.  Cancer Cell 2006; 10(6):515-527. 
Ogata H, Sato H, Takatsuka J, et al.  Human breast cancer MDA-MB-231 cells fail to 
express the neurofibromin protein, lack its type I mRNA isoform and show accumulation 
of P-MAPK and activated Ras.  Cancer Lett 2001; 172(2):159-164. 
Pearson A, Proszek P, Pascual J, et al.  Inactivating NF1 mutations are enriched in 
advanced breast cancer and contribute to endocrine therapy resistance.  Clin Cancer Res 
2020; 26(3):608-622. 
Razavi P, Chang MT, Xu G, et al.  The genomic landscape of endocrine-resistant 
advanced breast cancers.  Cancer Cell 2018; 34(3):427-438.e6. 
Robertson J, Bondarenko I, Trishkina E, et al.  Fulvestrant 500 mg versus anastrozole  
1 mg for hormone receptor-positive advanced breast cancer (FALCON): an international, 
randomised, double-blind, phase 3 trial.  Lancet 2016; 388(10063):2997-3005. 
Shang Y, Hu X, DiRenzo J, et al.  Cofactor dynamics and sufficiency in estrogen 
receptor-regulated transcription.  Cell 2000; 103(6):843-852. 
Shiau AK, Barstad D, Loria PM, et al.  The structural basis of estrogen 
receptor/coactivator recognition and the antagonism of this interaction by tamoxifen.  

 
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Cell 1998; 95(7):927-937. 
Sokol ES, Feng YX, Jin DX, et al.  Loss of function of NF1 is a mechanism of acquired 
resistance to endocrine therapy in lobular breast cancer.  Ann Oncol 2019; 30(1):115-123. 
TCGA.  Breast cancer related resources 2014 [Available from: 
http://cancergenome.nih.gov/search/breast. 
Wieand S, Schroeder G, O’Fallon JR.  Stopping when the experimental regimen does not 
appear to help.  Stat Med 1994; 13 (13-14):1453-1458. 
Zill OA, Banks KC, Fairclough SR, et al.  The landscape of actionable genomic 
alterations in cell-free circulating tumor DNA from 21,807 advanced cancer patients.  
Clin Cancer Res 2018; 24(15):3528-3538. 
 
 

 
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APPENDIX A 
ASSESSMENT OF PERFORMANCE STATUS AND ACTIVITIES OF DAILY LIVING 
1.0 
PERFORMANCE STATUS 
ECOG or Zubrod Scale 
 
Karnofsky Score 
0 
Fully active; able to carry on 
all pre-disease performance 
without restriction 
90-100% 
1 
Restricted in physically 
strenuous activity but 
ambulatory 
70-80% 
2 
Ambulatory and capable of  
self-care; but unable to carry 
out any work activities 
50-60% 
3 
Capable of only limited self-
care; confined to bed or chair 
more than 50% of waking 
hours 
30-40% 
4 
Completely disabled 
10-20% 
 
 
2.0 
ACTIVITIES OF DAILY LIVING 
The following definitions for activities of daily living (ADL) should be used when the  
CTCAE v5.0 grading criteria are based on ADL: 
x Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using 
the telephone, managing money, etc. 
x Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, 
taking medications, and not bedridden. 
 
 
 

 
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APPENDIX B 
CTEP COLLABORATIVE AGREEMENTS LANGUAGE 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the 
NCI under a Collaborative Agreement (CRADA, CTA, CSA) between the 
Pharmaceutical Company(ies) (hereinafter referred to as ”Collaborator(s)”) and the NCI 
Division of Cancer Treatment and Diagnosis.  Therefore, the following 
obligations/guidelines, in addition to the provisions in the “Intellectual Property Option to 
Collaborator” (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) 
contained within the terms of award, apply to the use of the Agent(s) in this study: 
x Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) 
and shall be maintained as such by the investigators.  The protocol documents for 
studies utilizing Agent(s) contain confidential information and should not be shared 
or distributed without the permission of the NCI.  If a copy of this protocol is 
requested by a patient or patient’s family member participating on the study, the 
individual should sign a confidentiality agreement.  A suitable model agreement can 
be downloaded from: http://ctep.cancer.gov. 
x For a clinical protocol where there is an investigational Agent used in combination 
with (an) other Agent(s), each the subject of different Collaborative Agreements, the 
access to and use of data by each Collaborator shall be as follows (data pertaining to 
such combination use shall hereinafter be referred to as "Multi-Party Data"): 
 NCI will provide all Collaborator(s) with prior written notice regarding the 
existence and nature of any agreements governing their collaboration with 
NCI, the design of the proposed combination protocol, and the existence 
of any obligations that would tend to restrict NCI's participation in the 
proposed combination protocol. 
 Each Collaborator shall agree to permit use of the Multi-Party Data from 
the clinical trial by any other Collaborator solely to the extent necessary to 
allow said other Collaborator to develop, obtain regulatory approval or 
commercialize its own Agent. 
 Any Collaborator having the right to use the Multi-Party Data from these 
trials must agree in writing prior to the commencement of the trials that it 
will use the Multi-Party Data solely for development, regulatory approval, 
and commercialization of its own Agent. 
x Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available exclusively to Collaborator(s), the NCI, and the 
FDA, as appropriate and unless additional disclosure is required by law or court order 
as described in the IP Option to Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 

 
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disclosed consistent with all applicable federal statutes and regulations for the 
protection of human subjects, including, if applicable, the Standards for Privacy of 
Individually Identifiable Health Information set forth in 45 C.F.R. Part 164. 
x When a Collaborator wishes to initiate a data request, the request should first be sent 
to the NCI, who will then notify the appropriate investigators (Group Chair for 
Cooperative Group studies, or PI for other studies) of Collaborator's wish to contact 
them. 
x Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with 
the guidelines and policies of the responsible Data Monitoring Committee (DMC), if 
there is a DMC for this clinical trial. 
x Any manuscripts reporting the results of this clinical trial must be provided to CTEP 
by the Group office for Cooperative Group studies or by the principal investigator for  
non-Cooperative Group studies for immediate delivery to Collaborator(s) for advisory 
review and comment prior to submission for publication.  Collaborator(s) will have 
30 days from the date of receipt for review.  Collaborator shall have the right to 
request that publication be delayed for up to an additional 30 days in order to ensure 
that Collaborator’s confidential and proprietary data, in addition to Collaborator(s)’s 
intellectual property rights, are protected.  Copies of abstracts must be provided to 
CTEP for forwarding to Collaborator(s) for courtesy review as soon as possible and 
preferably at least three (3) days prior to submission, but in any case, prior to 
presentation at the meeting or publication in the proceedings.  Press releases and other 
media presentations must also be forwarded to CTEP prior to release.  Copies of any 
manuscript, abstract and/or press release/media presentation should be sent to: 
 
 
 
 
E-mail: ncicteppubs@mail.nih.gov 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No 
publication, manuscript or other form of public disclosure shall contain any of 
Collaborator’s confidential/ proprietary information. 
 
 

 
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APPENDIX C 
EXPLORATORY BIOSPECIMEN RESEARCH 
Refer to Master Registration (screening) protocol for methods for MDNet WES and 
ctDNA. 
1. NF1 immunohistochemistry (IHC) 
Immunohistochemistry (IHC) is one of the key methods to detect, monitor, and select the 
predictive biomarker in cancer therapeutics even in the modern oncology.  A robust 
biomarker detection by IHC is critical in the translational development of such 
biomarkers.  Thus, BCM researchers developed an IHC assay of the neurofibromin (NF1) 
staining using the section of the pre-treatment tumors and core biopsies.  Given large size 
and multiple function of the NF1 gene, it is rare to have both alleles to be deleted or 
mutated, and yet functionally, one allele alteration sufficiently alters the function of the 
NF1 protein.  Our preliminary study using the PDX model study confirmed this finding.  
As part of the Baylor Breast SPORE project, the IHC antibodies have been established 
and continue to optimize to test the NF1.  This is a novel approach since this has not been 
done in other NF1 relevant disease. 
2. Microscaled Proteogenomics Assay 
Cancer proteogenomics integrates data from cancer genomics and transcriptomics along 
with cancer proteomics to provide deeper insights into cancer biology and therapeutic 
vulnerabilities.  Both by improving the functional annotation of genomic aberrations and 
through insights into pathway activation, this multi-dimensional approach to the 
characterization of human tumors shows promise for application to precision oncology.  
However real-life translation of proteogenomic approach is limited by the requirement of 
large sample acquisition.  For example, the Clinical Proteomic Tumor Analysis 
Consortium (CPTAC) requires at least 100 mg of tumor tissue, which typically yields 
quantitative information on > 10,000 proteins and > 30,000 phosphosites per sample.  To 
reduce these tissue requirements, BCM researchers developed methods to generate high- 
quality DNA, RNA and protein for deep-scale DNA and RNA sequencing and proteome 
and phosphoproteome analysis from a single 14 G core needle biopsy (Biopsy Trifecta 
Extraction, (BioTExt)) and a microscaled liquid chromatography-mass spectrometry (LC-
MS/MS)-based proteome and phosphoproteome analysis pipeline (MiProt) that requires 
only 25 μg peptide per sample.  Using this approach, BCM researchers successfully 
identified a downregulated ERBB2 protein, and the perturbation in phosphosite signature 
that correlated with lack of pCR, in ERBB2 targeted therapeutic trials.  Based on the 
success of proof-of-concept trial data, the plan is to apply this novel assay to this 
ComboMATCH trial pre-treatment sample.  BCM researchers hope to identify a 
phosphosite signature that is specific to the therapeutic sensitivity of FuBi combination 
and associated ER and Ras/MAPK pathway proteogenomic signatures.   
Details of the assay can be further found in our recent paper: 
https://www.nature.com/articles/s41467-020-14381-2 
 

 
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3. ctDNA ddPCR assay – four time points 
Digital PCR affords the ability to determine ultrasensitive measurements of mutated and 
wild type copies of DNA over tens of thousands of individual droplets based on emission 
of HEX and FAM-labeled primer probes.  An automated water-emulsion droplet 
generator (QX200DG, BioRad) creates tens of thousands of individual droplets that 
partition analyte molecules and detection probes into separate PCR reactions.  A typical 
starting sample of 20 μL should yield up to 20,000 droplets.  The QX200 can process and 
analyze up to 96 samples per run, yielding and counting approximately 1.5 million 
droplets per 96-well plate.  Such microfluidics-based sample partitioning and statistical 
analyses of up to millions of droplets provide absolute quantification of target DNA or 
RNA molecules for probe-based detection at high sensitivity without the need for 
standard curves.  Completed droplet reactions are streamed single file through a 
specialized reader for fluorescence analysis using a multi-pixel photon counter.  Positive 
droplets exhibit increased fluorescence of target (mutant) probes compared to negative 
droplets (wild type), and the fraction of PCR-positive droplets are quantitated according 
to Poisson distribution.  Thus, the fractional abundance of the mutant allele can be 
calculated by the ratio of the number of mutant-FAM probe copies per droplet over the 
total DNA concentration of the reaction.  
 
 
 
 
 
 
 
 
 
 
 
For ddPCR the mutations to be detected must be known a priori, as unlike next 
generation sequencing panels, the method is specific to confirming the presence or 
absence of a mutation at specific locus.  Qualifying mutations for the longitudinal ctDNA 
analysis by ddPCR will be selected from the sequenced surgical tissue samples with 
mutations prioritized by likely clonal/driver status.  For each mutant allele, a custom 
ddPCR probe set (BioRad) will be designed and used for serial ctDNA monitoring across 
blood collection timepoints in the study.  Digital droplet construction will be performed 
Figure 1. Representative mutation analysis by ddPCR. (A) Detection of the frameshift mutation NF1 p.Y2285fs*5 in MDA-175 
cells (top panel) and its absence in MDA-231(bottom panel) using custom-–designed ddPCR primer/probes. Positive detection 
of the NF1 mutation is identified by the cluster of blue dots (FAM channel, y axis), where the green dots (HEX channel, x axis) 
indicate wild type. Quadrant thresholds that discriminate probe signals were calculated using the BioRad QuantaSoft® 
software package.  The fractional abundance or allelic frequency of the NF1 mutant is ~51%, consistent with the 
heterozygous nature of this alteration.  (B) Table inset.  Representative data from commercial cfDNA reference standards 
prepared in synthetic plasma that were extracted using Promega ctDNA extraction chemistry followed by digital droplet PCR.  
Two independent mutations at varying mutant allelic fractions (VAF%) were examined by ddPCR are demonstrated to be 
within range of acceptable (%CV) published manufacturer criteria.

 
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on the BioRad AutoDG QX200 (automatic droplet generator) ddPCR system with assays 
utilizing TaqMan hydrolysis chemistry with custom and/or commercially available 
primer-probe sets (BioRad).  The partitioned PCR droplet assays will be subjected to 
amplification using a C1000 Touch™ thermal cycler (BioRad) and fluorometrically 
assessed on the QX200 droplet reader.  The fraction of positive droplets will be fitted to a 
Poisson distribution using available QuantaSoft Pro software (BioRad) to calculate the 
number of mutant and wild-type (WT) copies of DNA in the sample.  BCM researchers 
demonstrated that custom probes can be designed and used to detect specific mutations, 
as illustrated in Figure 1A above for a frame-shift alteration in NF1 (NF1 p.Y2285fs*5).  
BCM researchers previously confirmed that high sensitivity and specificity can be 
achieved on this platform using commercially available ctDNA reference standards 
prepared in synthetic plasma (Horizon Discovery) (Figure 1B).  This assay platform will 
be utilized in collaboration with Dr. George Miles to monitor abundance of ctDNA 
isolated from blood plasma at sampled timepoints outlined in this proposed study to 
combine fulvestrant and binimetinib.  It is believed that this preliminary data and track 
record of developing and applying ddPCR-based serial monitoring of ctDNA justifies the 
NF1 mutant allele detection to monitor the therapy induced clonal/ subclonal changes 
incorporated into the ComboMATCH fulvestrant + binimetinib study.  
As noted, all these three exploratory assays will be supported as a part of newly funded 
Baylor Breast SPORE2020. 
 

 
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APPENDIX D 
RESEARCH BIOSPECIMEN SUBMISSION GUIDELINES 
I.  Kit Ordering [Kit Order Form located on the CTSU website] 
II.  Tissue Submissions 
The relevant pathology and surgical reports and the following forms must accompany all 
tissue submissions: 
x Copy of the REDACTED diagnostic or surgical pathology report associated with the 
submitted tissue 
x The original diagnostic pathology report 
x Other immunologic and cytologic reports 
x Initial Activation: EA Generic Specimen Submission Form 2981 (CTSU website) 
x Post-Activation Transition: Rave-generated Samples Tracking and Manifest Form 
x Initial Activation: Local Pathology Group Information Form (CTSU website) 
x Post-Activation Transition: Rave-generated Local Pathology Group Information Form 
x A copy of all pathology and cytologic reports should be uploaded via the EAY191 
OPEN Registration  
x For initial activation, fax EA Generic Specimen Submission Form and Local 
Pathology Group Information Form to MD Anderson TQL 713-745-4925 
NOTE: The CLIA Submission Form available in Rave is NOT required for ComboMATCH. 
A.  Fresh Research Biopsy Samples 
The biopsies are to occur: 
x After registration to the Treatment Trial, prior to initiation of treatment (MANDATORY). 
x At end of treatment or progression if the patient has been on protocol treatment for 6 or 
more months and there is a lesion amenable to a minimal risk biopsy (OPTIONAL). 
NOTE: The EOT may serve as the ‘prior to start of treatment’ research biopsy for a 
subsequent cTT. 
The biopsies must be minimal or less than minimal risk (no more than 2% risk of serious 
complication requiring hospitalization).  If it is determined during or just prior to the biopsy 
procedure that it would be greater than minimal risk, no biopsy is to be performed with no 
impact on patient participation in the treatment trial. 
The following specimens are to be submitted: 
x Two core biopsies, 16-18 gauge in diameter and at least 1 cm in length.  Place each core 
between sponges in a cassette, snap the cassette lid in place, place the cassette into the 
formalin-filled container, secure the container lid, and place the container into the 
shipping kit. 
 

 
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x Two cores embedded in OCT.  
- 
Use 14- or 16-gauge needle to obtain 2 replicate cores.  Quality of the collected core 
specimens is essential.  Cores containing tumor appear white and dense.  Cores 
containing fat are not suitable for analysis and should be recollected.  If uncertain, 
cores can be immersed briefly (< 30 seconds) in saline.  Tumor containing cores sink, 
whereas predominantly fatty cores float. 
- 
Place two, square, clear plastic cryomolds on pre-cooled metal platform.  Keep metal 
platform on dry ice.  Place two cores (one core/mold) fully extended into cryomolds 
and immediately cover each core with 4 mL OCT from provided pre-filled 10 mL 
OCT syringe. 
- 
Allow OCT to freeze completely.  OCT is frozen when it is completely white and 
chalky in appearance.  Once frozen, push on back of the cryomold to eject OCT pellet 
into a white cryomold cassettes (1 pellet per cryomold cassette).  Close cryomold 
cassettes. 
- 
Place cryomold cassettes in frozen specimen bag and seal. 
B.  Research Biopsy Guidelines 
These instructions are for patients that are undergoing fresh tumor biopsy rather than using 
archival tissue that is less than 12 months old.  
1. 
If a non-cutaneous lesion site is deemed appropriate for biopsy with minimal risk to 
the participant by agreement between the investigator, patient and Interventional 
Radiologist an attempt at biopsy will be made.  All internal organ biopsies will be 
done by the Interventional Radiologist with a percutaneous approach, or during a 
clinically necessary surgical/endoscopic procedure, including craniotomy for brain 
metastasis or primary tumor. 
2. 
No endoscopic, laparoscopic, or surgical procedure will be done solely to obtain a 
biopsy for this protocol. 
3. 
The choice of imaging modality to be used to facilitate tissue acquisition during the 
biopsy procedure will be decided by members of the Interventional Radiology team 
at the clinical site and may include ultrasound, CT scan, or MRI.  Tumor biopsies 
will be performed only if they are considered to be of low risk (< 2% major 
complication rate) to the participant as determined by the investigator and 
Interventional Radiologist.  Biopsies will be performed under local anesthesia 
and/or sedation. 
C.  FFPE Tissue Block 
FFPE tumor tissue may be submitted in lieu of the “Prior to start of treatment” fresh tissue 
biopsy if it meets the following requirements: 
x Tissue must have been collected within 12 months prior to registration to the 
EAY191 Registration Trial. 
x Patient may have received treatment after tissue collection; however, lack of response 
must be documented prior to registration to EAY191. 

 
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The optimal block is 70% tumor tissue with: 
x Surface area: 25mm2 is optimal.  Minimum is 5 mm2 
x Volume: 1mm3 optimal.  Minimum volume is 0.2 mm3; however, the success of DNA 
extraction decreases at suboptimal tissue volume. 
If an existing block is not available, the following is to be submitted: 
x One (1) H&E slide, AND 
x Ten (10) to twenty (20) or more recently cut 4-5 micron unstained sections on 
positively charged slides 
D.  Peripheral Blood Submissions: 
Research bloods must be collected and submitted “prior to start of treatment,” on days 
C1D15 and C2D1 of treatment and at “end of treatment/progression.”  
Streck tube: 
a. Draw 10mL peripheral blood into each of 4 vacutainers (2 vacutainers on C1D15 
and C2D1) for plasma and buffy coat.  Gently invert 8-10 times. 
b. Ship at ambient temperature the day of collection. 
E.  Shipping Procedures 
The tissue and blood specimens are to be shipped at ambient temperature (use a cool pack in 
warm weather).  The Rave-generated shipping manifest must accompany the samples.  
Ship to: 
MD Anderson Cancer Center CTO TQL 
ATTN: For ComboMATCH Clinical Trial 
1515 Holcombe Blvd. 
G1.3598 
Houston, TX 77030 
Phone: Toll Free 844-744-2420 (713-745-4901 Local or International Sites) 
Fax: 713-745-4925 
F.  Precision Medicine Specimen Tracking Manifest Form and Pathology Group Form 
Once the Rave-based Forms become available, it is required (barring special circumstances) 
that all samples submitted on this trial be entered and tracked in the Screening Instance of 
Rave.  A Rave-generated shipping manifest must be generated and shipped with all sample 
submissions.  Additionally, a Pathology Group Form should be completed for submitted 
tissue reviewed by a local pathologist. 
Please direct your questions or comments pertaining to the specimen tracking system to 
combo-match-support@nih.gov or https://service.cancer.gov/ComboMATCH. 

 
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If Rave is unavailable, the Generic Specimen Submission Form (#2981) is to be used as a 
substitute for the Rave generated shipping manifest (see the CTSU website).  Additionally, 
the paper version of the Pathology Group Form should also be completed (see the CTSU 
website).  The completed forms are to be faxed to the receiving laboratory the day the 
samples are shipped.  Indicate the appropriate lab on the submission form: 
MD Anderson Cancer Center CTO TQL: 713-745-4925 
Retroactively enter all specimen collection and shipping information when Rave is available. 
G.  Sample Inventory Submission Guidelines 
Inventories of all samples submitted will be tracked via Rave/CSMS and receipt verified by 
the receiving laboratory.  Sites will be contacted by the receiving laboratory or 
ComboMATCH Help Desk if usability issues arise.  Inventories of specimens forwarded and 
utilized for the study will be submitted by the laboratory to the ECOG-ACRIN Operations 
Office - Boston on a monthly basis in an electronic format defined by the ECOG-ACRIN 
Operations Office - Boston. 
 
 

 
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APPENDIX E 
MEDICATION DIARY 
Protocol: EAY191-N2/Cohort 1, Treatment Regimen 1 or Cohort 2 
 
Page 1 
Study Medication: Binimetinib 
Prescribed dose: (insert number) tablets (15 mg each) orally twice each day 
x Please record information daily. 
x Take binimetinib in the morning and evening (with or without food) approximately  
12 hours apart. 
x Tablets should be swallowed whole. 
x If a dose of binimetinib is missed, take it if there is > 6 hours until the next dose.  If it is 
within 6 hours of the next scheduled dose, skip this dose and take the next dose at the 
scheduled time.  Do not make up for the missed doses.  
x If a dose is vomited, skip the dose.  Take the next dose at the scheduled time. 
x Please remember to bring this diary (all pages) and your binimetinib containers (even if 
they are empty) to each visit with your study team. 
Cycle 1 
(Start 
binimetinib 
on Day15) 
Date 
Time taken/Dose 
Notes 
Include any side effects that you 
are having.   
AM/dose 
PM/dose 
15 
 
 
 
 
16 
 
 
 
 
17 
 
 
 
 
18 
 
 
 
 
19 
 
 
 
 
20 
 
 
 
 
21 
 
 
 
 
22 
 
 
 
 
23 
 
 
 
 
24 
 
 
 
 
25 
 
 
 
 
26 
 
 
 
 
27 
 
 
 
 
28 
 
 
 
 

 
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Patient's name: ______________________________ 
 
 
Physician's office will complete this section: 
Total number of binimetinib 15 mg tablets taken this reporting period: _______ 
Research Staff Signature: ____________________________________ 
Date: _______ 
 
 
 

 
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Protocol: EAY191-N2/Cohort 1, Treatment Regimen 1 or Cohort 2 
 
 
Page 1 
Study Medication: Binimetinib 
Prescribed dose: (insert number) tablets (15 mg each) orally twice each day 
x Please record information daily. 
x Take binimetinib in the morning and evening (with or without food) approximately 12 hours 
apart. 
x Tablets should be swallowed whole. 
x If a dose of binimetinib is missed, take it if there is > 6 hours until the next dose.  If it is within 
6 hours of the next scheduled dose, skip this dose and take the next dose at the scheduled time.  
Do not make up for the missed doses.  
x If a dose is vomited, skip the dose.  Take the next dose at the scheduled time. 
x Please remember to bring this diary (all pages) and your binimetinib containers (even if they are 
empty) to each visit with your study team. 
Cycle 
(insert 
cycle #) 
Day 
Date 
Time taken/dose 
Notes 
Include any side effects that you 
are having.   
AM/dose 
PM/dose 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
11 
 
 
 
 
12 
 
 
 
 
13 
 
 
 
 
14 
 
 
 
 
15 
 
 
 
 
16 
 
 
 
 
17 
 
 
 
 
18 
 
 
 
 
19 
 
 
 
 
 

 
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Protocol: EAY191-N2/Cohort 1, Treatment Regimen 1 or Cohort 2  
 
 
Page 2 
Study Medication: Binimetinib 
Cycle 
(insert 
cycle #) 
Day 
Date 
Time taken/dose 
Notes 
Include any side effects that you are 
having.   
AM/dose 
PM/dose 
20 
 
 
 
 
21 
 
 
 
 
22 
 
 
 
 
23 
 
 
 
 
24 
 
 
 
 
25 
 
 
 
 
26 
 
 
 
 
27 
 
 
 
 
28 
 
 
 
 
 
Patient's name: ______________________________ 
 
 
Physician's office will complete this section: 
Total number of binimetinib 15 mg tablets taken this reporting period: ___________ 
Research Staff Signature: __________________________________Date: _______________