Clinical trial NCT04390243
Conditions: Locally Advanced Pancreatic Carcinoma Metastatic Pancreatic Carcinoma Recurrent Pancreatic Carcinoma Stage III Pancreatic Cancer AJCC v8 Stage IV Pancreatic Cancer AJCC v8
Sponsor: Academic and Community Cancer Research United
Start date: 2020-11-16; Completion date: 2023-11-01
Enrollment: 6 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies the side effects and how well the combination of binimetinib and encorafenib work in treating patients with pancreatic cancer with a somatic BRAF V600E mutation. Binimetinib and encorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving binimetinib and encorafenib may work better compared to the usual treatment in treating patients with pancreatic cancer and a somatic BRAF V600E mutation.

Detailed description:
PRIMARY OBJECTIVE:

I. To determine the efficacy of the combination of binimetinib and encorafenib as \>= 2nd line of treatment for patients with metastatic pancreatic cancer with BRAF V600E mutation.

SECONDARY OBJECTIVES:

I. To determine in patients treated with the combination of binimetinib and encorafenib as \>= 2nd line of treatment for patients with metastatic pancreatic cancer with BRAF V600E mutation:

Ia. The median progression-free survival. Ib. The median overall survival. Ic. Duration of response. Id. Time to response. Ie. The safety and tolerability.

OUTLINE:

Patients receive encorafenib orally (PO) once daily (QD) and binimetinib PO twice daily (BID) on days 1-25. Treatment repeats every 28 days for up to 36 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for up to 5 years.

Arms: arm 1: Patients receive encorafenib PO QD and binimetinib PO BID on days 1-25. Treatment repeats every 28 days for up to 36 cycles in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Binimetinib intervention 2: Encorafenib
Intervention descriptions: intervention 1: Given PO intervention 2: Given PO

Protocol documents:
Prot_SAP_000.pdf: 
 
1 
ACCRU-GI-1907 
 
Academic and Community Cancer Research United (ACCRU) 
 
BrafPanc: A Phase II Trial of Binimetinib in combination with Encorafenib in patients with 
Pancreatic Malignancies and a somatic BRAFV600E mutation 
 
For any communications regarding this protocol, please contact the person indicated on the 
Protocol Resource page. This is a stand-alone document found on the ACCRU web site 
(
).  
 
 
 
ACCRU Study Chair: 
 
 
 
 
           Study Co-Chair:  
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
Correlative Science Co-Chairs 
 
 
 
 
 
 
   
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
  
     
 
 
  
 
√ Study contributor(s) not responsible for patient care. 
Drug Availability 
 
Drug Company Supplied: Binimetinib and encorafenib IND Exempt 
 
Research Coordinating Center 
 
 
 
Document History 
(effective date) 
Initial Version 
April 15, 2020 


 
2  
ACCRU-GI-1907 
 
Index 
 
Schema 
 1.0 
Background 
 2.0 
Goals 
 3.0 
Patient Eligibility 
 4.0 
Test Schedule 
 5.0  
Stratification Factors 
 6.0 
Registration/Randomization Procedures 
 7.0 
Protocol Treatment 
 8.0 
Dosage Modification Based on Adverse Events  
 9.0 
Ancillary Treatment/Supportive Care 
10.0 
Adverse Event (AE) Reporting and Monitoring  
11.0 
Treatment Evaluation Using RECIST Guideline 
12.0 
Descriptive Factors 
13.0 
Treatment/Follow-up Decision at Evaluation of Patient  
14.0 
Body Fluid Biospecimens 
15.0 
Drug Information 
16.0 
Statistical Considerations and Methodology 
17.0 
Pathology Considerations/Tissue Biospecimens 
18.0 
Records and Data Collection Procedures 
19.0 
Budget 
20.0 
References 
 
Appendix I – Patient Medication Diary 
Appendix II – Contraception  
 
 


 
3 
ACCRU-GI-1907 
 
 
 
 
 
  
Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle length = 28 days 
Treat until progression or maximum of 36 cycles 
 
 
 
 
 
 
 
 
 
 
 
Generic name:   Binimetinib 
Brand name(s):  MEKTOVI 
Availability: Clinical Research Services 
Generic name: Encorafenib 
  
 
Brand name(s):  BRAFTOVI 
Availability: Clinical Research Services 
 
PD at any time 
Unacceptable adverse Events 
Patient refusal 
Investigator decision 
 
 
 
        Event Monitoring 
 
Pre-Registration 
 
Registration 
Treatment with 
Encorafenib + 
Binimetinib 
Event Monitoring 


 
4  
ACCRU-GI-1907 
 
1.0 
Background  
 
1.1 
Treatment 
 
1.11  
Therapy for Pancreatic Cancer 
 
While the treatments for metastatic pancreatic cancer have improved in the last 
decade, and modern chemotherapy regimens, including FOLFIRINOX and 
gemcitabine + nab-paclitaxel have improved survival times, the hard reality is 
that the vast majority of patients do not respond to standard chemotherapy. 
Specifically, the objective response rate (ORR) with front line FOLFIRINOX or 
gemcitabine + nab-paclitaxel are 32% and 23% respectively (Conroy et al, 2011; 
Von Hoff et al, 2013). In the 2nd line setting, those percentages drop 
considerably. For patients treated with the only FDA-approved second line 
therapy regimen, 5-flurouracil + nano-liposomal irinotecan, the ORR is only 
17%, and the median progression-free (PFS) and overall survival (OS) was only 
4 and 6 months, respectively (Wang-Gillam et al, 2016). Multiple other Phase II 
trials as 2nd line therapy for patients have yielded ORR of 2.5 to 24%, with a 
PFS typically of 2 – 4 months, and OS typically of 4 – 6 months (Boeck et al, 
2008; Boeck et al, 2007; Cantore et al, 2004; Cereda et al, 2016; Cereda et al, 
2011; Demols et al, 2006; Kim et al, 2012; Milella et al, 2004; Oettle et al, 2000; 
Tsavaris et al, 2005; Ulrich-Pur et al, 2003; Xiong et al, 2008; Zaniboni et al, 
2012).  
 
1.12 
Predictive Biomarkers in Pancreatic Cancer, and BRAF mutations 
 
There are no FDA approved targeted therapies for patients with pancreatic 
cancer. However, broad-based genetic sequencing efforts have consistently 
revealed that ≥25% of pancreatic cancers have potentially highly actionable 
molecular biomarkers with the definition of “highly actionable” being identified 
as a biomarker that predicts for a high response rate, or otherwise high degree of 
clinical activity for a therapy targeted to that biomarker, as defined in any cancer 
type (Aguirre et al, 2018; Bailey et al, 2016; Biankin et al, 2012; Collisson et al, 
2011; Lowery et al, 2017; Pishvaian et al, 2018; Waddell et al, 2015; Witkiewicz 
et al, 2015). Two biomarkers that are clearly linked to a high degree of anti-
cancer activity across tumors types include MSI-high or MMR deficient solid 
tumors, and NTRK fusions. Pembrolizumab and nivolumab are FDA approved 
for MSI-high or MMR deficient solid tumors (Le et al, 2015); while larotrectinib 
is FDA approved for tumors that harbor NTRK gene fusions (Drilon et al, 2018). 
 
One such predictive biomarker is an activating mutation in the BRAF gene. In the 
population of pancreatic cancers lacking KRAS mutations, probable driver 
mutations have been identified including BRAF, GNAS, CTNNB1, as well as 
NRG1 fusions (Cancer Genome Atlas Research Network. Electronic address & 
Cancer Genome Atlas Research, 2017; Heining et al, 2018). BRAF mutations 
specifically have been previously identified in KRAS wild-type and mutant 
pancreatic cancer cell lines and patient tumors (Foster et al, 2016; Ishimura et al, 
2003; Singhi et al, 2019).  
 
BRAF alterations have also been identified in multiple cancer types including 
lung, colon, thyroid, and melanoma, as well as in non-Hodgkin lymphoma 


 
5  
ACCRU-GI-1907 
 
(Davies et al, 2002; El-Osta et al, 2011). In pancreatic acinar cell carcinomas, 
rearrangements involving BRAF and RAF1 (CRAF) have been identified in 
approximately 23% of tumors (Chmielecki et al, 2014). Combined BRAF and 
MEK inhibition is now FDA approved for metastatic melanoma, non-small cell 
lung cancer and anaplastic thyroid cancer. In addition, targeting BRAFV600 
alterations with combinations of RAF/MEK inhibition with and anti-EGFR 
therapy has improved outcomes in colorectal cancer (Hyman et al, 2015; 
Planchard et al, 2016; Van Cutsem et al, 2019) and received breakthrough FDA 
status in 2018.    
 
These alterations have been recently classified into 3 functional classes based on 
dependence of RAS activation, BRAF kinase activity, and signaling properties 
(Yaeger & Corcoran, 2019). Class I BRAF mutations result in RAS-independent 
kinase activation and signal as monomers (Poulikakos et al, 2010; Pratilas et al, 
2009). To date, this class typically includes BRAFV600E mutations.  Class II 
mutations are also RAS-independent but signal as heterodimers and do not 
commonly co-occur with other alterations in the MAPK pathway (Yao et al, 
2015). This group includes activating BRAF mutations, several fusions, and in-
frame deletions. Class III mutations are RAS-dependent and occur when these 
mutations heterodimerize with wild-type CRAF and amplify Ras signaling. Class 
III mutations often co-occur with activating RAS mutations, or NF1 loss-of-
function mutations. 
 
We recently evaluated several large pancreatic cancer next-generation 
sequencing (NGS) datasets, and we identified four categories of BRAF 
alterations: BRAFV600 mutations, other missense mutations, in-frame deletions, 
and fusions all of which were evenly represented across patients (Table 1). 
Acinar cell carcinomas frequently harbored BRAF fusions (4/6, 67%); while 
patients with neuroendocrine tumors most frequently had BRAFV600 mutations and 
non-canonical BRAF mutations (8/9, 89%). BRAFV600E mutations were also 
found in rare histologies, with one in a pancreatoblastoma and one in a solid and 
pseudopapillary neoplasm. The most common BRAF alterations in pancreatic 
acinar cell cancer patients were BRAF fusions (12/53), in-frame deletions (11/53, 
N486_P490del, △NVTAP) and the canonical BRAFV600 mutation (11/53). 
 
 
 
 
 


 
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ACCRU-GI-1907 
 
Histology 
Dataset 
#Altered / 
# Total 
Fraction 
mutated 
Alterations 
Pancreatic 
adenocarcinoma 
GENIE 
13 / 587 
0.022 
N486_P490del (4); V600_K601delinsE (2); 
Y633H; 
*767Cext*3; 
V600E; 
L485F; 
D391N; G469S; H766Y 
ICGC 
4 / 572 
0.007 
V471I; V487S; P334L; D594G 
KYT 
23 / 926 
0.026 
N486_P490del (6); V600E (4); SND1-
BRAF fusion (3); V600_K601>E; deletion 
exons 2-10 + S467L; G596R; T310I; 
MKRN1-BRAF 
fusion; 
TMEM9-BRAF 
fusion; V600E + deletion exons 2-10 (after 
developing resistance to BRAF-targeted 
therapy); G469A; rearrangement; D594G; 
V487_P492>A 
MSK 
7 / 383 
0.018 
BRAF-SND1 fusion (2); BRAF-LUC7L2 
fusion; V600R; V600E; BRAF-JHDM1D 
fusion; V600E + BRAF-SND1 fusion 
TCGA 
3 / 150 
0.02 
T488_Q493delinsK; N486_P490del; R462T 
UTSW 
3 / 109 
0.028 
V600E (3) 
Total 
53 / 2,727 
0.019 
 
Pancreatic acinar cell 
carcinoma 
GENIE 
3 / 11 
0.273 
X327_splice; V600E; GLI2-BRAF fusion 
MSK 
3 / 13 
0.231 
BRAF-SND1 fusion (2); GIPC2-BRAF 
fusion 
Total 
6 / 24 
0.25 
 
Pancreatoblastoma 
KYT 
1 / 1 
1 
V600E 
Solid 
pseudopapillary 
neoplasm  
GENIE 
1 / 7 
0.143 
V600E 
Table 1. BRAF alterations in pancreatic cancers 
 
1.13 
BRAF Mutant Cell Lines are Responsive to MEK and RAF Inhibitors 
NIH/3T3 cells with stable expression of either BRAF V600E or BRAF△NVTAP were 
treated with varying concentrations of vemurafenib (BRAFV600E inhibitor), 
PLX8394 (BRAF inhibitor), LY300912 (pan-RAF inhibitor), trametinib (MEK 
inhibitor), or dabrafenib (BRAF inhibitor) and analyzed for ERK 
phosphorylation (Figure 1). All of the RAF and MEK inhibitors demonstrates 
significant single agent activity in the BRAF V600E mutant cell lines (Figure 1C). 
In the BRAF△NVTAP mutant lines, there appeared to be decreased sensitivity to 
vemurafenib and LY300912, and otherwise anti-tumor activity across other RAF 
and MEK inhibitors.  
 
Cell viability studies of BA/F3 populations expressing BRAF V600E or BRAF△NVTAP 
were performed with varying concentrations of different RAF or MEK inhibitors 


 
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ACCRU-GI-1907 
 
(Figure 1, E-H). These studies confirmed single agent activity across the RAF 
and MEK inhibitors, again with enhanced activity of the BRAF△NVTAP mutant to 
all treatments. 
 
Figure 1. BRAF Mutant Cell Lines are Responsive to MEK and RAF Inhibitors. (A) Western blot 
analysis from stable expression of the indicated BRAF mutants in NIH/3T3 and BA/F3 cells. The mutants 
include BRAF V600E and BRAF△NVTAP. (B) BA/F3 cell growth curve from stable expression of the indicated 
constructs including control vector, KRASG12V, BRAFWT, BRAF V600E, and BRAF△NVTAP. (C) Western blot of 
lysates from NIH/3T3 cells with BRAF V600E or BRAF△NVTAP after treatment with the indicated 
concentration of different RAF or MEK inhibitors for 2 hours. (D – H) Viability of BA/F3 populations 
with BRAF V600E or BRAF△NVTAP after 72 hour treatment with the indicated concentration of different RAF 
or MEK inhibitors. Error bars indicate +/- SD.   
 
1.14 
A retrospective case series of BRAF mutated pancreatic cancer 
 
In a retrospective case series of pancreatic cancer patients with clinically 
annotated data, we identified 81 patients with BRAF alterations (Table 1). The 
histologies were as follows: 65/81 adenocarcinoma, 13/81 acinar cell cancer or 
mixed acinar/neuroendocrine, 4/81 IPMN and 1 pancreaticoblastoma. Median 
age was 64 (42 – 86) and 40/81 were women. 69 of the 81 patients (85%) were 
KRAS wild-type. 18/81 of patients had a V600E, 19/81 non-canonical, 20/81 
deletion, and 25/81 fusion abnormalities. The majority of the cohort presented 
with advanced disease 61/81 (75%) and 20/81 (25%) presented with earlier stage 
disease. The median overall survival of the cohort was 1.92y [95%CI=1.36-2.44]. 
The median number of lines of therapy was 2.  
 
In our 81 patients with BRAF alterations, KRAS alterations were only found in 
12 (15%) patients. Additional genomic alterations involving the targeted genes of 
the various sequencing panel were identified in genes such as TP53 (43%), 
CDKN2A/B (36%), and SMAD4 (19%). 
 
Of the patients with BRAFV600E alterations, 15/18 were in pancreatic 


 
8  
ACCRU-GI-1907 
 
adenocarcinomas and 3/18 in acinar cell tumors, median age was 63, and 13/17 
were women. One had a KRASG12V alteration and 9 had alterations in p53, and 5 
alterations in CDKN2A and 4 with alterations in SMAD4. 
 
We then classified these alterations into functional categories using available 
literature regarding their activity and their response to BRAF targeted therapy. Of 
the 17 BRAFV600E alterations, 13 were placed in class 1 (13/17). If there were 
additional alterations in BRAF, KRAS, or other potential driving alterations they 
were placed in class 3 (4/17). In our cohort, co-existing alterations occurred in 
NTRKfusion, KRASG12V, BRAFQ609L, and SND1-BRAFfusion. Class 2 alterations 
included fusion abnormalities and in-frame deletions which were placed in 
separate categories. Our last category included Class 3 alterations, and those with 
multiple driver mutations. Of those with multiple drivers outside of the BRAF 
gene, 13/15 were KRAS alterations an NTRK fusion, and a RAF mutation. 3 
patients had 2 alterations in the BRAF gene; BRAFV600E + SND-1-BRAFFusion, 
BRAFV600E + BRAFQ609L, and BRAFS467L + Exon 2-10deletion.   
 
An overall survival analysis was performed for each of these functional BRAF 
categories. Patients with IPMN’s and resected disease were excluded. Class 1 
median overall survival was 1.3 years (N=8); Class 2 (fusion) was 1.9 years 
(N=18) and Class 2 (non-fusion) was 1.2 (n=12); and class 3 1.6 years (n=15). 
There were no significant differences found between these categories of BRAF 
alterations. 
 
1.15 
MEK and RAF inhibitors have activity in the patients with KRAS wild-type and 
BRAF-mutated pancreatic cancers 
 
In our case series, 17 patients were treated with BRAF directed therapy (Figure 
2). This includes 6 patients treated with combination BRAF and MEK and 8 
patients with MEK inhibitor therapy alone. 2 patients were treated with pan-RAF 
inhibitors. The median lines of previous therapy was 2 (1-4). In evaluable 
patients, median weeks of therapy was 21 (7-110).   
 
Responses to BRAF targeted therapy were evaluated based the recently described 
functional classification system previously described. All patients with Class-1 
alterations had significant responses to BRAF targeted therapy. This included 2 
BRAFV600E alterations with durable partial responses of 48 weeks and over 2 
years and in 1 patient with BRAF△NVTAP had stable disease after 21 weeks. In class 
2 BRAF fusions there was significant activity to single agent MEK inhibitors. 4/6 
patients had a treatment response to single agent trametinib. 2 with partial 
responses; one lasting 73 weeks and the other ongoing at 21 weeks.  2 with stable 
disease; one lasting 30 weeks and the other 12 weeks. In patients with class 2 
BRAF in-frame deletions, 2 out of 5 had therapeutic responses. There was a 
partial response to single agent MEK inhibition lasting 24 weeks and stable 
disease on MEK and BRAF combination lasting 21 weeks and on-going. Patients 
with class 3 alterations did not derive benefit form BRAF targeted therapy in our 
cohort (N=3). 
 
 


 
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ACCRU-GI-1907 
 
 
 
Figure 2. Therapeutic activity of BRAF targeted agents. Responses to 17 patients treated with BRAF directed 
therapy categorized by BRAF class, including 6 patients treated with combination BRAF and MEK and 8 patients 
with MEK inhibitor therapy alone. Each horizontal bar represents the time on therapy. Green bars represent patients 
with partial response as best response, light green are patients with stable disease, copper bars are patients with no 
response, and white bars indicate unevaluable subjects. Arrows indicate that patients continue on therapy.  
 
1.16 
Patients receiving BRAF directed therapy have improved outcomes 
 
Using a multivariate model including BRAF alteration type, we compared overall 
survival between patients with BRAF alterations (delineated by BRAF subclass) 
who received a molecularly-matched therapy targeting the MAPK signaling 
pathway (e.g. a BRAF, pan-RAF, MEK, or ERK inhibitor) vs patients with 
BRAF alterations did not. There was a significant survival benefit, matched vs 
unmatched: (p = 0.02068, HR = 0.36 [0.15-0.86]). The extent of the survival 
benefits with targeted BRAF therapy were associated with functional class.  
 
 
 
 
 
 
 


 
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ACCRU-GI-1907 
 
 
Figure 3. Overall survival of pancreatic cancers with BRAF alterations 
 
 
 
 
 
 
 


 
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ACCRU-GI-1907 
 
2.0 
Goals  
 
2.1 
Primary Goal 
To determine the efficacy of the combination of binimetinib and encorafenib as ≥ 2nd 
line of treatment for patients with metastatic pancreatic cancer with BRAFV600E mutation. 
 
2.11  
Primary Endpoint 
Objective response rate at 24 weeks post-registration, as defined by RECIST 1.1. 
 
2.2 
Secondary Goals 
To determine in patients treated with the combination of binimetinib and encorafenib as ≥ 
2nd line of treatment for patients with metastatic pancreatic cancer with BRAFV600E 
mutation: 
 
 
2.21  
The median progression-free survival  
Endpoint: The median time from study registration to clinical or radiographic 
disease progression or death, whichever occurs first, as defined by RECIST 1.1. 
 
2.22 
The median overall survival 
Endpoint: The median time from study registration to death. 
 
 
2.23 
Duration of Response 
Endpoint: The median duration of time from first documentation of an objective 
response to the earliest date progression is documented.  
 
 
2.24 
Time to Response 
Endpoint: The median duration of time from study registration to the first 
documentation of an objective response.  
 
2.25  
The safety and tolerability 
Endpoint: The rate of grade 3+ Adverse Events as defined by NIH CTCAE v5.0. 
 
2.3 
Correlative Research Goal 
 
2.31 
To determine the mechanisms of resistance, either primary or acquired through 
real time monitoring of the BRAF mutational profile evolution.   
 
2.32  
Endpoint: 
Additional mutations in BRAF or in other related genes as determined by next-
generation sequencing from plasma samples. 
 
 
3.0 
Patient Eligibility  
NOTE: Waivers to eligibility criteria are not allowed per ACCRU policy 
 
3.1 
Pre-registration – Inclusion Criteria 
 
 
3.11 
Age ≥18 years. 
 
3.12 
Histological confirmation of a pancreatic malignancy as confirmed by the local 
pathology lab 


 
12  
ACCRU-GI-1907 
 
 
3.13 
Patients whose disease has progressed on (or who were intolerant of) at least one 
line of therapy for metastatic disease 
 
3.14  
Patients whose disease has recurred with metastatic disease ≤12 weeks of 
completion of neoadjuvant or adjuvant systemic chemotherapy; or patients with 
locally advanced disease whose disease progressed to metastatic disease on, or 
≤12 weeks after completion of systemic chemotherapy would also be eligible 
 
3.15 
Provide informed written consent ≤28 days prior to pre-registration. 
 
3.16 
Central electronic/paper confirmation of the presence of a BRAFV600E mutation 
(Section 6.16). This review is mandatory prior to pre-registration to confirm 
eligibility.  
 
Results from a CLIA/CAP certified testing lab (commercial or institutional) that 
confirm the presence of a BRAFV600E mutation in the patient’s tumor must be 
submitted for central review. 
 
3.2 
Registration – Inclusion Criteria  
 
 
NOTE: Registration must occur ≤ 30 days after pre-registration.  
 
3.21 
Confirmation of the presence of BRAFV600E  mutation in the patient’s tumor 
(Section 6.2).  
 
3.22 
Measurable disease as defined in Section 11.0.  
 
3.23 
ECOG Performance Status (PS) 0, 1, or 2. (Form is available on the ACCRU 
web site)  
 
3.24 
The following laboratory values obtained ≤ 14 days prior to registration.   
 
NOTE: If your site laboratory reports use different units of measurements than 
what is required by the protocol eligibility requirements, please use the “Lab Test 
Unit Conversion Worksheet” available on the ACCRU website under “General 
Forms”.  
 
• 
Absolute neutrophil count (ANC) ≥1500/mm3 
• 
Platelet count ≥75,000/mm3 
• 
Hemoglobin ≥9.0 g/dL 
• 
Total bilirubin ≤1.5 x upper limit of normal (ULN) 
• 
Aspartate transaminase (AST) ≤ 2.5 x ULN; in participants with liver 
metastases ≤5 x ULN 
• 
Aminotransferase (ALT) ≤ 2.5 x ULN; in participants with liver metastases 
≤5 x ULN 
• 
Calculated creatinine clearance must be ≥45 ml/min using the Cockcroft-
Gault formula below: 
 


 
13  
ACCRU-GI-1907 
 
 
3.25 
Negative pregnancy test done ≤7 days prior to registration, for women of 
childbearing potential only. 
 
3.26 
Willing to return to enrolling institution for follow-up (during the Active 
Monitoring Phase of the study). 
 
Note: During the Active Monitoring Phase of a study (i.e., active treatment), 
participants must be willing to return to the consenting institution for follow-up. 
 
3.27 
Ability to swallow the investigational product tablets and capsules.  
 
3.28 
Willing to provide tissue and blood samples for correlative research purposes 
(see Sections 6.0, 14.0 and 17.0).  
 
3.3 
Registration – Exclusion Criteria   
 
 
3.31 
Patients whose tumor harbors a BRAF non-V600E mutation or a BRAF fusion. 
 
3.32 
Prior therapy with BRAF inhibitor (e.g., encorafenib, dabrafenib, vemurafenib) 
and/or a MEK inhibitor (e.g., binimetinib, trametinib, cobimetinib).  
 
3.33 
Known hypersensitivity or contraindication to any component of binimetinib or 
encorafenib or their excipients. 
 
3.34 
Any of the following because this study involves an investigational agent whose 
genotoxic, mutagenic and teratogenic effects on the developing fetus and 
newborn are unknown: 
 
• 
Pregnant women 
• 
Nursing women 
• 
Men or women of childbearing potential who are unwilling to employ 
adequate contraception  
NOTE: Female participants of childbearing potential must agree to use methods of 
contraception that are highly effective or acceptable, as described in Appendix II, 
and to not donate ova from Screening until 30 days after the last dose of study 
drug.  
NOTE: Male participants must agree to use methods of contraception that are 
highly effective or acceptable, as described in Appendix II, and to not donate sperm 
from Screening until 90 days after the last dose of study drug.  
 
Cockcroft-Gault Equation: 
 
Creatinine clearance for males =   
(140 - age)(weight in kg) 
    
  
 
 
 
 
 
 
(72)(serum creatinine in mg/dL) 
 
Creatinine clearance for females =   
(140 - age)(weight in kg)(0.85) 
 
 
 
 
 
 
(72)(serum creatinine in mg/dL) 


 
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ACCRU-GI-1907 
 
3.35 
Co-morbid systemic illnesses or other severe concurrent disease which, in the 
judgment of the investigator, would make the patient inappropriate for entry into 
this study or interfere significantly with the proper assessment of safety and 
toxicity of the prescribed regimens. 
 
3.36 
Immunocompromised patients and patients known to be HIV positive and 
currently receiving antiretroviral therapy. NOTE: Patients known to be HIV 
positive, but without clinical evidence of an immunocompromised state, are 
eligible for this trial. 
 
3.37 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study 
requirements. 
 
3.38 
History of acute coronary syndromes (including myocardial infarction, unstable 
angina, coronary artery bypass grafting, coronary angioplasty or stenting ) < 6 
months prior to registration. 
 
3.39a 
Left ventricular ejection fraction (LVEF) ≤50% as determined by MUGA or 
ECHO. 
 
3.39b Uncontrolled hypertension defined as persistent systolic blood pressure ≥ 
150/100 mmHg or diastolic blood pressure ≥100 mmHg despite current therapy. 
 
3.39c 
Triplicate average baseline QTc interval ≥480 ms.  
 
3.39d Receiving any other investigational agent which would be considered as a 
treatment for the primary neoplasm. 
 
3.39e 
Patients who have had another active malignancy within the past two years are 
ineligible EXCEPT FOR patients with cervical cancer in situ, in situ carcinoma 
of the bladder, non-melanoma carcinoma of the skin, or patients who have had 
therapy with curative intent for breast or prostate cancer, but remain on adjuvant 
hormonal therapy. 
 
3.39f 
Received anticancer therapy including chemotherapy, immunotherapy, or 
antineoplastic biologic therapy (e.g., erlotinib, cetuximab, bevacizumab etc.), 
≤14 days (≤ 28 days for an antibody-based therapy) prior to registration.  
 
3.39g Patients who have undergone major surgery (e.g., in-patient procedures) ≤ 6 
weeks prior to registration or who have not recovered from side effects of such 
procedure.  
 
3.39h Patients who have had radiotherapy ≤14 days prior to registration or who have 
not recovered from side effects of such procedure. NOTE: Palliative radiation 
therapy must be complete 7 days prior to the first dose of study treatment.  
 
3.39i 
Patient has not recovered to ≤ Grade 1 from toxic effects of prior therapy before 
registration.  
 


 
15  
ACCRU-GI-1907 
 
 
EXCEPTIONS: Stable chronic conditions (≤ Grade 2) that are not expected to 
resolve (such as neuropathy, myalgia, alopecia, prior therapy-related 
endocrinopathies).  
 
3.39j 
Uncontrolled or symptomatic brain metastases or leptomeningeal carcinomatosis 
that are not stable, require steroids, are potentially life-threatening or have 
required radiation ≤28 days prior to registration.  
 
 
NOTE: Patients with previously treated brain metastases may participate 
provided they are stable (e.g., without evidence of progression by radiographic 
imaging for ≤28 days prior to registration and neurologic symptoms have 
returned to baseline), and have no evidence of new or enlarging brain metastases 
or CNS edema, and does not require steroids at least 7 days before the first dose 
of study treatment.  
 
3.39k Impairment of gastrointestinal function or disease which may significantly alter 
the absorption of study drug (e.g., active ulcerative disease, uncontrolled 
vomiting or diarrhea, malabsorption syndrome, small bowel resection with 
decreased intestinal absorption), or recent (≤12 weeks) history of a partial or 
complete bowel obstruction, or other condition that will interfere significantly 
with the absorption or oral drugs.  
 
3.39l 
Known history of acute or chronic pancreatitis.  
 
3.39m Concurrent neuromuscular disorder that is associated with elevated CK (e.g., 
inflammatory myopathies, muscular dystrophy, amytrophic lateral sclerosis, 
spinal muscular atrophy).  
 
3.39n History or current evidence of RVO or current risk factors for RVO (e.g., 
uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or 
hypercoagulability syndromes); history of retinal degenerative disease.  
 
3.39o Current use of prohibited medication (including herbal medications, supplements, 
or foods), as described in Section 9.6, or use of prohibited medication ≤ 7 days 
prior to registration.  
 
3.39p History of thromboembolic or cerebrovascular events ≤ 12 weeks prior to 
registration. Examples include transient ischemic attacks, cerebrovascular 
accidents, hemodynamically significant (i.e. massive or sub-massive) deep vein 
thrombosis or pulmonary emboli.  
 
 
NOTE: Patients with either deep vein thrombosis or pulmonary emobli that do 
not result in hemodynamic instability are allowed to enroll as long as they are on 
a stable dose of anticoagulants for ≤4 weeks prior to registration.  
 
 
NOTE: Patients with thromboembolic events related to indwelling catheters or 
other procedures may register.  
 
3.39q Evidence of Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) infection.  
 
 
NOTE: Patients with laboratory evidence of cleared HBV or HCV infection may 


 
16  
ACCRU-GI-1907 
 
register.  
 
 
NOTE: Patients with no prior history of HBV infection who have been 
vaccinated against HBV and who have a positive antibody against hepatitis B 
surface antigen as the only evidence of prior exposure may register. 


17 
ACCRU-GI-1907 
4.0 
Test Schedule 
 
 
 
Active Monitoring Phase 
 
 
 
Tests and procedures 
≤28 
Days 
Prior 
to 
Pre-
reg 
 
≤14 
days 
prior to 
reg 
Baseline (Prior 
to Cycle 1 Day 
1 treatment) 
C1D15 ±3 
days 
C2 and 
Beyond 
(±5 days) 
 
At PD, 
withdrawal, 
or removal 
30 Days 
after last 
dose 
History and exam, weight, ECOG PS  
 
X 
 
X 
X 
X 
X 
Height 
 
X 
 
 
 
 
 
Adverse event assessment 
 
 
 
X  
X 
X 
X 
Informed Consent 
X 
 
 
 
 
 
 
ECHO/MUGAR, 9 
 
X 
 
 
X 
X 
 
Hematology: CBC/ differential 
 
X 
X 
X 
X 
X 
X 
Chemistry: AST, ALT, alk phos, T. bili, 
creatinine, calcium, glucose, Na, K 
 
X 
X 
X 
X 
 
X 
 
X 
CPK and troponin10 
 
 
X 
 
X 
 
 
Ophthalmic exam R, 5, 6 
 
X 
 
 
 
 
 
Imaging (CT/PET CT or MRI) and tumor 
measurement1  
 
X 
 
 
X4 
X 
 
Urine pregnancy test2 
 
X 
 
 
 
 
 
Central electronic/paper confirmation of a 
BRAFV600E mutation7  
X 
 
 
 
 
 
 
Mandatory tissue sample (see Section 17.0)R,8 
 
 
X 
 
 
 
 
Mandatory blood sample (see Section 14.0)R 
 
 
X 
 
X 
X 
 
Patient Medication Diary (Appendix I)3  
 
 
 
X 
X 
X 
 
1 
CT scans – chest, abdomen, and pelvis with IV and PO contrast; in the case of iodine contrast allergies an MRI of the abdomen and pelvis with 
gadolinium + a non-contrast chest CT is appropriate. Use same imaging throughout the study. Imaging at PD should only be repeated if not 
done within 28 days prior. 
2 
For women of childbearing potential only. Must be done ≤ 7 days prior to registration. 
3 
The diary must begin the day the patient starts taking the medication and must be completed per protocol and returned at the end of every 
cycle to the treating institution.  
4 
To be completed prior to cycle 2 and prior to 3rd cycle and subsequent odd cycles (±5 days) 
 


 
18  
ACCRU-GI-1907 
 
5 
A full ophthalmic exam will be performed by an ophthalmologist at screening, and as needed during on-study treatment phase and include best 
corrected visual acuity, slit lamp examination, intraocular pressure, dilated fundoscopy and Ocular Coherence Tomography (OCT). 
Examination of the retina is required, especially to identify findings associated with serous retinopathy and RVO.  
6 
After baseline, patients receiving binimetinib should be assessed at every physical examination for decreased visual acuity using a gross 
perimetry test (as opposed to automated visual field testing). Symptomatic patients should be referred for a full ophthalmic consultation. 
7    Results from a CLIA/CAP certified testing lab (commercial or institutional) that confirm the presence of a BRAFV600E mutation in the patient’s            
tumor must be submitted for central review after the patient is pre-registered. See section 6.16 for detailed instructions. 
8 
Receipt of archival tumor tissue is not required for study registration and initiation of therapy. However, it is mandatory to receive the required 
tissue within 30 days from registration. See section 17.0. 
9 
ECHO/MUGA scans are to be performed at screening, on Cycle 2 Day 1, then every 12 weeks and at the end of treatment. 
10 CPK and Troponin levels to be completed Cycle 1 Day 1 and Cycle 2 Day 1.  
 
R Research funded (see Section 19.0) 
 
 
 


 
19  
ACCRU-GI-1907 
 
5.0 
Stratification Factors OR Grouping Factor:  
N/A 
 
6.0  
Registration/Randomization Procedures 
 
6.1 
Pre-Registration (Step 0) 
 
6.11 
To pre-register a patient, access the ACCRU web page at 
 go to the 
Application section and click on “Registration” and enter the 
registration/randomization application. The registration/randomization application is 
available 24 hours a day, 7 days a week. Back up and/or system support contact 
information is available on the Web site. If unable to access the Web site, call the 
Academic and Community Cancer Research United (ACCRU) Registration Office at 
between the hours of 8 a.m. and 4:30 p.m. Central Time (Monday 
through Friday). 
 
 
Users should refer to the section titled “Pre-Registration Components” for details 
on how to pre-register a patient to a study. At the time of pre-registration the 
patient will receive an ACCRU patient identification number. This number is to 
be used when submitting paper confirmation of the presence of a BRAFV600E 
mutation for the study. Patient pre-registration via the registration/randomization 
application can be confirmed in any of the following ways: 
• 
Contact the ACCRU Registration Office 
 If the patient was 
pre-registered, the ACCRU Registration Office staff can access the 
information from the centralized database and confirm the registration. 
• 
Refer to “Application Training” at 
; click on “Registration, 
Installation & Entry Instructions”. 
 
6.12 
Documentation of IRB approval must be on file in the Registration Office 
before an investigator may register any patients. Approvals should be 
uploaded using the online ACCRU Regulatory Management System 
(ARMS). 
 
 
In addition to submitting initial IRB approval documents, ongoing IRB 
approval documentation must be on file (no less than annually) with 
ACCRU. Approvals should be uploaded using the online ACCRU 
Regulatory Management System (ARMS). If the necessary documentation 
is not submitted in advance of attempting patient registration, the 
randomization will not be accepted and the patient may not be enrolled in 
the protocol until the situation is resolved.  
 
 
Submission of annual IRB approvals is required until the study has been 
closed through your IRB. 
 
6.13 
Prior to accepting the pre-registration, the registration/randomization application 
will verify the following: 
• 
IRB approval at the registering institution 
• 
Patient pre-registration eligibility 
• 
Existence of a signed consent form 


 
20  
ACCRU-GI-1907 
 
• 
Existence of a signed authorization for use and disclosure of protected health 
information  
 
6.14 
Pre-registration tests/procedures (see Section 4.0) must be completed within the 
guidelines specified on the test schedule.   
 
6.15 
Submission of central electronic/paper confirmation of the presence of a 
BRAFV600E mutation.  
 
 
6.151 Once the patient has completed the pre-registration step, sites will 
complete the top portion of the central review form and email it to 
along results from a CLIA/CAP 
certified testing lab (commercial or institutional) that confirm the 
presence of a BRAFV600E mutation in the patient’s tumor for central 
review.  
 
6.2 
Registration (Step 1) 
 
Upon completion of the patient’s central review, the person provided on the central 
review form will be contacted by email with the results approximately one week after 
submission. If based upon the review the subject is approved for registration, the site will 
send the central review form to the ACCRU Registration Office via fax 
 
or email 
 The pre-registering institution must register the subject to 
the protocol.   
 
6.21 
To register a patient, access the ACCRU web page at 
, go to the 
Application section and click on “Registration” and enter the 
registration/randomization application. The registration/randomization application is 
available 24 hours a day, 7 days a week. Back up and/or system support contact 
information is available on the Web site. If unable to access the Web site, call the 
Academic and Community Cancer Research United (ACCRU) Registration Office at 
between the hours of 8 a.m. and 4:30 p.m. Central Time (Monday 
through Friday). 
 
Users should refer to the section titled “Pre-Registration Component” for details 
on how to register a patient on step 2 of a study that has a pre-registration and 
registration step. The instructions for the registration/randomization application 
are available using the Help button. Prior to initiation of protocol treatment, this 
process must be completed in its entirety and an ACCRU subject ID number 
must be available as noted in the instructions. It is the responsibility of the 
individual registering the patient to confirm the process has been successfully 
completed prior to release of the study agent. Patient registration via the 
registration/randomization application can be confirmed in any of the following 
ways: 
• 
Contact the ACCRU Registration Office 
 If the patient was 
pre-registered, the ACCRU Registration Office staff can access the 
information from the centralized database and confirm the registration. 
• 
Refer to “Application Training” at 
 click on “Registration, 
Installation & Entry Instructions”. 
 
6.22 
Correlative Research 


 
21  
ACCRU-GI-1907 
 
 
A mandatory correlative research component is part of this study, the patient will 
be automatically registered onto this component (see Sections 3.0, 14.0 and 
17.0). 
 
6.23 
Prior to accepting the registration, the registration/randomization application will 
verify the following: 
• 
Patient eligibility 
 
6.24 
At the time of registration, the following will be recorded: 
• 
Patient has/has not given permission to store and use his/her blood sample(s) 
for future research to learn about, prevent, or treat cancer. 
• 
Patient has/has not given permission to store and use his/her blood sample(s) 
for future research to learn, prevent, or treat other health problems (for 
example: diabetes, Alzheimer’s disease, or heart disease). 
• 
Patient has/has not given permission to store and use his/her tissue sample(s) 
for future research to learn about, prevent, or treat cancer. 
• 
Patient has/has not given permission to store and use his/her tissue sample(s) 
for future research to learn, prevent, or treat other health problems (for 
example: diabetes, Alzheimer’s disease, or heart disease). 
• 
Patient has/has not given permission for ACCRU to give his/her sample(s) to 
outside researchers. 
 
6.25 
Treatment on this protocol must commence at an ACCRU institution under the 
supervision of a medical oncologist. 
 
6.26 
Treatment cannot begin prior to registration and must begin ≤14 days after 
registration. 
 
6.27 
Pretreatment tests/procedures (see Section 4.0) must be completed within the 
guidelines specified on the test schedule. 
 
6.28 
All required baseline symptoms (see Section 10.3) must be documented and 
graded. 
 
6.29a 
Blood draw kit is available on site.  
 
 
7.0 
Protocol Treatment  
 
 
7.1 
Treatment Schedule  
Starting Day 1 of Cycle 1 (28 day Cycles), patient will self-administer: 
- 
Encorafenib 450 mg orally daily 
- 
Binimetinib 45 mg orally twice daily 
 
 
7.2 
Anti-cancer treatment by a local medical doctor (LMD) is not allowed. However, 
symptom management that cannot wait until the next visit to the study site can be 
handled by the LMD. 
 


 
22  
ACCRU-GI-1907 
 
8.0 
Dosage Modification Based on Adverse Events  
 
Strictly follow the modifications in this table for the first two cycles, until individual treatment 
tolerance can be ascertained. Thereafter, these modifications should be regarded as guidelines to 
produce mild-to-moderate, but not debilitating, side effects. If multiple adverse events are seen, 
administer dose based on greatest reduction required for any single adverse event observed. 
Reductions or increases apply to treatment given in the preceding cycle and are based on adverse 
events observed since the prior dose. 
 
ALERT: 
ADR reporting may be required for some adverse events (See Section 10) 
 
8.1  
Dose Levels (Based on Adverse Events in Tables 8.2 and 8.3), if applicable – This is 
potentially different information than what is found in the tables in Section 7.0. 
 
Dose 
Level 
Encorafenib 
Binimetinib 
 0 
 
450 mg 
45 mg 
-1 
 
300 mg 
30 mg 
-2 
 
225 mg 
15 mg 
* Dose level 0 refers to the starting dose. 
 
The lowest recommended dose level of encorafenib is 225 mg QD and the lowest recommended dose 
level of binimetinib is 15 mg BID. When the AE that resulted in a dose reduction improves to and 
remains stable at the patient’s baseline level for a minimum of 14 days, the dose can be re-escalated to the 
next dose level at the discretion of the Investigator, provided there are no other concomitant toxicities that 
would prevent drug re-escalation. There is no limit to the number of times the patient can have their dose 
reduced or re-escalated, however: 
• 
No dose re-escalation of encorafenib is allowed after a dose reduction due to prolonged QTcF 
≥ 501 msec  
• 
No dose re-escalation of binimetinib is allowed after a dose reduction due to LVEF dysfunction  
• 
No dose re-escalation of binimetinib or encorafenib is allowed after a dose reduction due to 
retinal toxicity ≥ Grade 2. 
• 
If binimetinib is withheld, consider reducing encorafenib to a maximum dose of 300 mg daily 
until binimetinib is resumed. 
Please refer to Dose Modification Table for recommended dose modifications for encorafenib and/or 
binimetinib, if applicable, based on the occurrence of treatment-related AEs. 
 
 
 
8.2 
Recommended Encorafenib Dose Modifications 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0* unless 
otherwise specified   


 
23  
ACCRU-GI-1907 
 
CTCAE 
System/Organ/Class 
(SOC) 
 
ADVERSE EVENT 
 
 
ACTION** 
BASED ON INTERVAL ADVERSE EVENT 
 
Non-cutaneous RAS 
mutation-positive 
malignancies 
Permanently discontinue 
Eye Disorder 
Uveitis 
 
Grade 1-3 
If Grade 1 or 2 does not respond to specific ocular 
therapy, or for Grade 3 uveitis, withhold encorafenib 
and binimetinib for up to 6 weeks 
Grade 4 
Permanently discontinue encorafenib and binimetinib 
 
Eye disorders-Other, 
specify 
 
Grade 1-2 
Maintain dose level of encorafenib and binimetinib and 
increase frequency of ophthalmic monitoring to at least 
every 14 days until stabilization or resolution. 
Grade 3 
Interrupt dosing of encorafenib and binimetinib and 
refer patient to ophthalmologist within 7 days.  
• 
If resolved to Grade ≤ 1 in ≤ 21 days, resume 
treatment at 1 reduced dose level of 
encorafenib and binimetinib. 
• 
If not resolved to Grade ≤ 1 in ≤ 21 days, 
permanently discontinue encorafenib and 
binimetinib and close follow-up with 
ophthalmic monitoring until stabilization or 
resolution. 
Grade 4 
Permanently discontinue encorafenib and binimetinib 
and immediate follow-up with ophthalmic monitoring 
until stabilization or resolution. 
Investigations 
Electrocardiogram QT 
corrected interval 
prolonged 
 
QTcF > 500 ms and ≤ 
60 ms increase from 
baseline 
1st occurrence:  
• 
Temporarily interrupt dosing of encorafenib 
until QTcF < 500 ms. Then resume treatment 
at 1 reduced dose level of encorafenib. 
2nd occurrence: 
• 
Temporarily interrupt dosing of encorafenib 
treatment until QTcF < 500 ms. Then resume 
treatment at 1 reduced dose level of 
encorafenib.  
3rd occurrence:  
• 
Permanently discontinue encorafenib. 


 
24  
ACCRU-GI-1907 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0* unless 
otherwise specified   
CTCAE 
System/Organ/Class 
(SOC) 
 
ADVERSE EVENT 
 
 
ACTION** 
QTcF > 500 ms and > 
60 ms increase from 
baseline 
Permanently discontinue encorafenib.  
Alanine 
aminotransferase or 
aspartate 
aminotransferase 
increased 
 
Grade 2 
Maintain encorafenib dose. 
• 
If no improvement within 4 weeks, withhold 
encorafenib until improved to Grade 0-1 or to 
pretreatment/baseline levels and then resume at 
the same dose.  
Grade 3 or 4 
See Other Adverse Reactions 
Investigations-Other, 
specify 
 
Recurrent Grade 2 or 
First occurrence of any 
Grade 3 
Withhold for up to 4 weeks.  
• 
If improves to Grade 0-1 or to 
pretreatment/baseline levels, resume at reduced 
dose.  
• 
If no improvement, permanently discontinue 
encorafenib.  
First occurrence of ay 
Grade 4 
Withhold for up to 4 weeks.  
• 
If improves to Grade 0-1 or to 
pretreatment/baseline levels, then resume at a 
reduced dose.  
• 
If no improvement, permanently discontinue 
encorafenib.  
Recurrent Grade 3 
Consider permanently discontinuing encorafenib and 
binimetinib. 
Recurrent Grade 4 
Permanently discontinue encorafenib and binimetinib.  
Skin and 
subcutaneous tissue 
disorders 
Palmar-plantar 
erythrodysesthesia 
syndrome 
 
Grade 1 
Maintain dose of encorafenib. Promptly institute 
supportive measures, such as topical therapy, for 
symptomatic relief. Give instruction on life-style 
modifications. 


 
25  
ACCRU-GI-1907 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0* unless 
otherwise specified   
CTCAE 
System/Organ/Class 
(SOC) 
 
ADVERSE EVENT 
 
 
ACTION** 
 
Grade 2 
1st occurrence:  
• 
Maintain dose of encorafenib and HFSR 
should be closely monitored. Promptly institute 
supportive measures, such as topical therapy, 
for symptomatic relief. Give instruction on 
life-style modifications. 
• 
If no improvement ≤ 14 days, interrupt dosing 
of encorafenib until resolved to Grade ≤ 1. 
Resume treatment with encorafenib at current 
dose level. Continue supportive measures, such 
as topical therapy, for symptomatic relief. Give 
instruction on life-style modifications. 
Additional occurrence:  
• 
Treatment with encorafenib may be maintained 
or interrupted based upon the Investigator’s 
discretion. Continue supportive measures, such 
as topical therapy, for symptomatic relief. Give 
instruction on life-style modifications. 
If interrupted dosing of encorafenib per Investigator’s 
judgment, interrupt until resolved to Grade ≤ 1. Resume 
treatment with encorafenib at the same dose level or 
1 reduced dose level based upon the Investigator’s 
discretion. 


 
26  
ACCRU-GI-1907 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0* unless 
otherwise specified   
CTCAE 
System/Organ/Class 
(SOC) 
 
ADVERSE EVENT 
 
 
ACTION** 
 
Grade 3 
1st or additional occurrence:  
Interrupt dosing of encorafenib until resolved 
to Grade ≤ 1. Promptly initiate supportive 
measures, such as topical therapy, for 
symptomatic relief. Give instruction on life-
style modifications. Reassess the patient 
weekly. Then resume treatment at one reduced 
dose level of encorafenib. 
• 
Consider referral to dermatologist and manage 
HFSR per dermatologist’s recommendation. 
> 3nd occurrence: 
Interrupt dosing of encorafenib until resolved to 
Grade ≤ 1, decision to resume treatment with 
encorafenib at one reduced dose level or permanently 
discontinue encorafenib should be based upon the 
Investigator’s discretion. 
Skin and subcutaneous 
tissue disorders-Other, 
specify 
 
Grade 2 
If no improvement within 2 weeks, withhold until 
Grade 0-1. Resume at same dose if first occurrence or 
reduce dose if recurrent.  
Grade 3 
Withhold until Grade 0-1. Resume at same dose if first 
occurrence or reduce dose if recurrent.  
Grade 4 
Permanently discontinue encorafenib.  
Gastrointestinal 
disorders 
Nausea/Vomiting 
 
Grade 1-2 
Maintain dose level of encorafenib and binimetinib. 
Promptly institute antiemetic measure. 
Grade 3 
Interrupt dosing of encorafenib and binimetinib until 
resolved to Grade ≤ 1. Then resume treatment at 
1 reduced dose level of encorafenib. Resume treatment 
with binimetinib at the current dose if, in the judgment 
of the Investigator, the toxicity is considered to be 
unrelated to binimetinib, or at 1 reduced dose level. 
Note: Interrupt dosing of encorafenib and binimetinib 
for ≥ Grade 3 vomiting or Grade 3 nausea only if the 
vomiting or nausea cannot be controlled with optimal 
antiemetics (as per local practice). 
Grade 4 
Permanently discontinue encorafenib and binimetinib.  
* 
  


 
27  
ACCRU-GI-1907 
 
** Use the following to describe actions in the Action column: 
 
• 
Modified=A modification indicates a change in dose level during the current cycle. However, if a 
modification was issued after the last dose was received in the current cycle, the modification should be 
reported on the subsequent cycle. "Yes, planned" should be selected if the dose level was changed 
according to protocol guidelines (i.e. due to adverse events, lab values, etc.); "Yes, unplanned" should be 
selected if the dose level change was not a part of protocol guidelines (e.g. vacation, mistake, etc.). Held 
doses (including omissions and delays) should not be reported as modifications. 
 
• 
Omitted=An omission indicates a dose was skipped and not made up, or that the drug was discontinued. 
 
• 
Delayed=A delay indicates dose was postponed or not received when expected. 
 
 
 
8.3 
Recommended Binimetinib Dose Modifications 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0* unless 
otherwise specified   
CTCAE 
System/Organ/Class 
(SOC) 
 
ADVERSE EVENT 
 
 
ACTION** 
BASED ON INTERVAL ADVERSE EVENT 
Eye Disorders 
Retinopathy and 
Retinal detachment 
 
Grade 2 or above 
Withhold binimetinib for up to 10 days.  
• 
If improves and becomes asymptomatic, 
resume at the same dose. 
• 
If not improved, resume at a lower dose level 
or permanently discontinue binimetinib.  
Retinal Vein Occlusion 
(RVO) 
 
Any Grade 
Permanently discontinue binimetinib. 
Eye disorders-Other, 
specify 
 
Grade 1-2 
Maintain dose level of encorafenib and binimetinib and 
increase frequency of ophthalmic monitoring to at least 
every 14 days until stabilization or resolution.  
Grade 3 
Interrupt dosing of encorafenib and binimetinib and 
refer patient to ophthalmologist within 7 days.  
• 
If resolved to Grade ≤ 1 in ≤ 21 days, resume 
treatment at 1 reduced dose level of 
encorafenib and binimetinib. 
• 
If not resolved to Grade ≤ 1 in ≤ 21 days, 
permanently discontinue encorafenib and 
binimetinib and close follow-up with 
ophthalmic monitoring until stabilization or 
resolution. 


 
28  
ACCRU-GI-1907 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0* unless 
otherwise specified   
CTCAE 
System/Organ/Class 
(SOC) 
 
ADVERSE EVENT 
 
 
ACTION** 
Grade 4 
Permanently discontinue encorafenib and binimetinib 
and immediate follow-up with ophthalmic monitoring 
until stabilization or resolution.  
Uveitis 
 
 
Grade 1-3 
If Grade 1 or 2 does not respond to specific ocular 
therapy, or for Grade 3 uveitis, withhold binimetinib 
and encorafenib for up to 6 weeks. 
• 
If improved, resume at same or reduced dose. 
If not improved, permanently discontinue binimetinib. 
Grade 4 
Permanently discontinue encorafenib and binimetinib. 
Cardiac Disorders 
Heart Failure and Left 
ventricular systolic 
dysfunction 
 
Grade 1 
Withhold binimetinib for up to 4 weeks, evaluate 
LVEF every 2 weeks.  
Resume binimetinib at a reduced dose if the following 
are present:  
• 
LVEF is at or above the LLN and  
• 
Absolute decrease from baseline is 10% or less 
and 
• 
Patient is asymptomatic.  
If LVEF does not recover within 4 weeks permanently 
discontinue binimetinib. 
Grade 3-4 
Permanently discontinue binimetinib. Closely monitor 
LVEF until resolution or up to 16 weeks.  
Respiratory, thoracic 
and mediastinal 
disorders 
Pneumonitis, 
pulmonary fibrosis 
 
Grade 2 
Withhold binimetinib for up to 4 weeks.  
• 
If improves to Grade 0-1, resume at a reduced 
dose.  
• 
If not resolved within 4 weeks, permanently 
discontinue.  
Grade 3 or Grade 4 
Permanently discontinue binimetinib.  
Investigations 
Alanine 
aminotransferase or 
aspartate 
aminotransferase 
increased 
 


 
29  
ACCRU-GI-1907 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0* unless 
otherwise specified   
CTCAE 
System/Organ/Class 
(SOC) 
 
ADVERSE EVENT 
 
 
ACTION** 
Grade 2 
Maintain binimetinib dose.  
• 
If no improvement within 2 weeks, withhold 
binimetinib until improved to Grade 0-1 or to 
pretreatment/baseline levels and then resume at 
the same dose.  
Grade 3 or 4 
See Other Adverse Reactions 
CPK increased 
 
Investigations 
Grade 4 asymptomatic 
or Any Grade with 
symptoms or with renal 
impairment 
Withhold binimetinib dose for up to 4 weeks.  
• 
If improved to Grade 0-1 resume at a reduced 
dose.  
• 
If not resolved within 4 weeks, permanently 
discontinue binimetinib.  
Investigations-Other, 
specify 
 
Recurrent Grade 2 or 
First occurrence of any 
Grade 3 
Withhold for up to 4 weeks.  
• 
If improves to Grade 0-1 or to 
pretreatment/baseline levels, resume at reduced 
dose.  
• 
If no improvement, permanently discontinue 
encorafenib and binimetinib.  
First occurrence of any 
Grade 4 
Permanently discontinue or withhold for up to 4 weeks.  
• 
If improves to Grade 0-1 or to 
pretreatment/baseline levels, then resume at a 
reduced dose.  
• 
If no improvement, permanently discontinue 
encorafenib and binimetinib.  
Recurrent Grade 3 
Consider permanently discontinuing encorafenib and 
binimetinib.  
Recurrent Grade 4 
Permanently discontinue.  
Gastrointestinal 
disorders 
Nausea/Vomiting 
 
Grade 1-2 
Maintain dose level of encorafenib and binimetinib. 
Promptly institute antiemetic measure.  


 
30  
ACCRU-GI-1907 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0* unless 
otherwise specified   
CTCAE 
System/Organ/Class 
(SOC) 
 
ADVERSE EVENT 
 
 
ACTION** 
Grade 3 
Interrupt dosing of encorafenib and binimetinib until 
resolved to Grade ≤ 1. Then resume treatment as 1 
reduced dose level of encorafenib. Resume treatment 
with binimetinib at the current dose if, in the judgement 
of the Investigator, the toxicity is considered to be 
unrelated to binimetinib, or at 1 reduced dose level.  
Note: Interrupt dosing of encorafenib and binimetinib 
for ≥ Grade 3 vomiting or Grade 3 nausea only if the 
vomiting or nausea cannot be controlled with optimal 
antiemetics (as per local practice).  
Grade 4 
Permanently discontinue encorafenib and binimetinib.  
Skin and 
subcutaneous tissue 
disorders 
Skin and subcutaneous 
tissue disorders-Other, 
specify 
 
Grade 2 
If no improvement within 2 weeks, withhold until 
Grade 0-1. Resume at same dose if first occurrence or 
reduce dose if recurrent.  
Grade 3 
Withhold until Grade 0-1. Resume at same dose if first 
occurrence or reduce dose if recurrent.  
Grade 4 
Permanently discontinue encorafenib and binimetinib.  
* 
  
** Use the following to describe actions in the Action column: 
 
• 
Modified=A modification indicates a change in dose level during the current cycle. However, if a 
modification was issued after the last dose was received in the current cycle, the modification should be 
reported on the subsequent cycle. "Yes, planned" should be selected if the dose level was changed 
according to protocol guidelines (i.e. due to adverse events, lab values, etc.); "Yes, unplanned" should be 
selected if the dose level change was not a part of protocol guidelines (e.g. vacation, mistake, etc.). Held 
doses (including omissions and delays) should not be reported as modifications. 
 
• 
Omitted=An omission indicates a dose was skipped and not made up, or that the drug was discontinued. 
 
• 
Delayed=A delay indicates dose was postponed or not received when expected. 
 
9.0 
Ancillary Treatment/Supportive Care 
 
9.1 
Antiemetics may be used at the discretion of the attending physician. 
 
9.2 
Blood products and growth factors should be utilized as clinically warranted and 
following institutional policies and recommendations. The use of growth factors should 
follow published guidelines of the American Society of Clinical Oncology (ASCO), 
Recommendations for the Use of WBC Growth Factors: American Society of Clinical 
Oncology Clinical Practice Guideline Update. J Clin Oncol 2015;33:3199-3212.  
 


 
31  
ACCRU-GI-1907 
 
9.3 
Patients should receive full supportive care while on this study. This includes blood 
product support, antibiotic treatment, and treatment of other newly diagnosed or 
concurrent medical conditions. All blood products and concomitant medications such 
as antidiarrheals, analgesics, and/or antiemetics received from the first day of study 
treatment administration until 30 days after the final dose will be recorded in the 
medical records. 
 
9.4 
Diarrhea: This could be managed conservatively with loperamide. The recommended 
dose of loperamide is 4 mg at first onset, followed by 2 mg every 2-4 hours until diarrhea 
free (maximum 16 mg/day). 
 
In the event of grade 3 or 4 diarrhea, the following supportive measures are allowed: 
hydration, octreotide, and antidiarrheals.  
 
If diarrhea is severe (requiring intravenous rehydration) and/or associated with fever or 
severe neutropenia (grade 3 or 4), broad-spectrum antibiotics must be prescribed. Patients 
with severe diarrhea or any diarrhea associated with severe nausea or vomiting should be 
hospitalized for intravenous hydration and correction of electrolyte imbalances. 
 
9.5 
Permitted Concomitant Therapy Requiring Caution and/or Action 
Encorafenib is a reversible inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP3A4 
and UGT1A1. It is also a time-dependent inhibitor of CYP3A4, and induced CYP2B6, 
CYP2C9 and CYP3A4 in human primary hepatocytes. Permitted medications to be used 
with caution in this study include those that are sensitive substrates of CYP1A2, 
CYP2B6, CYP2C9, CYP2C9, CYP3A4, and UGT1A1 or those substrates that have a 
narrow therapeutic index. 
There is a potential for encorafenib to induce CYP3A4, which may reduce the 
effectiveness of hormonal contraception methods. Therefore, the use of at least 1 form of 
non-hormonal contraception is required for females of childbearing potential during 
participation in this study. Caution should be used in participants receiving concomitant 
treatment with other drugs that are substrates of CYP3A4 as the efficacy of these drugs 
could be reduced when administered with encorafenib.  
Encorafenib has been identified in vitro to be metabolized by CYP3A4 and to a lesser 
extent by CYP2C19. The use of strong inhibitors of CYP3A4 is prohibited. Concomitant 
use of moderate CYP3A4 inhibitors while on study should be avoided. If use of moderate 
CYP3A4 inhibitors is unavoidable and no alternatives are available, short-term use (≤ 30 
days) is permitted with accompanying dose reduction to one-half of the encorafenib dose 
prior to use of moderate CYP3A4 inhibitors (or as close as can be achieved without 
exceeding the target dose). The encorafenib dose that was taken prior to initiating the 
CYP3A4 inhibitor may be resumed after the inhibitor has been discontinued for 3 to 5 
elimination half-lives. Strong inhibitors of CYP2C19 should be used with caution when 
co-administered with encorafenib. Use of moderate and strong inducers of CYP3A4 is 
prohibited. 
In vitro data showed that encorafenib is a substrate of the transporter P-gp. Thus, drugs 
that are known to inhibit or induce P-gp should be used with caution. Encorafenib is also 
a potent inhibitor of the renal transporters, OAT1, OAT3 and OCT2, and the hepatic 
transporters OATP1B1 and OATP1B3. The co-administration of drugs that are known to 
be sensitive or narrow therapeutic index substrates of OAT1, OAT3, OCT2, OATP1B1 
or OATP1B3 should be used with caution. 


 
32  
ACCRU-GI-1907 
 
In vitro, binimetinib has been identified to be primarily metabolized by glucuronidation 
through UGT1A1. Binimetinib has also been shown to be a substrate of P-gp and BCRP. 
It is advised that inhibitors and inducers of UGT1A1, P-gp or BCRP transporters should 
be taken with caution when co-administered with binimetinib.  
For a listing of examples of substrates, inhibitors and inducers to be used with caution, 
please consult with the FDA website: Drug Development and Drug Interactions: Table of 
Substrates, Inhibitors and Inducers. Note that this list is not exhaustive. 
Investigators should use caution when administering encorafenib and binimetinib with 
concomitant medications with a known, conditional or possible risk to prolong the QT 
interval and/or induce TdP. Subjects receiving such medications must be carefully 
monitored for potentiation of toxicity due to any individual concomitant medication, and 
may require dose titration of the concomitant medication. See the CredibleMeds® website 
for examples: Combined List of Drugs That Prolong QT and/or cause Torsades de 
Pointes (TDP). Note that this list is not exhaustive. 
9.6 
Prohibited Concomitant Therapy 
Concomitant strong systemic CYP3A4 inhibitors and strong or moderate systemic 
CYP3A4 inducers are likely to significantly increase or decrease encorafenib exposure, 
respectively, and thus should not be used during this study. 
 
10.0 
Adverse Event (AE) Reporting and Monitoring 
 
Definitions 
 
Adverse Event 
Any untoward medical occurrence associated with the use of a drug in humans, whether 
or not considered drug related.  
 
Suspected Adverse Reaction 
Any adverse event for which there is a reasonable possibility that the drug caused the 
adverse event. 
 
Expedited Reporting 
Events reported to sponsor within 24 hours, 5 days or 10 days of study team becoming 
aware of the event. 
 
Routine Reporting 
Events reported to sponsor via case report forms 
Events of Interest 
Events that would not typically be considered to meet the criteria for expedited reporting, 
but that for a specific protocol are being reported via expedited means in order to 
facilitate the review of safety data (may be requested by the FDA or the sponsor).  
 
10.1 
Adverse Event Characteristics 
 
CTCAE term (AE description) and grade: The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 will be utilized for AE reporting. All appropriate treatment areas should have access 
to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be 


 
33  
ACCRU-GI-1907 
 
downloaded from the CTEP web site: 
     
 
a. Adverse event monitoring and reporting is a routine part of every clinical trial.  
  
b. Identify the grade and severity of the event using the CTCAE version 5.0.   
 
c. Determine whether the event is expected or unexpected (see Section 10.2).  
 
d. Determine if the adverse event is related to the study intervention (agent, treatment or 
procedure) (see Section 10.3). 
 
e. Determine whether the event must be reported as an expedited report. If yes, 
determine the timeframe/mechanism (see Section 10.4).  
 
f. Determine if other reporting is required (see Section 10.5). 
 
g. Note: All AEs reported via expedited mechanisms must also be reported via the 
routine data reporting mechanisms defined by the protocol (see Sections 10.6 and 
18.0). 
 
Each CTCAE term in the current version is a unique representation of a specific event 
used for medical documentation and scientific analysis and is a single MedDRA Lowest 
Level Term (LLT). 
NOTE: A severe AE, as defined by the above grading scale, is NOT the same as serious 
AE which is defined in the table in Section 10.4. 
 
10.2  
Expected vs. Unexpected Events  
 
Expected events - are those described within the Section 15.0 of the protocol, the study 
specific consent form, package insert (if applicable), and/or the investigator brochure, (if 
an investigator brochure is not required, otherwise described in the general 
investigational plan).  
 
Unexpected adverse events or suspected adverse reactions are those not listed in Section 
15.0 of the protocol, the study specific consent form, package insert (if applicable), or in 
the investigator brochure (or are not listed at the specificity or severity that has been 
observed); if an investigator brochure is not required or available, is not consistent with 
the risk information described in the general investigational plan. 
 
Unexpected also refers to adverse events or suspected adverse reactions that are 
mentioned in the investigator brochure as occurring with a class of drugs but have not 
been observed with the drug under investigation. 
 
 
10.3 
Assessment of Attribution 
 
When assessing whether an adverse event is related to a medical treatment or 
procedure, the following attribution categories are utilized: 
 
Definite - The adverse event is clearly related to the agent(s). 


 
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ACCRU-GI-1907 
 
Probable - The adverse event is likely related to the agent(s). 
Possible - The adverse event may be related to the agent(s). 
Unlikely - The adverse event is doubtfully related to the agent(s). 
Unrelated - The adverse event is clearly NOT related to the agent(s). 
 
Events determined to be possibly, probably or definitely attributed to a 
medical treatment suggest there is evidence to indicate a causal relationship 
between the drug/device and the adverse event.  
 
10.4  
Expedited Reporting Requirements for Studies using Commercial Agent(s) ONLY: 
 
Expedited Reporting Requirements for Adverse Events that Occur in a Non-IND/IDE trial 
within 30 Days of the Last Administration of a Commercial Agent 1, 2 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether or not they 
are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the sponsor within 
the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
7 Calendar Days 
24-Hour 3 
Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
7 Calendar Days 
 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 3 Calendar Days” - The AE must initially be reported via MedWatch within 24 hours of 
learning of the AE, followed by a complete expedited report within 3 calendar days of the initial 24-
hour report. 
o “7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar days 
of learning of the AE. 


 
35  
ACCRU-GI-1907 
 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 3 calendar days for: 
• All Grade 4, and Grade 5 AEs 
Expedited 7 calendar day reports for: 
• Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• Grade 3 adverse events 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
  
 Special Instructions: 
 
• 
Follow site-specific reporting guidelines. 
• 
Submit the Serious Adverse Event (SAE) Form to the ACCRU SAE Coordinator via fax 
The ACCRU SAE Coordinator 
will forward to the encorafenib and binimetinib manufacturer as per the current reporting 
instructions. 
• 
The ACCRU SAE Coordinator will forward to ACCRU IND Coordinator 
as appropriate. The ACCRU IND Coordinator will 
assist the sponsor-investigator in notifying the FDA if required.  
Reporting of Serious Adverse Events to Array BioPharma, Inc. 
All serious adverse events must be reported by the ACCRU SAE Coordinator by facsimile within 1 
business day of notification to Array Drug Safety. 
 
All SAEs occurring in patients from the first dose of Array study drug until 30 days after the last dose of 
Array study drug must be reported to Array BioPharma Inc. within 24 hours of the Investigator’s 
knowledge by sending the SAE report to Array or designee via facsimile or email transmission, as 
described on the Array provided SAE cover page. SAEs occurring greater than 30 days after the last dose 
of Array study drug should be reported to Array BioPharma Inc. only if considered related to the Array 
product. 
If new information becomes available for a previously reported SAE, a follow-up SAE report should be 
sent within 24 hours. The follow-up information should describe whether the event has resolved or 
continues, if and how it was treated, and whether the patient continued or withdrew from study 
participation.  
Investigators must follow patients with SAEs until the event has resolved, the condition has stabilized, 
withdrawal of consent, the patient is lost to follow up, or death OR until 30 days after the last dose of 
Array study drug, whichever occurs first. Ongoing treatment-related SAEs may be followed beyond this 
time period if clinically indicated. 
 
 
 


 
36  
ACCRU-GI-1907 
 
10.5 
Other Required Reporting 
 
10.51 Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSOS) in 
general, include any incident, experience, or outcome that meets all of the 
following criteria: 
 
1. Unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 
 
2. Related or possibly related to participation in the research (in this guidance 
document, possibly related means there is a reasonable possibility that the 
incident, experience, or outcome may have been caused by the procedures 
involved in the research); and 
 
3. Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
 
Some unanticipated problems involve social or economic harm instead of the 
physical or psychological harm associated with adverse events. In other cases, 
unanticipated problems place subjects or others at increased risk of harm, but no 
harm occurs. 
 
If the event meets the criteria for an UPIRTSO, submit to your IRB as required 
by your institutional policies. 
 
10.52 Death 
• 
Any death occurring within 30 days of the last dose, 
regardless of attribution to an agent/intervention under an 
IND/IDE requires expedited reporting within 24-hours. 
 
• 
Any death occurring greater than 30 days with an attribution 
of possible, probable, or definite to an agent/intervention 
under an IND/IDE requires expedited reporting within 24-
hours. 
• 
Reportable categories of Death  
• 
Death attributable to a CTCAE term. 
• 
Death Neonatal: A disorder characterized by cessation 
of life during the first 28 days of life. 


 
37  
ACCRU-GI-1907 
 
• 
Death NOS: A cessation of life that cannot be attributed to 
a CTCAE term associated with Grade 5. 
• 
Sudden death NOS: A sudden (defined as instant or 
within one hour of the onset of symptoms) or an 
unobserved cessation of life that cannot be attributed to a 
CTCAE term associated with Grade 5. 
• 
Death due to progressive disease that cannot be attributed 
to a CTCAE term associated with Grade 5 should be 
reported as Grade 5 “Disease progression” under the 
system organ class (SOC) of General Disorders and 
Administration Site Conditions. Evidence that the death 
was a manifestation of underlying disease (e.g., 
radiological changes suggesting tumor growth or 
progression: clinical deterioration associated with a 
disease process) should be submitted. 
 
10.521 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. 
• 
All secondary malignancies that occur following treatment with an 
agent under an IND/IDE to be reported. Three options are available to 
describe the event: 
 
o Leukemia secondary to oncology chemotherapy (e.g., Acute 
Myeloctyic Leukemia [AML]) 
 
o Myelodysplastic syndrome (MDS) 
 
o Treatment-related secondary malignancy 
 
• 
Any malignancy possibly related to cancer treatment (including 
AML/MDS) should also be reported via the routine reporting 
mechanisms outlined in each protocol. 
10.522 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 reporting. 


 
38  
ACCRU-GI-1907 
 
10.523 Pregnancy  
 
If a patient becomes pregnant during the study, administration of study 
drug is to be discontinued immediately. 
 
Pregnancies (both those of female patients and female partners of male 
patients) must be reported to Array BioPharma Inc. within 24 hours of 
the Investigator’s knowledge. All pregnancies should be followed 
through to outcome and the outcome must be reported to Array 
BioPharma Inc.  
 
Pregnancies themselves are not considered AEs or SAEs. However, any 
AEs or SAEs occurring during pregnancy are to be reported following 
AE and SAE reporting guidelines. 
 
Prior to obtaining private information about a pregnant woman and her 
infant, the investigator must obtain consent from the pregnant woman 
and the newborn infant’s parent or legal guardian before any data 
collection can occur. A consent form will need to be submitted to the 
IRB for these subjects if a pregnancy occurs. If informed consent is not 
obtained, no information may be collected. 
In cases of fetal death, miscarriage or abortion the mother is the patient. 
In cases where the child/fetus experiences a serious adverse event other 
than fetal death, the child/fetus is the patient. 
 
NOTE: When submitting
 
the potential risk of 
exposure of the fetus to the investigational agent(s) or chemotherapy 
agent(s) should be documented in the “Description of Event” section. 
Include any available medical documentation.  
 
 
10.53 Baseline and Adverse Events Evaluations 
 
 
The following pre-treatment symptoms/conditions are to be graded at baseline 
and adverse events are to be graded at each evaluation using CTCAE v5.0 
grading.  
 
 
System Organ 
Class (SOC) 
 
Adverse event/Symptoms 
 
Baseline 
Each  
evaluation 
Eye disorders 
Blurred vision 
X 
X 
Flashing lights 
X 
X 
Floaters 
X 
X 
Retinal vascular disorder 
X 
X 
Investigations 
Ejection fraction decreased 
X 
X 
Musculoskeletal 
and connective 
tissue disorders 
Arthralgia 
X 
X 
Myalgia 
X 
X 
Skin and 
Photosensitivity 
X 
X 


 
39  
ACCRU-GI-1907 
 
subcutaneous 
tissue disorders 
Rash acneiform 
X 
X 
Rash maculo-papular 
X 
X 
General disorders 
and 
administration 
site conditions 
Fatigue 
X 
X 
Gastrointestinal 
disorders 
Diarrhea 
# stools per 
day 
X 
 
10.54 Case Report Forms - Academic and Community Cancer Research United 
(ACCRU) 
 
Submit the following AEs not specified in Section 10.5 (paper or electronic, as 
applicable)  
 
 
10.541 Grade 2 AEs deemed possibly, probably, or definitely related to the study 
treatment or procedure. 
 
10.542 Grade 3 and 4 AEs regardless of attribution to the study treatment or 
procedure. 
 
10.543 Grade 5 AEs (Deaths) 
 
10.5431 Any death within 30 days of the patient’s last study 
treatment or procedure regardless of attribution to the 
study treatment or procedure. 
 
10.5432 Any death more than 30 days after the patient’s last 
study treatment or procedure that is felt to be at least 
possibly treatment related must also be submitted as a 
Grade 5 AE, with a CTCAE type and attribution 
assigned. 
 
10.55    Late occurring adverse events are any adverse event that occurs during Event 
Monitoring reporting period. These are reported in compliance with Section 4.0 
and Section 18.0.   
 
10.56 Monthly Report: Research Coordinating Center will provide Array BioPharma, 
Inc. with accrual report on a monthly basis. 
 
11.0 
Treatment Evaluation Using RECIST Guideline 
 
NOTE: This study uses protocol RECIST v1.1 template dated 2/16/2011. See the footnote for the 
table regarding measureable disease in Section 11.44, as it pertains to data collection and 
analysis. 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guidelines 
(version 1.1). Changes in the largest diameter (unidimensional measurement) of the tumor lesions 


 
40  
ACCRU-GI-1907 
 
and the short axis measurements in the case of lymph nodes are used in the RECIST guideline 
(Eisenhauer et al, 2009). 
 
11.1 
Schedule of Evaluations: For the purposes of this study, patients should be reevaluated 
every 8 weeks. In addition to a baseline scan, confirmatory scans should also be obtained 
not less than 4 weeks following initial documentation of objective response. 
 
11.2 
Definitions of Measurable and Non-Measurable Disease 
 
11.21  Measurable Disease 
 
11.211 A non-nodal lesion is considered measurable if its longest diameter can be 
accurately measured as ≥1.0 cm with CT scan, CT component of a 
PET/CT, or MRI.  
 
11.212 A superficial non-nodal lesion is measurable if its longest diameter is ≥ 
1.0 cm in diameter as assessed using calipers (e.g. skin nodules) or 
imaging. In the case of skin lesions, documentation by color photography, 
including a ruler to estimate the size of the lesion, is recommended. 
 
11.213 A malignant lymph node is considered measurable if its short axis is >1.5 
cm when assessed by CT scan (CT scan slice thickness recommended to 
be no greater than 5 mm).  
 
NOTE: Tumor lesions in a previously irradiated area are not considered 
measurable disease.  
 
11.22 Non-Measurable Disease 
 
11.221 All other lesions (or sites of disease) are considered non-measurable 
disease, including pathological nodes (those with a short axis ≥1.0 to <1.5 
cm). Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, and 
abdominal masses (not followed by CT or MRI), are considered as non-
measurable as well. 
 
Note: ‘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 present 
in the same patient, these are preferred for selection as target lesions. In 
addition, lymph nodes that have a short axis <1.0 cm are considered non- 
pathological (i.e., normal) and should not be recorded or followed. 
 
11.3 
Guidelines for Evaluation of Measurable Disease 
 
11.31 Measurement Methods:  
 
• 
All measurements should be recorded in metric notation (i.e., decimal 
fractions of centimeters) using a ruler or calipers. 
 


 
41  
ACCRU-GI-1907 
 
• 
The same method of assessment and the same technique must be used to 
characterize each identified and reported lesion at baseline and during follow-
up. For patients having only lesions measuring at least 1 cm to less than 2 cm 
must use CT imaging for both pre- and post-treatment tumor assessments.  
 
• 
Imaging-based evaluation is preferred to evaluation by clinical examination 
when both methods have been used at the same evaluation to assess the 
antitumor effect of a treatment.  
 
11.32 Acceptable Modalities for Measurable Disease:  
 
• 
Conventional CT and MRI: This guideline has defined measurability of 
lesions on CT scan based on the assumption that CT slice thickness is 5 mm 
or less. If CT scans have slice thickness greater than 5 mm, the minimum size 
for a measurable lesion should be twice the slice thickness.  
 
• 
As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type 
and site of disease. The lesions should be measured on the same pulse 
sequence. Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans. 
Body scans should be performed with breath-hold scanning techniques, if 
possible. 
 
• 
PET-CT: If the site can document that the CT performed as part of a PET-CT 
is of identical diagnostic quality to a diagnostic CT (with IV and oral 
contrast), then the CT portion of the PET-CT can be used for RECIST 
measurements and can be used interchangeably with conventional CT in 
accurately measuring cancer lesions over time.  
 
 
• 
Physical Examination: For superficial non-nodal lesions, physical examination 
is acceptable, but imaging is preferable, if both can be done. In the case of 
skin lesions, documentation by color photography, including a ruler to 
estimate the size of the lesion, is recommended. 
 
• 
FDG-PET: FDG-PET scanning is allowed to complement CT scanning in 
assessment of progressive disease [PD] and particularly possible 'new' disease. 
A ‘positive’ FDG-PET scanned lesion is defined as one which is FDG avid 
with an update greater than twice that of the surrounding tissue on the 
attenuation corrected image; otherwise, an FDG-PET scanned lesion is 
considered ‘negative.’ New lesions on the basis of FDG-PET imaging can be 
identified according to the following algorithm: 
 
a. Negative FDG-PET at baseline with a positive FDG-PET at follow-up is a 
sign of PD based on a new lesion. 
 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  
 


 
42  
ACCRU-GI-1907 
 
i. 
If the positive FDG-PET at follow-up corresponds to a new site of 
disease confirmed by CT, this is PD.  
 
ii. If the positive FDG-PET at follow-up is not confirmed as a new site 
of disease on CT at the same evaluation, additional follow-up CT 
scans (i.e., additional follow-up scans at least 4 weeks later) are 
needed to determine if there is truly progression occurring at that site. 
In this situation, the date of PD will be the date of the initial abnormal 
FDG-PET scan.  
 
iii If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the 
anatomic images, it is not classified as PD. 
 
11.33 Measurement at Follow-up Evaluation:  
 
• 
A subsequent scan must be obtained not less than 4 weeks following initial 
documentation of an objective status of either complete response (CR) or 
partial response (PR).  
 
• 
In the case of stable disease (SD), follow-up measurements must have met the 
SD criteria at least once after study entry at a minimum interval of not less 
than 6-8 weeks (see Section 11.44). 
 
• 
The cytological confirmation of the neoplastic origin of any effusion that 
appears or worsens during treatment when the measurable tumor has met 
criteria for response or stable disease is mandatory to differentiate between 
response or stable disease (an effusion may be a side effect of the treatment) 
and progressive disease. 
 
11.4 
Measurement of Effect 
 
11.41 Target Lesions & Target Lymph Nodes 
 
• 
Measurable lesions (as defined in Section 11.21) up to a maximum of 5 
lesions, representative of all involved organs, should be identified as “Target 
Lesions” and recorded and measured at baseline. These lesions can be non-
nodal or nodal (as defined in 11.21), where no more than 2 lesions are from 
the same organ and no more than 2 malignant nodal lesions are selected.  
 
Note: If fewer than 5 target lesions and target lymph nodes are identified (as 
there often will be), there is no reason to perform additional studies beyond 
those specified in the protocol to discover new lesions.  
 
• 
Target lesions and target lymph nodes should be selected on the basis of their 
size, be representative of all involved sites of disease, but in addition should 
be those that lend themselves to reproducible repeated measurements. It may 
be the case that, on occasion, the largest lesion (or malignant lymph node) 
does not lend itself to reproducible measurements in which circumstance the 
next largest lesion (or malignant lymph node) which can be measured 
reproducibly should be selected.  


 
43  
ACCRU-GI-1907 
 
 
• 
Baseline Sum of Dimensions (BSD): A sum of the longest diameter for all 
target lesions plus the sum of the short axis of all the target lymph nodes will 
be calculated and reported as the baseline sum of dimensions (BSD). The 
BSD will be used as reference to further characterize any objective tumor 
response in the measurable dimension of the disease.  
 
• 
Post-Baseline Sum of the Dimensions (PBSD): A sum of the longest diameter 
for all target lesions plus the sum of the short axis of all the target lymph 
nodes will be calculated and reported as the post-baseline sum of dimensions 
(PBSD). If the radiologist is able to provide an actual measure for the target 
lesion (or target lymph node), that should be recorded, even if it is below 0.5 
cm. If the target lesion (or target lymph node) is believed to be present and is 
faintly seen but too small to measure, a default value of 0.5 cm should be 
assigned. If it is the opinion of the radiologist that the target lesion or target 
lymph node has likely disappeared, the measurement should be recorded as 0 
cm. 
 
• 
The minimum sum of the dimensions (MSD) is the minimum of the BSD and 
the PBSD. 
 
 
11.42  Non-Target Lesions & Non-Target Lymph Nodes 
 
Non-measurable sites of disease (Section 11.22) are classified as non- target 
lesions or non-target lymph nodes and should also be recorded at baseline. These 
lesions and lymph nodes should be followed in accord with 11.433. 
 
11.43 Response Criteria 
 
11.431 All target lesions and target lymph nodes followed by CT/MRI/PET-
CT/physical examination must be measured on re-evaluation at 
evaluation times specified in Section 11.1. Specifically, a change in 
objective status to either a PR or CR cannot be done without re-
measuring target lesions and target lymph nodes.  
 
Note: Non-target lesions and non-target lymph nodes should be 
evaluated at each assessment, especially in the case of first response or 
confirmation of response. In selected circumstances, certain non-target 
organs may be evaluated less frequently. For example, bone scans may 
need to be repeated only when complete response is identified in target 
disease or when progression in bone is suspected. 
 
11.432 Evaluation of Target Lesions 
 
• Complete Response (CR): All of the following must be true: 
 
a. Disappearance of all target lesions. 
 
b. Each target lymph node must have 
reduction in short axis to <1.0 cm. 
 


 
44  
ACCRU-GI-1907 
 
• Partial Response (PR): 
At least a 30% decrease in PBSD (sum of 
the longest diameter for all target lesions 
plus the sum of the short axis of all the 
target lymph nodes at current evaluation) 
taking as reference the BSD (see Section 
11.41). 
 
• Progression (PD): 
At least one of the following must be true: 
 
a. At least one new malignant lesion, 
which also includes any lymph node 
that was normal at baseline (< 1.0 cm 
short axis) and increased to ≥ 1.0 cm 
short axis during follow-up.  
 
b. At least a 20% increase in PBSD (sum 
of the longest diameter for all target 
lesions plus the sum of the short axis 
of all the target lymph nodes at current 
evaluation) taking as reference the 
MSD (Section 11.41). In addition, the 
PBSD must also demonstrate an 
absolute increase of at least 0.5 cm 
from the MSD.  
 
c. See Section 11.32 for details in 
regards to the requirements for PD via 
FDG-PET imaging. 
  
• Stable Disease (SD): 
Neither sufficient shrinkage to qualify for 
PR, nor sufficient increase to qualify for 
PD taking as reference the MSD. 
 
11.433 Evaluation of Non-Target Lesions & Non-target Lymph Nodes 
 
• Complete Response (CR): 
All of the following must be true: 
 
a. Disappearance 
of 
all 
non-target 
lesions.  
 
b. Each non-target lymph node must 
have a reduction in short axis to <1.0 
cm. 
 
• Non-CR/Non-PD: 
Persistence of one or more non-target 
lesions or non-target lymph nodes. 
 
• Progression (PD): 
At least one of the following must be true: 
 
a. At least one new malignant lesion, 
 
which also includes  any lymph node 


 
45  
ACCRU-GI-1907 
 
 
that was normal at baseline (< 1.0 cm 
 
short axis) and increased to ≥ 
 
1.0 cm short axis during follow-up.  
 
b. Unequivocal progression of existing 
non-target lesions and non-target 
lymph nodes. (NOTE: Unequivocal 
progression 
should 
not 
normally 
trump target lesion and target lymph 
node status. It must be representative 
of overall disease status change.)  
  
c. See Section 11.32 for details in 
regards to the requirements for PD 
via FDG-PET imaging. 
 
11.44 Overall Objective Status 
 
 
The overall objective status for an evaluation is determined by combining the 
patient’s status on target lesions, target lymph nodes, non-target lesions, non-target 
lymph nodes, and new disease as defined in the following tables:  
 
For Patients with Measurable Disease  
 
Target Lesions & 
Target Lymph Nodes 
Non-Target Lesions & 
Non-Target Lymph 
Nodes 
New  
Sites of Disease 
Overall Objective 
Status 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
PR 
CR 
Non-CR/Non-PD 
No 
PR 
CR/PR 
Not All Evaluated* 
No 
PR** 
SD 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
No 
SD 
Not all Evaluated 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
No 
Not Evaluated 
(NE) 
PD 
Unequivocal PD 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
Yes or No 
PD 
CR/PR/SD/PD/Not all 
Evaluated 
Unequivocal PD 
Yes or No 
PD 
CR/PR/SD/PD/Not all 
Evaluated 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
Yes 
PD 
*See Section 11.431 
** NOTE: This study uses the protocol RECIST v1.1 template dated 2/16/2011. For data collection 
and analysis purposes the objective status changed from SD to PR in the ACCRU protocol RECIST 


 
46  
ACCRU-GI-1907 
 
v1.1 template as of 2/16/2011 and to match RECIST v1.1 requirements. 
 
11.45 Symptomatic Deterioration: Patients with global deterioration of health status 
requiring discontinuation of treatment without objective evidence of disease 
progression at that time, and not either related to study treatment or other medical 
conditions, should be reported as PD due to “symptomatic deterioration.” Every 
effort should be made to document the objective progression even after 
discontinuation of treatment due to symptomatic deterioration. A patient is 
classified as having PD due to “symptomatic deterioration” if any of the 
following occur that are not either related to study treatment or other medical 
conditions: 
 
• Weight loss >10% of body weight. 
• Worsening of tumor-related symptoms. 
• Decline in performance status of >1 level on ECOG scale. 
 
12.0 
Descriptive Factors  
 
 
12.1 
ECOG Performance Status: 0 vs. 1 vs. 2 
 
 
12.2  
2nd line vs. ≥3rd line 
 
 
 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient  
 
 
13.1 
Patients who are CR, PR, or SD will continue treatment per protocol for a maximum of 
36 cycles. After 36 cycles, patients will go to event monitoring. 
 
13.2 
Patients who develop PD while receiving therapy will go to the event-monitoring phase. 
 
13.3 
Patients who go off protocol treatment for reasons other than PD will go to the event-
monitoring phase per Section 18.0. 
 
13.4 
Patients who develop non-CNS PD at any time should go to event monitoring. These 
patients should be treated with alternative chemotherapy if their clinical status is good 
enough to allow further therapy.  
 
13.5 
Event monitoring is every 3 months (±14 days) for 5 years after registration. If the patient 
is still alive 5 years after registration, no further follow up is required.  
 
 
13.6 
A patient is deemed ineligible if after registration, it is determined that at the time of 
registration, the patient did not satisfy each and every eligibility criteria for study entry. 
The patient may continue treatment off-protocol at the discretion of the physician as long 
as there are no safety concerns, and the patient was properly registered. The patient will 
go directly to the event-monitoring phase of the study (or off study, if applicable).  
 
• 
If the patient received treatment, all data up until the point of confirmation of 
ineligibility must be submitted. Event monitoring will be required per Section 18.0 of 
the protocol.  
 


 
47  
ACCRU-GI-1907 
 
13.7 
A patient is deemed a major violation if protocol requirements regarding treatment in 
cycle 1 of the initial therapy are severely violated that evaluability for primary end point 
is questionable. All data up until the point of confirmation of a major violation must be 
submitted. The patient will go directly to the event-monitoring phase of the study. The 
patient may continue treatment off-protocol at the discretion of the physician as long as 
there are no safety concerns, and the patient was properly registered. Event monitoring 
will be required per Section 18.0 of the protocol. 
 
13.8 
A patient is deemed a cancel if he/she is removed from the study for any reason before 
any study treatment is given. On-study material and the Off Treatment Form must be 
submitted.  
 
 
14.0 
Body Fluid Biospecimens  
 
 
14.1 
Blood/Blood Products Handling   
 
14.11 Kits are required for this study. 
 
14.111 The kit contains supplies and instructions for collecting, processing, and 
shipping specimens. 
 
14.112 Participating institutions may obtain kits by completing and faxing the 
Supply Order Form (found in the Forms Packet) to the number listed on 
the form. Fill out the site address to where the kits will be shipped on the 
Fax Supply form. Because we are now being charged for all outgoing 
kits, a small, but sufficient, supply of the specimen collection kits should 
be ordered prior to patient entry. Do not send the unused kits back to 
Biospecimen Accessioning and Processing (BAP) Receiving or the BAP 
Shared Resource.  Note: Expired tubes may be replaced with site stock if 
available. 
 
14.113 Kits will be sent via FedEx® Ground at no additional cost to the 
participating institutions. Allow at least two weeks to receive the kits. 
Kits will arrive inside the shipping boxes.   
 
14.114 Kits will not be sent via rush delivery service unless the participating 
institution provides their own FedEx® account number or alternate 
billing number for express service. ACCRU will not cover the cost for 
rush delivery of kits. 
 
14.12 All samples must be collected Monday-Friday ONLY. 
 
14.13 Label specimen tube(s) with protocol number, ACCRU patient ID number, and 
time and date blood is drawn. 
 
14.14 Collect and process all blood/blood products according to specific kit instructions 
and table below.  
 
14.241 Summary Table of Research Blood/Blood Products to Be Collected for 


 
48  
ACCRU-GI-1907 
 
This Protocol  
 
 
Indicate if 
specimen is 
mandatory 
or optional 
Collection 
tube 
description 
and/or 
additive 
(color of 
tube top) 
Volume 
to collect 
per tube 
(number 
of tubes 
to be 
collected) 
Blood 
product 
being 
processed 
and 
submitted by 
participating 
site 
Baseline 
Prior to 
Treatment 
Every 4 
weeks Prior 
to 
Treatment  
Off 
study 
or 
Progre
ssion 
Additional 
processing 
required 
at site 
after blood 
draw? 
Storage 
/shipping 
conditions1 
Mandatory 
STRECK 
(black/tan) 
10 ml (2) 
Platelet poor 
plasma 
X 
X 
X 
No 
Ambient 
(room 
tempera-
ture cold 
packs) 
Mandatory 
EDTA 
(purple 
top) 
10mL (2) 
Plasma and 
White 
Blood Cells 
(buffy coat) 
X 
X 
X 
No 
Refrig-
erate  
(cold 
packs) 
1. After all samples have been processed according to kit instructions, ship all specimens 
According to shipping instructions (see Section 14.25 for detailed shipping instructions.) 
2.   Blood draws should not be collected and submitted until after the patient is registered onto the 
study. 
 
14.15 Shipping 
 
14.151 Verify ALL sections of the Blood Specimen Submission Form (see 
Forms Packet), BAP Requisition Form (provided in kit) (if applicable)], 
and specimen collection labels are completed and filled in correctly. 
 
14.152 Specimens must be shipped the same day they are drawn. 
 
 
14.153 Specimens will be shipped in a dual-temperature shipping container.  
Place the refrigerated EDTA tubes with a properly prepared cold pack in 
one compartment. See kit instructions for specific details for cold pack 
preparation (i.e., frozen or refrigerated) and proper packing of blood and 
cold pack to avoid freezing of specimen.  Place the STRECK tubes with 
an ambient cold pack in the other compartment of the dual-temperature 
shipping container. 
 
14.154 Ship specimens via Priority Overnight service, Monday – Friday 
ONLY, to BAP Receiving according to kit instructions. Do not send 
samples on weekends or just prior to federal holidays. 
 
14.155 The BAP kits will include a smart shipper label (3x5 white barcoded 
label) affixed to the shipping boxes. The smart shipper label is a pre-
addressed return label, which replaces the need for an airbill. Shipping 
costs will be covered by ACCRU if the shipping box provided with the 
BAP kit is used for shipping specimens to BAP Receiving.  


 
49  
ACCRU-GI-1907 
 
 
Ship blood samples to:           
 
 
  
 
 
BAP Freezer will receive the samples for ACCRU. 
 
 
14.2 
Study Methodology and Storage Information 
 
14.21 Blood/blood product samples will be collected for the following research  
 
14.211 DNA extraction and storage of DNA for future research (e.g., for genetic 
polymorphisms or cfDNA sequence and analysis) Plasma/cells/DNA will 
be stored frozen at -70ºC by BAP and at the end of the trial all specimens 
will be sent to Dana-Farber Cancer Institute, according to patient consent 
information (see Section 6.22) until specific analyses are identified. As 
protocols are developed, they will be presented for ACCRU and IRB 
review and approval. (This collection is part of a general strategy of 
investigation for the majority of ACCRU studies.) 
 
 
 
ACCRU will ship samples to:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
14.212 As part of ongoing ACCRU research, we will collect plasma for future 
research studies, according to patient consent information (see Section 
6.24), on molecular determinants of efficacy and tolerability. Samples 
will be stored frozen at -70ºC by BAP until specific analyses are 
identified. As protocols are developed, they will be presented for 
ACCRU and IRB review and approval.  
 
 
14.3 
Return of Genetic Testing Research Results 
 
Because the results generated by the genetic testing included in this section are not 
currently anticipated to have clinical relevance to the patient or their family members, the 
genetic results will not be disclosed to the patients or their physicians. 
 
If, at any time, genetic results are obtained that may have clinical relevance, IRB review 
and approval will be sought regarding the most appropriate manner of disclosure and 
whether or not validation in a CLIA-certified setting will be required.  Sharing of 


 
50  
ACCRU-GI-1907 
 
research data with individual patients should only occur when data have been validated 
by multiple studies and testing has been done in CLIA-approved laboratories. 
 
15.0 
Drug Information 
 
IND exempt 
 
• 
Investigator brochure available on the ACCRU website. 
 
15.1 
Binimetinib (MEK162, ARRY-438162, ONO-7703) 
 
15.11 Background:  Binimetinib is an orally bioavailable, selective and potent MEK1 
and MEK 2 inhibitor. As a MEK inhibitor, this compound has the potential to 
benefit patients with advanced cancers by inhibiting the MAPK (mitogen-
activated protein kinases) pathway. 
 
15.12 Formulation: Binimetinib drug product is supplied as film-coated tablets in a 
dose strength of 15 mg. The film coated-tablets consist of binimetinib, colloidal 
silicon dioxide/silica colloidal anhydrous; croscarmellose sodium; lactose 
monohydrate; magnesium stearate; microcrystalline cellulose/cellulose, 
microcrystalline; and a commercial film coating. The tablet is ovaloid biconvex 
(capsule shaped), yellow to dark yellow in color.   
 
15.13 Preparation and storage:  Binimetinib film-coated tablets should not be stored 
above 25°C and should be protected from light. Tablets are packaged in plastic 
bottles acceptable for pharmaceutical use.  
 
15.14 Administration:  Binimetinib is administered twice daily with water, 
approximately 12 hours apart with or without meals. Tablets should be 
swallowed whole and should not be chewed.  
 
 
15.15 Pharmacokinetic information: 
Absorption:  The pharmacokinetics of binimetinib are characterized by 
moderate to high variability, accumulation of approximately 1.5-fold, and steady 
state concentrations reached within 15 days. The human ADME study 
CMEK162A2102 indicated that approximately 50% of binimetinib dose was 
absorbed.  
 
Distribution:  Binimetinib is more distributed in plasma than blood. The 
blood-to-plasma concentration ratio of binimetinib in humans is 0.718. It is 
highly bound to plasma proteins (humans: 97.2%). 
 
Metabolism:  The primary metabolic pathways include glucuronidation (up to 
61.2% via UGT1A1), N-dealkylation (up to 17.8% via CYP1A2 and CYP2C19) 
and amide hydrolysis.  
 
Excretion: The excretion route was 31.7% of unchanged binimetinib in feces 
and 18.4% in urine. Estimated renal clearance of unchanged binimetinib was 
6.3% of total dose. 
 
15.16 Potential Drug Interactions:   


 
51  
ACCRU-GI-1907 
 
Overall, the risk for binimetinib to be a cause of or be affected by significant 
drug-drug interactions is predicted to be low. However, given the predominant 
role of UGT1A1 in the metabolism of binimetinib, and because the effect of a 
UGT1A1 inhibitor or inducer has not been evaluated in a formal clinical study, 
special consideration should be taken for co-administration of drugs that are 
UGT1A1 inhibitors or inducers, and administration of binimetinib to patients 
with low UGT1A1 activity.  
 
Binimetinib has been shown to be a substrate for P-gp and BCRP in vitro. The 
impact of P-gp/BCRP inhibitors on the PK of binimetinib in vivo is unknown; 
therefore, it is recommended that P-gp and BCRP inhibitors are dosed with 
caution. 
 
15.17 Known potential toxicities:   
Very Common (≥ 10%) - diarrhea, nausea, vomiting, fatigue, peripheral edema, 
increased AST, increased blood creatine phosphokinase, dermatitis acneiform, 
dry skin, pruritus, rash, decreased ejection fraction  
Common (≥1% - <10%) - chorioretinopathy, dry eye, macular edema, retinal 
detachment, retinal vein occlusion, retinopathy, serous retinal damage, blurred 
vision, reduced visual acuity, visual impairment, abdominal pain, constipation, 
dyspepsia, gastroesophageal reflux disease, asthenia, facial edema, edema, 
malaise, pyrexia, folliculitis, paronychia, pustular rash, increased ALT, increased 
amylase, increased blood alkaline phosphatase, increased blood creatinine, 
increased GGT, lipase increased, arthralgia, muscular weakness, myalgia, 
dizziness, dysgeusia, epistaxis, alopecia, xerosis, nail disorder, palmar-plantar 
erythrodysesthesia syndrome, eczema, erythema, erythematous rash, papular 
rash, macular rash, maculo-papular rash, skin fissures, hypertension, neutropenia, 
pneumonitis  
Uncommon (≥0.1 - <1%) – anemia, left ventricular dysfunction, eye edema, 
gastritis, gastrointestinal hemorrhage, colitis, general physical health 
deterioration, infection, skin infection, cellulitis, erysipelas, irregular heart rate, 
hypoglycemia, musculoskeletal pain, rhabdomyolysis, dropped head syndrome, 
ageusia, pulmonary embolism, xeroderma, follicular rash, pruritic rash, deep vein 
thrombosis, hypertensive crisis, hypotension 
 
 
15.18 Nursing Guidelines:  
 
15.181 Agent can cause decreased LVEF function. Instruct patients to report any 
lower extremity swelling, shortness of breath, and/or chest pain to study 
team. 
15.182 Diarrhea and other gastrointestinal side effects are common. Treat 
symptomatically and monitor for effectiveness of intervention. 
15.183 Rash is common and is usually acneiform in nature. Instruct patient to 
report any rash immediately. 
15.184 Bleeding including serious and/or fatal hemorrhage can be seen. Instruct 
patient to report any bleeding to study team. 


 
52  
ACCRU-GI-1907 
 
15.185 Monitor LFT’s. 
15.186 Rarely interstitial lung disease can be seen. Instruct patient to report any 
cough, dyspnea to the study team. 
15.187 Rhabdomyolysis is a rare but serious side effect of this agent. Instruct 
patients to report any weakness, muscle pain, or just feelings or 
unwellness to the study team immediately. 
15.188 Rarely ocular complications can occur, including chorioretinopathy, 
serous retinal damage, retinal detachment and other visual disturbances. 
Instruct patients to report any visual disturbances and/or eye pain to the 
study team immediately. 
15.189a Strenuous physical activities, such as competitive sports, can results in 
significant increases in CK levels while on binimetinib treatment. 
Instruct patients to not start a new strenuous exercise regimen after first 
dose of study treatment.  
15.19a Drug procurement:  Drug procurement: Array BioPharma, Inc will supply the 
drug to Clinical Research Services, a division of Rx Crossroads by McKesson. 
Each participating ACCRU treating location will order the drug from Clinical 
Research Services, a division of Rx Crossroads by McKesson. Submit the Drug 
Order Request Form (found on the ACCRU web site) to: 
 
 
  
 
Each participating ACCRU treating location will be responsible for 
monitoring the supply of binimetinib and will use the Drug Order 
Request Form to order additional supplies as needed. 
 
Outdated or remaining drug is to be destroyed on-site as per procedures 
in place at each institution. 
 
 
15.19bTemperature excursions that occur at the site should be reported by the site to 
Clinical Research Services, a division of Rx Crossroads by McKesson via email 
to: 
 Any shipment deviations (those not 
occurring at the site) should be reported to Clinical Research Services, a division 
of Rx Crossroads by McKesson, via email to: 
 Clinical Research Services, a division 
of Rx Crossroads by McKesson, will report any temperature and shipment 
deviations (those not occurring at the site) to Array BioPharma Inc. via email to: 
 
 
15.19b1 When reporting a temperature excursion to Clinical Research Services, 
please include the following information as required by Array:  


 
53  
ACCRU-GI-1907 
 
• 
Study/protocol number 
• 
Name and contact information 
• 
Site location and address 
• 
Array lot and kit numbers affected (if applicable) 
• 
High/low temperature recorded for event 
• 
Duration of the event 
• 
All supporting data or charts (Temp Log, TempTale, etc.) 
• 
Temperature deviation event form (if site has their own) 
 
Following temperature deviation, the affected material should be 
physically quarantined by the site until a response is received from Array 
regarding the disposition of the affected materials. 
 
 
15.2 Encorafenib (LGX818, ONO-7702, Braftovi®):  
 
 
15.21  Background: Encorafenib is a potent and selective ATP-competitive inhibitor of 
BRAF V600-mutant kinase. 
 
15.22 Formulation: The encorafenib drug product is supplied as a hard gelatin capsule 
in dosage strengths 75 mg. The dosage forms for each strength have identical 
formulations which are packaged in different colored capsules:  
• 
75 mg capsule (FMI): Size #00 hard gelatin capsules; flesh opaque cap 
and white opaque body, with the markings “NVR” or stylized “A” on the 
cap and “LGX 75mg” on body.  
The capsules consist of encorafenib drug substance, copovidone, poloxamer 188, 
succinic acid, microcrystalline cellulose, colloid silicon dioxide, crospovidone, 
and magnesium stearate of vegetable origin.  
 
15.23 Preparation and storage:  Encorafenib hard gelatin capsules should not be 
stored above 25°C and should be protected from moisture. Capsules are packaged 
in plastic bottles acceptable for pharmaceutical use and should not be repackaged 
at the site.  
  
 
15.24 Administration:  Encorafenib capsules are intended for oral administration with 
water; capsules should be swallowed whole and should not be chewed. 
Encorafenib capsules may also be opened and the powder mixed with sweetened 
applesauce; the soft food preparation is intended for oral administration with 
water. Encorafenib can be administered without regard to food. 
 
 
15.25 Pharmacokinetic information: 
Absorption:  At least 86% of the dose is absorbed 
Metabolism:  N-dealkylation is the primary metabolic pathway; CYP3A4 
(primary), CYP2C19, and CYP2D6 (minor) contribute to total oxidative 
clearance in human liver microsomes  
 
Half-life elimination:  6.32 hours (range 3.74 to 8.09 hours) 
 
Excretion:  Feces (39%); urine (47.2%) 
 


 
54  
ACCRU-GI-1907 
 
15.26 Potential Drug Interactions:   
Since encorafenib is mainly metabolized by CYP3A, the co-administration 
of CYP3A inducers might decrease the exposure of encorafenib in clinical 
practice. Thus, long term co-administration of strong and moderate 
inducers of CYP3A with encorafenib should be avoided. 
 
Clinical results from a dedicated DDI study with encorafenib and CYP3A 
inhibitors indicated concomitant administration of encorafenib with strong 
or moderate CYP3A inhibitors may increase encorafenib plasma 
concentration. If co-administration with strong or moderate CYP3A 
inhibitors cannot be avoided, dose reduction of encorafenib may be 
warranted. 
 
 
Since no clinical data are available, caution should be used for co-
administering substrates of CYP3A4 and UGT1A1.  
 
 
Based on in vitro transporter studies, encorafenib can potentially inhibit 
the transporters P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3 and 
OCT2 at clinical concentrations. Co-administration of encorafenib with 
drugs that are substrates for these enzymes and/or transporters may alter 
the exposure of the co-administered medication. 
 
15.27 Known potential toxicities: 
 
Very Common (≥10%) 
Gastrointestinal:  diarrhea 
Metabolism and nutrition:  decreased appetite 
Nervous system:  peripheral neuropathy 
Psychiatric:  insomnia 
Skin and subcutaneous:  hair loss, dry skin, hyperkeratosis, pruritis, Palmar-
plantar erythrodysesthesia syndrome, palmoplantar keratoderma, erythema 
Vascular:  flushing 
Common (≥1% - <10%) 
Blood and lymphatic:  anemia 
Cardiac:  tachycardia 
Ear and labyrinth:  vertigo 
Eye:  iridocyclitis 
Gastrointestinal:  nausea, vomiting, abdominal pain, constipation, dyspepsia, 
stomatitis 
General:  asthenia, fatigue, pyrexia, xerosis, chills, face edema, peripheral edema 
Immune system:  hypersensitivity 
Investigations:  AST and ALT increased, blood alkaline phosphatase  
increased, blood creatinine increased, gamma-glutamyltransferase increased, 
amylase increased, lipase increased, electrocardiogram QT prolonged 
Metabolism and nutrition:  dehydration, hyponatremia 
Musculoskeletal and connective tissue:  arthralgia, musculoskeletal pain,  
myalgia, muscle spasms, muscular weakness 
Neoplasms benign, malignant and unspecified:  keratoacanthoma, melanocytic 
nevus, skin papilloma, squamous cell carcinoma, dysplatic nevus, malignant 
melanoma 
Nervous system:  facial paralysis, facial paresis, ageusia, dysgeusia, dysesthesia, 
hyperesthesia, neuralgia 


 
55  
ACCRU-GI-1907 
 
Renal and urinary:  acute kidney injury, renal failure 
Skin and subcutaneous:  rash, photosensitivity reaction, skin exfoliation, skin 
hyperpigmentation 
Uncommon (≥0.1% - <1%) 
Eye:  uveitis 
Gastrointestinal:  pancreatitis 
Metabolism and nutrition:  hyperglycemia 
Musculoskeletal and connective tissue:  back pain, pain in extremity 
Neoplasms benign, malignant and unspecified:  acanthoma, basal cell 
carcinoma 
Nervous system:  hypoaesthesia 
Skin and subcutaneous:  drug eruption, urticarial  
 
 
 
15.28 Nursing Guidelines:  
 
15.281 Diarrhea and nausea are common. Treat symptomatically and monitor for 
effectiveness. 
15.282 Warn patients of possibility of secondary skin cancers. Instruct patients 
to report any new lesions to study team immediately. 
15.283 Monitor LFT’s, especially in combination therapy. 
15.284 Agent may cause arthralgias. Treat symptomatically and monitor for 
effectiveness. 
15.285 Agent causes QTc prolongation. Instruct patients to discuss any new 
medications with the study team, prior to starting such agents. 
15.286 Agent can cause peripheral edema.   
15.287 Rarely ocular toxicity can occur including retinitis, uveitis, and retinal 
vein occlusion. Instruct patients to report any vision changes and/or eye 
pain to the study team. 
15.288 Monitor renal function, encourage patients drink adequate fluids. 
15.289aRash can be seen. Instruct patient to report rash to study team.  
15.289bAgent can cause pyrexia, especially in combination with binimetinib. 
Instruct patient to report any fever to the study team. 
15.29a Drug procurement:  Drug procurement: Array BioPharma, Inc will supply the 
drug to Clinical Research Services, a division of Rx Crossroads by McKesson. 
Each participating ACCRU treating location will order the drug from Clinical 
Research Services, a division of Rx Crossroads by McKesson. Submit the Drug 
Order Request Form (found on the ACCRU web site) to: 
 
Clinical Research Services, a division of Rx Crossroads by McKesson 


 
56  
ACCRU-GI-1907 
 
  
 
Each participating ACCRU treating location will be responsible for 
monitoring the supply of encorafenib and will use the Drug Order 
Request Form to order additional supplies as needed. 
 
Outdated or remaining drug is to be destroyed on-site as per procedures 
in place at each institution. 
 
15.29b Temperature excursions that occur at the site should be reported by the site to 
Clinical Research Services, a division of Rx Crossroads by McKesson via email 
to:  
Any shipment deviations (those not 
occurring at the site) should be reported to Clinical Research Services, a division 
of Rx Crossroads by McKesson, via email to: 
 Clinical Research Services, a division 
of Rx Crossroads by McKesson, will report any temperature and shipment 
deviations (those not occurring at the site) to Array BioPharma Inc. via email to: 
 
 
15.29b1 When reporting a temperature excursion to Clinical Research Services, 
please include the following information as required by Array:  
• 
Study/protocol number 
• 
Name and contact information 
• 
Site location and address 
• 
Array lot and kit numbers affected (if applicable) 
• 
High/low temperature recorded for event 
• 
Duration of the event 
• 
All supporting data or charts (Temp Log, TempTale, etc.) 
• 
Temperature deviation event form (if site has their own) 
 
Following temperature deviation, the affected material should be 
physically quarantined by the site until a response is received from Array 
regarding the disposition of the affected materials. 
. 
 
16.0  
Statistical Considerations and Methodology  
 
 
16.1 
Overview 
 
 
 
This is a single-arm phase II study designed to assess the efficacy of binimetinib and 
encorafenib in patients with advanced pancreatic cancer and somatic BRAFV600E mutation. 
Overall response rate (ORR) will be used as the primary endpoint. Based on historical 
data and clinical experience, an ORR of 10% or less would be of no interest (null 
hypothesis), and an ORR of 30% or more would be of interest (alternative hypothesis). In 
addition to ORR, progression-free survival (PFS), overall survival (OS), and adverse 
event rates will be of specific interest. Analysis of acquired BRAF alterations will be 
performed as correlative research.   
 
Investigation of the “Know Your Tumor” database shows that this subgroup of BRAF 


 
57  
ACCRU-GI-1907 
 
mutations has an approximate prevalence of 15-20% in KRAS wild type pancreatic 
cancers. Other studies have found that approximately 2% of pancreatic cancers have 
activating alterations in BRAF.   
 
To pre-register for this study, patients must have documentation indicating a BRAFV600E 
mutation. Successful registration to this trial requires that this document be centrally 
reviewed to confirm the existence of the BRAFV600E mutation. Therefore, we do not 
expect the number of patients pre-registered to the trial to be notably larger than the 
number of patients who eventually register to the trial.   
 
 
16.2 
Statistical Design 
 
 
A Simon two-stage optimal design with relaxed futility stopping will be used (Ivanova, et 
al, 2016). The largest success proportion where the proposed treatment regimen would be 
considered ineffective is 10%, and the smallest success proportion that would warrant 
subsequent studies with the proposed regimen in this patient population is 30%. Rates of 
maintaining stable disease throughout the first 24 weeks on treatment are expected to be 
between 30% and 60%. The following two-stage design uses 10 or 26 evaluable patients 
to test the null hypothesis that the true success proportion in this given patient population 
is at most 10%.   
 
 
 
16.21 Primary Endpoint 
 
The primary endpoint in this trial is objective response rate (ORR) at 24 weeks 
post-registration. An objective response is defined as a complete or partial 
response with a confirmation scan not less than 4 weeks after the initial scan. 
Disease status will be assessed using RECIST v. 1.1 criteria. Evaluable patients 
are defined as those who are eligible, consented, and received any protocol 
treatment. 
 
 
 
 
 
 
 
16.211 STAGE 1: 
 
Enter 10 evaluable patients into the study. If three or fewer patients 
experience an objective response or maintain stable disease within the 
predefined time period, we will consider this treatment ineffective in this 
patient population, and terminate the study. Otherwise, if four or more 
patients experience an objective response or maintain stable disease, we 
will proceed to Stage 2.  
 
 
 
 
16.212 STAGE 2:  
 
Enter an additional 16 patients into the study. If five or fewer patients 
among the 26 total evaluable patients accrued experience an objective 
response within the predefined time period, we will consider this 
treatment ineffective in this patient population. If 6 or more patients out 
of the 26 total evaluable patients accrued experience an objective 
response, we may recommend further testing of this regimen in 
subsequent studies. 
 
 
 
 
16.213 NOTE: 
 


 
58  
ACCRU-GI-1907 
 
Accrual will not be suspended between stages to allow the first 10 
patients to become evaluable, unless undue toxicity is observed.   
 
 
 
16.22 Power and Sample Size 
 
This two-stage study design outlined in 16.21 assumes the number of successes is 
binomially distributed, the null success proportion is 0.1, and the alternative 
success proportion is 0.3. Additionally, we assume the rate of stable disease has a 
uniform distribution U(0.3, 0.6) under the null hypothesis. Given these, the exact 
type 1 error rate (alpha) is 0.0397, and the exact power is 80.4% when the true 
response rate is 30%.    
 
 
A minimum of 10 and maximum of 26 evaluable patients are required under the 
stated assumptions, unless undue toxicity is observed. We anticipate accruing an 
additional 3 patients to account for ineligibility, cancellation, major treatment 
violation, or other reasons. Maximum projected accrual is therefore 29 patients. 
All sample size calculations were computed using PASS 15 software.   
 
 
 
16.23 Operating Characteristics 
 
The probability of declaring that this regimen warrants further studies (i.e. 
statistical power) under various success proportions can be tabulated as a 
function of the true success proportion as shown in the following table. 
 
 
 
 
If the true success proportion is: 
0.10 
0.15 
0.20 
0.25 
0.30 
then the probability of declaring that the regimen 
warrants further studies is: 
0.04 
0.18 
0.42 
0.66 
0.84 
 
 
 
 
16.24 Accrual Time and Study Duration 
 
The anticipated accrual rate is 1-2 patients per month. Therefore, the accrual 
period for the first stage of this study is expected to be approximately 10 months. 
If patients are accrued to the second stage, the total accrual period is expected to 
be approximately 26 months. Should the study continue to full accrual, the 
primary analysis can begin approximately 32 months after the trial begins; as 
soon as the last patient has either experienced a confirmed objective response, or 
been observed for 24 weeks.  
 
 
16.3 
Analysis Plan 
 
 
 
16.31 Primary Endpoint Analysis 
 
The analysis for this trial will begin at planned time points (see 16.2) and at the 
time the patients have become evaluable for the primary endpoint. Such a 
decision will be made by the statistician and Study Chair, in accord with CCS 
Standard Operating Procedures, availability of data for secondary and correlative 
endpoints, and the level of data maturity.   
 
 
 
 
16.311 Definition 
 
 
 
 


 
59  
ACCRU-GI-1907 
 
The primary endpoint for this study is defined in section 16.21. The final 
ORR point estimate and corresponding 95% confidence interval will be 
reported.  
 
 
 
 
16.312 Estimation 
 
The proportion of successes will be estimated by the number of 
successes divided by the total number of evaluable patients. Confidence 
intervals for the true success proportion will be calculated according to 
the approach of Clopper and Pearson.   
 
 
 
 
16.313 Over Accrual 
 
If more than the target number of patients are accrued, the additional 
patients will not be used to evaluate the stopping rule or used in any 
decision making process. However, they will be included in final point 
estimates and confidence intervals as though they were accrued in the 
final stage.   
 
 
 
16.32 Secondary Endpoint Analysis 
 
 
 
 
16.321 Progression-Free Survival 
 
Progression-free survival (PFS) is defined as the time from registration to 
the first of either disease progression or death from any cause, where 
disease progression is determined based on RECIST 1.1 criteria. PFS 
will be estimated using the Kaplan-Meier method. The median PFS and 
corresponding 95% confidence interval will be reported. Patients who do 
not experience disease progression or death while on protocol will be 
censored at the last disease assessment date.  
 
 
 
 
16.322 Overall Survival 
 
Overall survival (OS) is defined as the time from registration to death 
from any cause. Analysis of this endpoint will mirror that of PFS (section 
16.321). 
 
 
16.323 Duration of Response 
 
Duration of response is defined as the duration of time from first 
documentation of an objective response (defined in 16.21) to the earliest 
date disease progression is documented or death from any cause. 
Analysis of this endpoint will mirror that of PFS (Section 16.321). 
 
16.324 Time to Response 
 
Time to response is defined as the duration of time from registration to 
the first documentation of an objective response (defined in 16.21).  
Analysis of this endpoint will mirror that of PFS (section 16.321). 
 
 


 
60  
ACCRU-GI-1907 
 
 
 
 
16.325 Adverse Event Rate 
 
All patients who have initiated treatment will be considered evaluable for 
adverse event analyses. The rate of patients experiencing a grade 3+ 
adverse event will be reported. Further analyses of adverse event rates 
will be considered exploratory. 
 
16.33 Correlative Research 
 
16.331 Additional mutations in BRAF or in other related genes as determined by 
next-generation sequencing from plasma samples will be used to 
investigate the mechanisms of resistance, either primary or acquired 
through real time monitoring of the BRAF mutational profile evolution.  
 
16.322 Changes in tumor biomarker 
 
 
The absolute change and percentage change from baseline at each 
assessment of CA19-9 of CEA levels will be investigated.  
 
 
16.4 
Safety Monitoring  
 
 
 
 
16.41 Adverse Event Stopping Rule(s) 
 
The stopping rules specified below are based on the knowledge available at study 
development. We note that the Adverse Event Stopping Rule may be adjusted in 
the event of either (1) the study re-opening to accrual or (2) at any time during 
the conduct of the trial and in consideration of newly acquired information 
regarding the adverse event profile of the treatment(s) under investigation. The 
study team may choose to suspend accrual because of unexpected adverse event 
profiles that have not crossed the specified rule below.  
 
Accrual will be temporarily suspended to this study if at any time, we observe 
events considered to be at least possibly related to study treatment (i.e., an 
adverse event with attribute specified as “possible”, “probable”, or “definite”) 
that satisfy the following: 
 
If at any time, 3 of the initial 10 treated patients or 30% or more of all patients 
(when accrual is greater than 10 patients) have experienced a non-hematologic 
grade 4 or 5 adverse event. . 
 
We note that we will review Grade 4 and 5 adverse events deemed “unrelated” or 
“unlikely to be related”, to monitor the emergence of a previously unrecognized 
treatment-related adverse event. 
 
 
 
16.5 
Data Monitoring and Reporting  
 
 
 
16.51 DSMB Reporting 
 
The study chair(s) and the study statistician will review the study at least twice 


 
61  
ACCRU-GI-1907 
 
per year to identify accrual, adverse event, and any endpoint problems that might 
be developing. The Mayo Clinic Cancer Center (MCCC) Data Safety Monitoring 
Board (DSMB) is responsible for reviewing accrual and safety data for this trial 
at least twice per year, based on reports provided by the MCCC Statistical Office.  
 
Additionally, during the first Simon Stage, if and as soon as two patients have 
experienced a confirmed partial or complete response to therapy, then the study 
chair(s) and the study statistician will review the study to determine if the study 
can be opened for full accrual.  
 
 
 
 
16.52 CT.gov Reporting 
 
Expected durations and timelines for certain events (e.g. accrual) and endpoints 
for CT.gov reporting purposes can be found in sections 16.24 and 16.3 
respectively. 
 
Expected durations and timelines for certain events (e.g. accrual) and endpoints 
for CT.gov reporting purposes can be found in sections 16.24 and 16.3 
respectively. 
 
 
 
 
17.0  
Pathology Considerations/Tissue Biospecimens  
 
 
17.1 
Tissue Biospecimen Submission  
 
 
17.11 Summary Table of Tissue Biospecimens for This Protocol 
Type of tissue 
biospecimen 
to submit 
Mandatory or 
optional 
When to 
submit 
Reason for submission 
(background/methodology 
section) 
Where to 
find specific 
details for 
biospecimen 
submission 
Formalin-fixed 
paraffin-
embedded 
(FFPE) tissue 
blocks with 
corresponding 
H&E (OR 
twenty (23) 
5µM unstained 
slides with 
corresponding 
H&Es) 
Mandatory 
≤30 days after 
registration 
Correlative studies (Section 
17.5) 
Section 17.3 
 
 
 
17.2 
Paraffin Embedded Tissue Blocks/Slides  
 


 
62  
ACCRU-GI-1907 
 
17.21 Submit one formalin fixed paraffin-embedded (FFPE) tumor tissue block with 
largest amount of invasive tumor (at least 1 cm of tumor for cases of surgical 
resection) (from original) surgery. A corresponding H&E slide for each 
submitted block must be provided to permit quality assessment of each tissue 
block  
 
17.22 The FFPE tissue block is preferred; however, if an institution is unable to 
provide a tissue block, cut 23 five micron sections and mount on charged glass 
slides. Label the slides with ACCRU patient ID number, accession number, 
and order of sections. H&E stain every tenth slide (i.e., slides labeled 1, 11, 21, 
etc.). These H&E slides will be reviewed centrally under the research base’s 
protocol for assessing tissue quality. The remaining unstained slides will be 
processed as described in 17.5. Ideally, each slide must have a minimum of 75% 
tumor tissue on the slide to be deemed adequate for study. Do not bake or place 
covers slips on the slides. Labeling with sticky labels is not acceptable. 
 
17.23 The following materials below are mandatory (unless indicated otherwise) and 
required for shipment: 
 
• 
Paraffin embedded tissue blocks with corresponding H&E slide (OR 23 
unstained slides with corresponding H&E(s)).  
• 
Specimen Submission: Tissue form 
• 
Pathology Reports 
• 
Somatic Genetic Testing Results (e.g. Foundation Medicine, Caris or similar 
panel testing) 
• 
Operative Report (optional) 
 
• 
Note: Please include the ACCRU patient ID number on all materials 
listed above. 
 
17.24 The block/slides must be appropriately packed to prevent damage (e.g., slides 
should be placed in appropriate slide container) and placed in an individual 
plastic bag. Label the bag with the protocol number, ACCRU patient ID number, 
and patient initials. During warm weather months, paraffin blocks should be 
shipped using a refrigerant pack to avoid heat that may melt paraffin and damage 
blocks. 
 
17.25 Tissue specimens must be shipped ≤30 days after registration. 
 
17.26 Verify that the appropriate sections of the Specimen Submission: Tissue form are 
completed and filled in correctly. Enter information from the Specimen 
Submission: Tissue form into the remote data entry system on the same day the 
specimen is submitted (see Forms Packet). 
 
17.27 Ship all block/slide tissue specimens and accompanying materials to the ACCRU 
Research Base: 
 
 
 


 
63  
ACCRU-GI-1907 
 
 
 
 
17.3 
Study Methodology and Storage Information 
 
17.31 Submitted tissue samples will be analyzed as follows:  
 
 
17.311 At the completion of the study, any unused/remaining material will be 
shipped to Dana-Farber Cancer Institute and stored for future research 
according to the patient consent permission (see Section 6.24). Potential 
future research may include immunohistochemistry (IHC) analyses to 
analyze predictive biomarkers, changes in expression pattern with 
therapy, and correlation with response and/or adverse events. When a 
protocol is developed, it will be presented for IRB review and approval. 
 
 
 
 
ACCRU will ship samples to:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
17.312 Banking of tumor tissue, according to the patient consent permission (see 
Section 6.245), is for future research. As protocols are developed, they 
will be presented for ACCRU and IRB review and approval. (This 
collection is part of a general strategy of investigation for ACCRU 
melanoma studies). 
 
17.313 The institutional pathologist will be notified by the Pathology 
Coordinator if the block may be depleted. 
 
17.314 Blocks requested to accommodate individual patient management will be 
returned promptly upon request. 
 
 
17.4 
Return of Genetic Testing Research Results  
 
Because the results generated by the genetic testing included in this section are not 
currently anticipated to have clinical relevance to the patient or their family members, the 
genetic results will not be disclosed to the patients or their physicians. 
 
If, at any time, genetic results are obtained that may have clinical relevance, IRB review 
and approval will be sought regarding the most appropriate manner of disclosure and 
whether or not validation in a CLIA-certified setting will be required.  Sharing of 
research data with individual patients should only occur when data have been validated 
by multiple studies and testing has been done in CLIA-approved laboratories. 
 
 
18.0 
Records and Data Collection Procedures  
 


 
64  
ACCRU-GI-1907 
 
All data must be entered by Remote Date Entry (RDE) and completed by qualified and authorized 
personnel. Access the RAVE RDE system through the iMedidata portal at 
 All data on the CRF must reflect the corresponding source 
document. Please refer to the ACCRU website for instructions (
).  
 
18.1 
Submission Timetable 
 
Pre-Registration Material(s)  
Case Report Form (CRF) 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
Screening  
Complete for ALL patients 
Supporting Documentation: Baseline1 
See Section 6.0 (for central review, eligibility, etc. 
confirmation prior to Registration) 
1.  Results from a CLIA/CAP certified testing lab (commercial or institutional) that confirm the 
presence of a BRAFV600E mutation in the patient’s tumor.  
 
Initial Material(s) -  
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
Institutional Contacts 
≤2 weeks after registration 
On-Study  
On-Study: Prior Surgery1 
On-Study: Prior Systemic Therapy1 
On-Study: Prior Radiation1 
Adverse Event: Baseline  
RECIST Measurements: Baseline 
Supporting Documentation: Baseline2 
Specimen Submission: Blood (Baseline) (see 
Section 14.0) 
Specimen Submission: Tissue (Baseline) (see 
Section 17.0) 
Patient Status: Baseline  
Off Treatment 
Submit ≤2 weeks after registration if withdrawal/refusal 
occurs prior to beginning protocol therapy 
ACCRU Deviation Form1 
Submit only if applicable during all phases of the study  
(initial, active) 
1. Submit only if applicable. 
2.   Upload via the Supporting Documentation:  Baseline form. Central Review Form. Imaging report 
confirming measureable disease.  
 
Test Schedule Material(s)  
 
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
At each evaluation during 
treatment 
At end of treatment 
 


 
65  
ACCRU-GI-1907 
 
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
At each evaluation during 
treatment 
At end of treatment 
 
Treatment (Intervention) 
X 
X 
Treatment (Intervention): Dose 
Modifications, Omissions and Delays1 
X 
X 
Adverse Events: Solicited 
X 
X 
Adverse Events: Other1 
X 
X 
RECIST Measurements2 
X 
X 
Supporting Documentation2 
X 
X 
Specimen Submission: Blood (see Section 
14.0) 
X  
X 
Patient Status: Treatment (Intervention) 
X 
X 
Consent Withdrawal (choose appropriate 
form)1 
• 
Consent Withdrawal: Specimen Only 
• 
Consent Withdrawal: All Follow-Up 
X 
X 
Off Treatment 
 
X 
ACCRU Deviation1 
X 
X 
Lost to Follow-up1,3 
 
 
1. Submit only if applicable. 
2. Upload documentation of response or progression on the Supporting Documentation form. 
3. Patients are eligible to be confirmed lost to follow-up after 2 years of unsuccessful contact with the 
patient. 
 
Follow-up Material(s)  
CRF 
Event Monitoring Phase1 
 
q. 3 
months 
until PD 
 
At PD 
After 
PD q. 3 
mos. 
Death 
Patient Status: Survival and Disease 
Status Follow-Up/Event Monitoring  
X2 
X2 
X 
X 
Adverse Events: Late3 
 
 
 
 
Supporting Documentation2, 3 
 
 
 
 
Consent Withdrawal (choose 
appropriate form)3 
• Consent Withdrawal: Specimen 
Only 
• Consent Withdrawal: All Follow-Up 
 
 
 
 
Lost to Follow-Up3,4 
 
 
 
 
ACCRU Deviation Form3 
X3 
X3 
X3 
X3 
1. If a patient is still alive 5 years after registration, no further follow-up is required. 
2. Upload a copy of documentation of response or progression in RAVE on the Supporting 
Documentation Form. 


 
66  
ACCRU-GI-1907 
 
3. Submit only if applicable. 
4. Patients are eligible to be confirmed lost to follow-up after 2 years of unsuccessful contact with the 
patient. 
 
 
 
19.0 
Budget 
 
 
19.1 
Each site should review the test schedule (Section 4.0), taking into account local and 
regional coverage policies, to determine which items are standard of care and which are 
research at their site. Refer to the payment synopsis for funding provided per accrual for 
covering study costs, as well as any additional invoiceables that may be allowed. 
 
 
 
20.0 
References 
 
Aguirre AJ, et al. (2018) Real-time Genomic Characterization of Advanced Pancreatic Cancer to Enable 
Precision Medicine. Cancer Discov 8(9): 1096-1111 
 
Bailey P, et al. (2016) Genomic analyses identify molecular subtypes of pancreatic cancer. Nature 
531(7592): 47-52 
 
Biankin AV, et al. (2012) Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. 
Nature 491(7424): 399-405 
 
Boeck S, et al. (2008) Capecitabine plus oxaliplatin (CapOx) versus capecitabine plus gemcitabine 
(CapGem) versus gemcitabine plus oxaliplatin (mGemOx): final results of a multicenter randomized 
phase II trial in advanced pancreatic cancer. Ann Oncol 19(2): 340-7 
 
Boeck S, et al. (2007) Second-line chemotherapy with pemetrexed after gemcitabine failure in patients 
with advanced pancreatic cancer: a multicenter phase II trial. Ann Oncol 18(4): 745-51 
 
Cancer Genome Atlas Research Network. Electronic address aadhe, Cancer Genome Atlas Research N 
(2017) Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma. Cancer Cell 32(2): 
185-203 e13 
 
Cantore M, et al. (2004) Combined irinotecan and oxaliplatin in patients with advanced pre-treated 
pancreatic cancer. Oncology 67(2): 93-7 
 
Cereda S, et al. (2016) Capecitabine with/without mitomycin C: results of a randomized phase II trial of 
second-line therapy in advanced biliary tract adenocarcinoma. Cancer Chemother Pharmacol 77(1): 109-
14 
 
Cereda S, et al. (2011) Salvage therapy with mitomycin and ifosfamide in patients with gemcitabine-
resistant metastatic pancreatic cancer: a phase II trial. Chemotherapy 57(2): 156-61 
 
Chmielecki J, et al. (2014) Comprehensive genomic profiling of pancreatic acinar cell carcinomas 
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1398-405 


 
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Collisson EA, et al. (2011) Subtypes of pancreatic ductal adenocarcinoma and their differing responses to 
therapy. Nat Med 17(4): 500-3 
 
Conroy T, et al. (2011) FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 
364(19): 1817-25 
 
Davies H, et al. (2002) Mutations of the BRAF gene in human cancer. Nature 417(6892): 949-54 
 
Demols A, et al. (2006) Gemcitabine and oxaliplatin (GEMOX) in gemcitabine refractory advanced 
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Drilon A, et al. (2018) Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children. 
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Eisenhauer EA, et al. (2009) New response evaluation criteria in solid tumours: revised RECIST 
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El-Osta H, et al. (2011) BRAF mutations in advanced cancers: clinical characteristics and outcomes. 
PLoS One 6(10): e25806 
 
Foster SA, et al. (2016) Activation Mechanism of Oncogenic Deletion Mutations in BRAF, EGFR, and 
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Heining C, et al. (2018) NRG1 Fusions in KRAS Wild-Type Pancreatic Cancer. Cancer Discov 8(9): 
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Hyman DM, et al. (2015) Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations. 
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Ishimura N, et al. (2003) BRAF and K-ras gene mutations in human pancreatic cancers. Cancer Lett 
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Ivanova A, et al. (2016) Two-stage design for phase II oncology trials with relaxed futility stopping.  Stat 
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Kim HJ, et al. (2012) Phase II study of palliative S-1 in combination with cisplatin as second-line 
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Le DT, et al. (2015) PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med 372(26): 
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Lowery MA, et al. (2017) Real-Time Genomic Profiling of Pancreatic Ductal Adenocarcinoma: Potential 
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Pishvaian MJ, et al. (2018) Molecular Profiling of Patients with Pancreatic Cancer: Initial Results from 
the Know Your Tumor Initiative. Clin Cancer Res 24(20): 5018-5027 
 
Planchard D, et al. (2016) Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-
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gemcitabine-pretreated advanced pancreatic cancer: A phase II study. Invest New Drugs 23(4): 369-75 
 
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Von Hoff DD, et al. (2013) Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. 
N Engl J Med 369(18): 1691-703 
 
Waddell N, et al. (2015) Whole genomes redefine the mutational landscape of pancreatic cancer. Nature 
518(7540): 495-501 
 
Wang-Gillam A, et al. (2016) Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic 
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Xiong HQ, et al. (2008) Phase 2 trial of oxaliplatin plus capecitabine (XELOX) as second-line therapy for 
patients with advanced pancreatic cancer. Cancer 113(8): 2046-52 
 
Yaeger R, Corcoran RB (2019) Targeting Alterations in the RAF-MEK Pathway. Cancer Discov 9(3): 
329-341 
 
Yao Z, et al. (2015) BRAF Mutants Evade ERK-Dependent Feedback by Different Mechanisms that 
Determine Their Sensitivity to Pharmacologic Inhibition. Cancer Cell 28(3): 370-83 
 
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Appendix I: ACCRU-GI-1907 SUBJECT MEDICATION DIARY 
 
Name: 
Subject ID Number: 
Cycle:  
You will take:  
 
ORAL MEDICATION DIARY 
Subject Instructions 
• Please bring your Medication Diary and any empty or unused medication container(s) 
with you to every appointment 
• Please use an ink pen when completing the Medication Diary as these will be retained in 
our research record. 
• Please contact your physician and study coordinator any time you go into the hospital. 
Your physician can advise if you should continue or stop taking your medication. 
• To correct a mistake, please make a single line through that entry and write your initials 
and the date next to the mistake. 
• Please indicate on the calendar on the next page that you took your study medication by 
recording the date and dose taken on the line under the date. 
• If you miss a dose, place a “0” under the date, but remember to take your prescribed dose 
at the next regularly scheduled time. 
• If you accidentally take more than you are instructed to, contact your doctor or the 
emergency room immediately. 
• If you miss a dose, do not make up the dose. Wait until your next dose is due. 
 
 


 
71  
ACCRU-GI-1907 
 
ACCRU-GI-1907 SUBJECT MEDICATION DIARY 
 
 
 
 
 
 
 
 
 
 
Study Drug/Dose 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Date 
 
 
 
 
 
 
 
Encorafenib/__mg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Binimetinib 
(AM)/__mg 
 
 
 
 
 
 
 
Binimetinib 
(PM)/__mg 
 
 
 
 
 
 
 
Study Drug/Dose 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
Date 
 
 
 
 
 
 
 
Encorafenib/__mg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Binimetinib 
(AM)/__mg 
 
 
 
 
 
 
 
Binimetinib 
(PM)/__mg 
 
 
 
 
 
 
 
Study Drug/Dose 
Day 
15 
Day 16 
Day 17 
Day 18 
Day 19 
Day 20 
Day 21 
Date 
 
 
 
 
 
 
 
Encorafenib/__mg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Binimetinib 
(AM)/__mg 
 
 
 
 
 
 
 
Binimetinib 
(PM)/__mg 
 
 
 
 
 
 
 
Study Drug/Dose 
Day 
22 
Day 23 
Day 24 
Day 25 
Day 26 
Day 27 
Day 28 
Date 
 
 
 
 
 
 
 
Encorafenib/__mg     
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Binimetinib 
(AM)/__mg 
 
 
 
 
 
 
 
Binimetinib 
(PM)/__mg 
 
 
 
 
 
 
 


 
72  
ACCRU-GI-1907 
 
Date:__________________ Subject’s Signature___________________________________ 
 
Area Below Only To Be Completed only by Coordinator 
  
Week 
1 
2 
3 
4 
Discrepancy (Yes or 
No) 
Date of Pill Count 
 
 
 
 
 
Number of Pills 
Returned 
 
 
 
 
 
Study Coordinator 
Initials 
 
 
 
 
 
 


 
73  
ACCRU-GI-1907 
 
Appendix II: Contraception 
 
Female participants of childbearing potential must agree to take appropriate precautions to avoid 
pregnancy from Screening through 30 days after the last dose of study drug/treatment. In addition, female 
participants must refrain from donating ova during the study through 30 days after the end of systemic 
exposure of study drug/treatment. 
Male participants should use a condom during treatment and through 90 days after the end of systemic 
exposure to study drug/treatment. If the male participant has a partner that is of child-bearing potential, 
the partner should also use contraception through 90 days after the end of systemic exposure to study 
drug/treatment. In addition, male participants must refrain from donating sperm during the study through 
90 days after the end of systemic exposure of study drug/treatment. Males who have had a vasectomy 
qualify as having met the requirement for a highly effective birth control method. 
Definitions: 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a 
menstrual cycle cannot be confirmed before first dose of study treatment, additional evaluation should be 
considered. 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
• 
Documented hysterectomy 
• 
Documented bilateral salpingectomy 
• 
Documented bilateral oophorectomy 
 
For individuals with permanent infertility due to an alternate medical cause other than the above, 
(e.g., mullerian agenesis, androgen insensitivity), Investigator discretion should be applied to 
determining study entry. 
Note: Documentation can come from the site personnel’s: review of the participant’s medical 
records, medical examination, or medical history interview. 
3. Postmenopausal female 
• 
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause.  
• 
A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to 
confirm a postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy (HRT).  
• 
Females on HRT and whose menopausal status is in doubt will be required to use one of the 
non-estrogen hormonal highly effective contraception methods if they wish to continue their 
HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before study enrollment. 
 
Contraception Guidance: 
NOTE: There is a potential for encorafenib to induce CYP3A4, which may reduce the effectiveness of 
hormonal contraception methods. Therefore, the use of at least 1 form of non-hormonal contraception is 


 
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ACCRU-GI-1907 
 
required for females of childbearing potential during participation in this study. 
The contraception guidelines outlined below are adapted from the recommendations related to 
contraception and pregnancy testing in clinical trials guidance document (Clinical Trials Facilitation 
Group Guidelines 2014). Participants must agree to use highly effective methods of contraception if it is 
mandated locally or when, in the judgment of the Investigator, compliance with acceptable methods is 
likely to be suboptimal. 
The following methods have been classified as being highly effective (i.e., failure rate < 1% per year 
when used consistently and correctly) in preventing a pregnancy: 
• 
Complete abstinence from heterosexual intercourse during the entire period of risk associated 
with the study treatments; the reliability of sexual abstinence should be evaluated in relation to 
the duration of the clinical trial and the preferred and usual lifestyle of the participant 
• 
Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation: 
o Oral 
o Intravaginal 
o Transdermal 
• 
Progestogen-only hormonal contraception associated with inhibition of ovulation: 
o Oral 
o Injectable 
o Implantable 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) 
• 
Bilateral tubal occlusion 
• 
Vasectomised partner (considered highly effective provided the vasectomized male has received 
medical assessment of surgical success and that the male is a female participant’s sole sexual 
partner) 
Acceptable birth control methods characterized as having a failure rate of more than 1% per year include: 
• 
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary 
mode of action 
• 
Male or female condom with or without spermicide 
• 
Cap, diaphragm or sponge with spermicide