Clinical trial NCT03981614
Conditions: Metastatic Colorectal Carcinoma Stage IV Colorectal Cancer AJCC v8 Stage IVA Colorectal Cancer AJCC v8 Stage IVB Colorectal Cancer AJCC v8 Stage IVC Colorectal Cancer AJCC v8 Unresectable Carcinoma
Sponsor: Academic and Community Cancer Research United
Start date: 2019-10-29; Completion date: 2024-07-02
Enrollment: 102 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This phase II trial studies how well binimetinib and palbociclib work compared to TAS-102 in treating patients with KRAS and NRAS mutation positive colorectal cancer that has spread to other places in the body (metastatic) or cannot be removed by surgery (unresectable). Binimetinib and palbociclib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as TAS-102, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving binimetinib and palbociclib may work better compared to TAS-102 alone in treating patients with colorectal cancer.

Detailed description:
PRIMARY OBJECTIVE:

I. The primary objective is to compare the progression-free survival (PFS) between those randomized to palbociclib/binimetinib and those randomized to trifluridine and tipiracil hydrochloride (TAS-102) in patients with refractory KRAS- or NRAS-mutant metastatic colorectal cancer (CRC).

SECONDARY OBJECTIVES:

I. To compare the overall response rate by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria between those randomized to palbociclib/binimetinib and those randomized to TAS-102 in patients with refractory KRAS- or NRAS-mutant metastatic CRC.

II. To compare the overall survival (OS) between those randomized to palbociclib/binimetinib and those randomized to TAS-102 in patients with refractory KRAS- or NRAS-mutant metastatic CRC.

III. To determine the safety and tolerability of the recommended phase II dose of palbociclib in combination with binimetinib in patients with refractory KRAS- or NRAS-mutant metastatic CRC.

CORRELATIVE RESEARCH OBJECTIVES:

I. To determine the tumor mutational profiles that characterize groups of patients that predict for response or resistance to combination of palbociclib/binimetinib.

II. To determine the correlation between circulating tumor deoxyribonucleic acid (DNA) and tumor response or resistance to therapy with palbociclib/binimetinib or TAS-102.

III. To determine the association between Consensus Molecular Subtype based on gene expression profiling and response or resistance to combination of palbociclib/binimetinib.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive binimetinib orally (PO) twice daily (BID) on days 1-28 and palbociclib PO once daily (QD) on days 1-21. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive trifluridine and tipiracil hydrochloride PO BID on days 1-5 and 8-12. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. Patients with disease progression may optionally crossover to Arm A.

After completion of study treatment, patients are followed up within 30-37 days and then every 12 weeks for up to 24 months.

Arms: arm 1: Patients receive binimetinib PO BID on days 1-28 and palbociclib PO QD on days 1-21. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive trifluridine and tipiracil hydrochloride PO BID on days 1-5 and 8-12. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. Patients with disease progression may optionally crossover to Arm A.
Interventions: intervention 1: Binimetinib intervention 2: Palbociclib intervention 3: Trifluridine and Tipiracil Hydrochloride
Intervention descriptions: intervention 1: Given PO intervention 2: Given PO intervention 3: Given PO

Protocol documents:
Prot_SAP_000.pdf: 
1 
ACCRU-GI-1618 
 
 
 
Academic and Community Cancer Research United (ACCRU) 
 
Combination of MEK Inhibitor Binimetinib and CDK4/6 Inhibitor Palbociclib in KRAS and NRAS 
Mutant Metastatic Colorectal Cancers 
 
For any communications regarding this protocol, please contact the person listed on the Protocol 
Resource page. This is a stand-alone document found on the ACCRU web site (www.ACCRU.org). 
 
Study Chairs 
 
ACCRU: 
 
 
 
 
 
 
 
FDA IND Sponsor/Investigator: 
 
 
 
Study Co-chairs: 
 
 
 
 
Statistician: 
 
 
 
 
 Study contributor(s) not responsible for patient care. 
Drug Availability 
Commercial Agents: 
Trifluridine/Tipiracil (TAS-102), Binimetinib (MEK162) and Palbociclib -IND 
Exempt 
 
 
Research Coordinating Center 
Academic and Community Cancer Research United 
 
 
 
 
 
Document History 
(effective date) 
Initial Version 
April 22, 2019 
Addendum 1 
November 12, 2019 
Addendum 2 
June 15, 2020 
Addendum 3 
February 22, 2021 


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ACCRU-GI-1618 
 
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 
List of Medication to be used with Caution when Administered with Binimetinib 
Appendix II 
Patient Medication Diaries 
Appendix III 
Study Contraception Guidelines 
Appendix IV 
Patient Lifestyle Guidelines 
Appendix V 
Appendix VI  
Snellen Equivalence visual acuity conversion chart 
Pfizer Reportable Event Fax Cover Sheet (Internal Use Only by ACCRU)  




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ACCRU-GI-1618 
 
Definitions: 
 
Observation: Part of the Active Monitoring phase of a study; the time period following the active 
treatment phase when the participant continues to receive cycles of evaluation in compliance with the 
Test Schedule and will be required to return to the consenting site for protocol tests. 
 
Event Monitoring: Not part of the Active Monitoring phase of a study; the time period when the 
participant is no longer following the protocol test schedule. During Event Monitoring, the data collection 
schedule is dictated by the protocol but the visit schedule is determined by clinical practice at each 
participating site. During the Event Monitoring Phase of the study, the participant is being monitored for 
key study events such as progression, new primaries, and death. Participants will not be required to return 
to the consenting site for study-related reasons or required to have research-related tests performed. 
Samples from biospecimens collected in the course of clinical care may be requested but cannot be 
required of the participant. 
 
Generic name: Binimetinib 
Generic name: Palbociclib 
Generic name: Trifluridine/Tipiracil 
Brand name(s): MEKTOVI 
Brand name(s): IBRANCE 
(TAS-102) 
Availability: RxCrossroads 
by McKesson 
Availability: RxCrossroads 
by McKesson 
Brand name(s): LONSURF 
 
 
Availability: Commercially available 
Clinical Research Services 
Clinical Research Services 


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ACCRU-GI-1618 
 
1.0 
Background 
 
1.1 
KRAS and NRAS mutant colorectal cancers 
 
Colorectal cancer (CRC) is the third most common cancer in men and women in the 
United States, afflicting approximately 4.8% of men and women during their lifetimes 
and causing an estimated 50,310 deaths in 2014. Mortality is primarily driven by the 20% 
of CRC patients with metastatic disease, who suffer 5-year overall survival (OS) of only 
12.9% [1]. Patients with metastatic CRC have experienced improvements in median OS, 
from 14.2 months for those diagnosed in 1990-1997 to over 29 months for those 
diagnosed after 2004 [2]. Much of these improvements are attributable to development of 
novel therapies. Previously, only fluoropyrimidines like 5-fluorouracil were standard 
options for patients with CRC, but starting in the mid-2000s, increasing numbers of 
patients were treated with irinotecan, oxaliplatin, bevacizumab, and the monoclonal 
antibodies targeting the epidermal growth factor receptor (EGFR), and more widespread 
use of these agents contributed to improvements in survival [2]. Nevertheless, barring 
surgical resection of oligometastatic disease, inevitably metastatic cancers develop 
resistance to therapies, resulting in clinical progression and ultimately death. There 
remains a great unmet need to better understand biologic mechanisms of susceptibility to 
therapies and use this knowledge to personalize therapy choices for individual patients. 
 
EGFR and proteins involved in its downstream signal transduction play important roles in 
oncogenesis and tumor progression in CRC. EGFR is a transmembrane receptor tyrosine 
kinase, with an ectodomain that can bind known ligands such as epidermal growth factor 
(EGF), transforming growth factor alpha (TGF-α), amphiregulin, epiregulin, heparin- 
binding EGF, betacellulin, and epigen. Upon ligand binding, EGFR homodimerizes to 
activate downstream intracellular signal transduction cascades, notably including the 
mitogen activated protein kinase (MAPK) pathway via RAS, RAF, and mitogen-activated 
protein kinase kinase (MEK), to ultimately promote cell proliferation and survival [3]. 
There are three RAS genes in humans encoding homologous proteins, HRAS, NRAS, and 
KRAS [4]. Mutations in exons 2, 3, and 4 of KRAS and NRAS are found in 37-43% of 
CRC patients [5],and contribute to oncogenesis by driving cell proliferation in a growth 
factor-independent fashion [3]. The RAS proteins are G proteins that are in active 
conformation when bound to guanosine triphosphate (GTP) and in inactive conformation 
when bound to guanosine diphosphate (GDP). Oncogenic KRAS mutations hinder 
hydrolysis of GTP to GDP and thus keep KRAS in an active conformation [4]. The active 
conformation of GTP-bound KRAS can then bind other effector proteins, such as the 
RAF family of serine/threonine kinases, to activate them and facilitate activation of 
MEK. MEK also functions as a kinase that, when active, phosphorylates and activates 
ERK, ultimately activating a variety of transcriptions factors to drive cell proliferation. 
 
1.2 
Rationale for combination MEK and CDK4/6 inhibitors in RAS mutant cancers 
 
Although patients with KRAS and NRAS mutant metastatic CRC do not benefit from 
treatment with anti-EGFR monoclonal antibodies, these tumors are appealing targets for 
inhibition of signal transduction molecules downstream of RAS in the EGFR signaling 
cascade, such as MEK. Several preclinical studies have demonstrated that RAS mutated 
malignancies may be susceptible to MEK inhibitors, but that monotherapy with MEK 
inhibitors is unlikely to yield a durable and clinically meaningful response. Seven CRC 
cell lines with mutations in exon 4 of KRAS were found to rely on MEK activity for 
proliferation, as they had IC50 values <100 nM to the MEK inhibitor PD0325901 [6]. 


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ACCRU-GI-1618 
 
CRC cell lines with mutations in exon 2 of KRAS also demonstrated heterogeneous 
responses to MEK inhibitor monotherapy, with seven cell lines showing sensitivity to 
PD0325901 with IC50<20 nM, and seven cell lines showing resistance to anti- 
proliferative effect [6]. Thus, in vitro data suggests that KRAS mutant CRC cell lines may 
be susceptible to MEK inhibitors, although there are additional mechanisms of resistance 
that need to be elucidated. 
 
Several small molecule inhibitors of MEK have been in clinical trials in malignancies 
harboring mutations in BRAF, KRAS, or NRAS, including CRC. However, results with 
MEK inhibitor monotherapy have been unimpressive to date. Monotherapy with the 
MEK inhibitor trametinib (GSK1120212) in 12 KRAS mutated CRC patients yielded no 
responses. Four of the 12 patients had stable disease, with duration on study of 31, 28, 16, 
and 16 weeks [7]. Preclinical in vivo work and early phase clinical studies investigating 
combination MEK inhibitor and inhibitors of the PI3K/AKT/MTOR pathways have also 
been disappointing. For example, combination treatment with the MEK inhibitor 
selumetinib and the PI3K/MTOR inhibitor BEZ235 in murine patient derived xenografts 
from metastatic CRC patients showed no tumor responses [8]. 
 
Although MEK inhibitor monotherapy has not yielded significant responses in early 
clinical trials of KRAS-mutant CRC, it was able to yield significant duration of disease 
stability in one-third of KRAS-mutant CRC subjects. Combining MEK inhibitors with 
cyclin dependent kinase (CDK) 4/6 inhibitors is a rational combination to augment 
response. Alterations in cell cycle pathways including CDKs, p16INK4A, and 
retinoblastoma protein (Rb) are increasingly implicated in oncogenesis in RAS-mutated 
malignancies. Mitogenic signals lead to increased synthesis of cyclin D and binding to 
CDK4 or CDK6, which phosphorylate Rb. Hypophosphorylated Rb is bound to the 
transcription factor E2F, but phosphorylated Rb releases E2F, increasing transcription of 
genes promoting progression from G1 into S phase of the cell cycle. The protein 
p16INK4A induces senescence in G1 by leading to dissociation of the complex of cyclin 
D and CDK4/6. While loss of the Rb tumor suppressor is a common event in 
carcinogenesis, RB1 mutations are very uncommon in CRCs. Non-silent RB1 mutations 
are found in only about 2.7% of CRCs, which does not represent a significant increase 
over the expected background rate of mutations as detected by the MutSig algorithm [5]. 
Furthermore, since Rb is a tumor suppressor, both alleles of RB1 would need to be 
mutated in order to result in loss of Rb, which is extremely uncommon. In fact, the 
majority of CRCs have higher amounts of Rb detectable by immunohistochemistry [9]. 
Nevertheless, loss of functional Rb is vital to maintain ongoing cell proliferation, via a 
mechanism independent of the PI3K/AKT/MTOR pathway [10]. RAS mutated 
malignancies often dysregulate the p16/CDK/Rb pathway upstream of Rb. Methylation 
of p16 and subsequent loss of expression is common in KRAS mutant CRCs[11], and 
concomitant p16 methylation and KRAS mutation is associated with worse prognosis in 
CRCs [12]. Thus, CDK4/6 inhibition to restore the tumor suppressor ability of intact Rb 
is a potential strategy to inhibit proliferation in RAS-mutated malignancies, particularly 
in combination with MEK inhibition, and there is accumulating preclinical evidence 
supporting this strategy. 
 
Combination of MEK inhibitor and CDK4/6 inhibitor is a rational pairing in RAS mutant 
malignancies given the associations between the EGFR/MAPK pathway and the cell 
cycle machinery. Some of the activity of MEK inhibitors is likely mediated by affecting 
the cell cycle. LS1034 and CCCL-18 colon cancer cell lines, which both have mutations 
in KRAS A146T, demonstrated marked decrease in cyclin-D and hypophosphorylation of 


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ACCRU-GI-1618 
 
Rb when treated with the MEK inhibitor PD0325901[6]. Mechanisms of resistance to 
MEK inhibitors may use alternative pathways to uncouple the cell cycle effects from 
MEK inhibition. For example, concomitant PIK3CA mutations and KRAS mutations in 
HCT-15 and DLD-1 cell lines were associated with lack of decrease in cyclin D1 level or 
G1 cell cycle arrest, suggesting that concomitant PIK3CA mutations may decouple cell 
cycle regulation from the MAPK pathway [13]. Combination of MEK inhibitor and 
CDK4/6 inhibitor has yielded strong evidence of efficacy in murine models of RAS- 
mutated malignancies as well. A genetically engineered mouse model utilizing inducible 
NRAS Q61K mutation leads to spontaneous formation of NRAS-mutant melanomas. In 
these models, monotherapy with the MEK inhibitor GSK1120212 only caused cytostatic 
effect but did not cause tumor regression, as extinction of the mutant NRAS did. In an 
unbiased screen to determine differentially expressed genes between the NRAS- 
extinguished mice and the MEK inhibitor-treated mice, genes involved in cell cycle 
regulation were most significant, with CDK4 identified by pathway analysis as driving 
the differential gene regulation. Combination treatment with the CDK4/6 inhibitor 
palbociclib and either of the MEK inhibitors selumetinib or trametinib had synergistic 
effects in vivo in both the inducible NRAS melanoma model and in NRAS-mutant human 
melanoma xenograft models [14]. 
 
1.21 
Preliminary data supporting combination MEK and CDK4/6 inhibitors in RAS 
mutant CRC 
 
Indeed, the combination of MEK and CDK4/6 inhibitors has synergistic efficacy 
in KRAS mutant models of CRC in vitro and in vivo. Our work at the University 
of Texas MD Anderson Cancer Center demonstrated that the combination of 
binimetinib and palbociclib synergistically impaired cell viability and growth in 
vitro in a panel of 11 KRAS mutant CRC cell lines[15]. Reverse phase protein 
arrays performed on cell lines after 24 hours of treatment with binimetinib and 
palbociclib demonstrated that combination treatment synergistically decreased 
the level of phosphorylated ribosomal protein S6, which we confirmed on 
immunoblotting. Though this decrease was blunted in two cell lines with 
concomitant mutated PIK3CA, another cell line with mutated PIK3CA had brisk 
synergistic decrease of phosphorylated ribosomal protein S6, suggesting that 
PIK3CA mutation alone is not a biomarker of resistance to combination therapy. 
Additionally, the combination of palbociclib and trametinib caused tumor 
regression in KRAS mutant CRC cell line xenograft models and in KRAS mutant 
patient-derived xenograft (PDX) models, including notably a model with atypical 
KRAS A146T mutation [15]. Immunohistochemistry from the PDX model 
showed marked decrease in staining for the proliferative marker Ki67 with 
combination therapy. RPPA from PDX-derived tissues after 21 days of treatment 
showed greater downregulation of phospho-S6, polo-like kinase 1 (PLK1), and 
cyclin B1 (Ccnb1). 


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ACCRU-GI-1618 
 
Figure 1.21 
 
Figure 1.21: A, Clonogenic assay for six representative cell lines treated with 
palbociclib, binimetinib (MEK162), the combination, or with DMSO control for 10-14 
days. B, Summary colony assay results for a panel of 11 KRAS mutant CRC cell lines 
treated with DMSO control, PD, MEK, or MEK/PD at concentrations approximating the 
IC50 for MEK monotherapy for 10-14 days. Results here are normalized to DMSO 
control. A waterfall plot is depicted showing values, with cell lines consistently depicted 
in the same order of T84, LS174T, SW1116, SW948, LS1034, HCT116, SW837, 
SW403, SW480, Lovo, and SKCO1. The data represent mean values for 3-4 independent 
experiments. * p<0.05, ♦ p<0.006. All p-values were generated by Student’s t-test. C, 
Protein lysates were obtained from a panel of 9 KRAS mutant CRC cell lines after 
treatment with DMSO control, palbociclib (PD) 400 nM, MEK162 (MEK) 200 nM, or 
MEK162 200 nM + palbociclib 400 nM (MEK/PD) for 24 hours, and RPPA was 
performed. Protein levels were normalized to DMSO controls of each cell line, and a log2 
heatmap of the most differentially expressed proteins was generated. D, Western blotting 
of the indicated antibodies for KRAS mutant cell lines HCT116, SW480, SKCO1, Lovo, 
and SW403 treated with palbociclib 400 nM and/or MEK162 200 nM for 24 hours. E, 
Lovo cell line xenografts were treated with vehicle control daily, palbociclib 100 mg/kg 
daily, trametinib 3 mg/kg every 2 days, or palbociclib 100 mg/kg daily + trametinib 3 
mg/kg every 2 days, and tumor volume was measured twice per week. Data are mean ± 
SEM, with 10 mice/arm. * p<0.01 on day 21 for combination vs. each other arm by 
Student’s t-test. F, Xenografts implanted with patient-derived CRC cells harboring KRAS 
A146T mutation were treated with vehicle control daily, palbociclib 100 mg/kg daily, 
trametinib 3 mg/kg every 2 days, or palbociclib 100 mg/kg daily + trametinib 3 mg/kg 
every 2 days, and tumor volume was measured twice per week. Data are mean ± SEM, 
with 9-10 mice/arm. ♦ p<0.001 on day 21 for combination vs. any other arm by Student’s 
t-test. Dotted lines represent 50% decrease in tumor volume. G, Percentage of nuclear 
area stained by Ki67 antibody after KRAS A146T mutant PDX was treated with 
trametinib (MEK) alone, palbociclib (PD) alone, the combination (MEK/PD), or vehicle- 
treated control for 21 days. Data represent mean ± SD of samples from 3-4 mice. * 
p≤0.02, ♦ p<0.003 by Student’s t-test. H, Representative immunohistochemistry images 
for Ki67 staining.[15] 
 
Additional work performed at the University of Michigan demonstrated the 
efficacy of palbociclib and trametinib in a wider variety of KRAS mutant CRC 
PDX models[16]. This work independently also found synergistic activity of 


9 
ACCRU-GI-1618 
 
palbociclib and trametinib in vitro in HCT116 KRAS-mutant CRC cell lines and 
found that the combination potentiated cell cycle arrest. Additionally, 18/18 
CRC-derived PDX models had RB expression, confirming that RB loss is an 
exceedingly rare event in CRC. Three KRAS mutant PDX models were tested for 
efficacy of the combination of trametinib and palbociclib in vivo, and objective 
responses were observed in all three models with combination 
trametinib/palbociclib. These models were varied in their genotypes and were 
KRASG12V PIK3CAWT, KRASG12D PIK3CAQ546L, and KRASQ61H PIK3CAE542K. 
[16]. The combination of trametinib and palbociclib indeed significantly reduced 
phospho-RB as seen on immunohistochemistry and immunoblotting. This strong 
preclinical evidence motivated the current clinical trial. 
 
1.3 
Investigational Agent Binimetinib (MEK162 / ARRY-438162) 
 
Binimetinib is an oral, ATP non-competitive, highly selective inhibitor of MEK1/2. The 
compound has nanomolar activity against purified MEK enzyme (IC50 = 12 nM) and 
inhibits both basal and induced levels of ERK phosphorylation in numerous cancer cell 
lines with IC50 values as low as 5 nM. Binimetinib is undergoing clinical evaluation for 
the treatment of a range of BRAF V600E and RAS-mutated solid-tumor indications 
including melanoma, colorectal and biliary cancers. Binimetinib was approved by the 
U.S. Food and Drug Administration in June 2018 for treatment of unresectable or 
metastatic melanoma with a BRAF V600E or V600K mutation when combined with the 
BRAF inhibitor encorafenib. 
 
Binimetinib potently inhibits the cell proliferation of mutant BRAF and RAS human 
cancer cell lines in vitro. Binimetinib has demonstrated in vitro and in vivo antitumor 
activity in several cancer models driven by the MAPK pathway (melanoma, CRC, 
pancreatic, non-small cell lung) with tumor regressions in some. Tumor growth inhibition 
correlated with decreased phospho-ERK levels in all tumor xenografts. Binimetinib has 
also shown significant anti-tumor activity in xenograft models in combination with the 
CDK 4/6 inhibitor LEE011, targeted agents like LGX818, RAF265, and standard-of-care 
agents such as cisplatin, 5 FU, and taxanes. 
 
1.31 
Preclinical pharmacology and toxicology 
 
Preclinical toxicological studies indicated that binimetinib was well-tolerated. 
The most prominent findings were dose-related, reversible hair loss and/or 
scabbing in rats and dose-related, reversible loose or watery stools in monkeys. 
Administration of binimetinib to rats was associated with microscopic findings of 
soft tissue mineralization, skin effects, and minimal to mild clinical pathology 
changes. Gastric mucosal lesions were associated with binimetinib administration 
to rats at 100 mg/kg. In cynomolgus monkeys, administration of binimetinib was 
associated with soft stools, moderate clinical pathology changes in some animals 
and reversible histopathologic changes in the gastrointestinal tract. 
 
There was no evidence of genotoxicity. Embryo-fetal development studies 
showed evidence of teratogenicity in rabbits (ventricular septal defects and 
outflow tract defects) and decreased ossification that is considered to be 
secondary to decreased fetal body weights at maternally toxic doses in rats. 


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ACCRU-GI-1618 
 
1.32 
Clinical Experience with Binimetinib 
 
As of 20 January 2018, a total of 2816 healthy subjects and patients have 
received at least 1 dose of binimetinib, either as a single agent or in combination 
with other targeted agents, standard chemotherapy agents or immunomodulating 
agents. These patients constitute the binimetinib safety population, which 
includes 229 healthy subjects, 17 subjects with hepatic dysfunction, 6 subjects 
with renal dysfunction, 164 patients with rheumatoid arthritis and 2400 patients 
with advanced cancer. 
 
Overall, binimetinib has demonstrated an acceptable safety profile. Available 
clinical data indicates a safety profile consistent with those reported for other 
allosteric MEK1/2 inhibitors. The adverse events observed are generally 
reversible and manageable by appropriate supportive medical care and/or dose 
modification. The most frequent treatment-related AEs in patients receiving 
binimetinib include rash, dermatitis acneiform, nausea, vomiting, diarrhea, 
peripheral edema, fatigue, and CPK elevation. Other clinically relevant toxicities 
are retinal events, increase of blood pressure, decrease of ejection fraction, and 
noninfectious pneumonitis which are monitored closely. 
 
Important potential adverse effects associated with the administration of the 
binimetinib have been established primarily from safety data from the phase 3 
COLUMBUS study in which it was combined with the BRAF inhibitor 
encorafenib in patients with unresectable or metastatic melanoma 
(https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210498lbl.pdf), and 
include: 
 
• 
Left ventricular dysfunction: Symptomatic or asymptomatic decreases 
in ejection fraction occurred in 7% of patients, with Grade 3 left 
ventricular dysfunction occurring in 1.6% of patients. 
• 
Hemorrhage: Hemorrhage occurred in 19% of patients, with events ≥ 
Grade 3 occurring in 3.2% of patients. Fatal intracranial hemorrhage in 
the setting of new or progressive brain metastases occurred in 1.6% of 
patients. The most frequent hemorrhagic events were gastrointestinal, 
including rectal hemorrhage (4.2%), hematochezia (3.1%), and 
hemorrhoidal hemorrhage (1%). 
• 
Venous thromboembolism: Occurred in 6% of patients, including 
3.1% of patients who developed pulmonary embolism. 
• 
Ocular toxicities: Serous retinopathy is a class effect of MEK 
inhibitors. It is generally asymptomatic or mildly symptomatic and 
reversible [22]. Serous retinopathy occurred in 20% of patients. 
Symptomatic serous retinopathy occurred in 8% of patients with no 
cases of blindness. The median time to onset of the first event of serous 
retinopathy (all grades) was 1.2 months. RVO is a known class-related 
adverse reaction of MEK inhibitors and may occur in patients treated 
with binimetinib in combination with encorafenib. In patients with 
BRAF mutation-positive melanoma across multiple clinical trials, 0.1% 
of patients experienced RVO. 
• 
Pneumonitis/Interstitial Lung Disease: Pneumonitis occurred in 0.3% 
of patients with BRAF mutation-positive melanoma across multiple 
clinical trials. 


11 
ACCRU-GI-1618 
 
• 
Hepatotoxicity: The incidence of Grade 3 or 4 increases in liver 
function laboratory tests was 6% for alanine aminotransferase (ALT), 
2.6% for aspartate aminotransferase (AST), and 0.5% for alkaline 
phosphatase. No patient experienced Grade 3 or 4 serum bilirubin 
elevation. 
• 
CK Elevation/Rhabdomyolysis: Asymptomatic elevations of laboratory 
values of serum CK occurred in 58% of patients. Rhabdomyolysis was 
reported in 0.1% of patients with BRAF mutation-positive melanoma 
across multiple clinical trials. 
• 
Embryo-Fetal Toxicity: Binimetinib can cause fetal harm when 
administered to pregnant women. 
 
1.4 
Investigational Agent Palbociclib (PD-0322991) 
 
1.41 
Preclinical pharmacology and toxicity 
 
Altered glucose metabolism (glycosuria, hyperglycemia, decreased insulin) 
associated with changes in the pancreas (islet cell vacuolation), eye (cataracts, 
lens degeneration), teeth (degeneration/necrosis of ameloblasts in actively 
growing teeth), kidney (tubule vacuolation, chronic progressive nephropathy), 
and adipose tissue (atrophy) were identified in the 27-week repeat-dose 
toxicology study in rats and were most prevalent in males at doses ≥30 
mg/kg/day (approximately 11 times the human exposure [AUC] at the 
recommended dose). Some of these findings (glycosuria/hyperglycemia, 
pancreatic islet cell vacuolation, and kidney tubule vacuolation) were present in 
the 15-week repeat-dose toxicology study in rats, but with lower incidence and 
severity. The rats used in these studies were approximately 7 weeks old at the 
beginning of the studies. Altered glucose metabolism or associated changes in 
pancreas, eye, teeth, kidney, and adipose tissue were not identified in dogs in 
repeat-dose toxicology studies up to 39 weeks duration. 
 
Carcinogenicity studies have not been conducted with palbociclib. 
 
Palbociclib was aneugenic in Chinese Hamster Ovary cells in vitro and in the 
bone marrow of male rats at doses ≥100 mg/kg/day for 3 weeks. Palbociclib was 
not mutagenic in an in vitro bacterial reverse mutation (Ames) assay and was not 
clastogenic in the in vitro human lymphocyte chromosome aberration assay. 
 
In a fertility study in female rats, palbociclib did not affect mating or fertility at 
any dose up to 300 mg/kg/day (approximately 4 times human clinical exposure 
based on AUC) and no adverse effects were observed in the female reproductive 
tissues in repeat-dose toxicity studies up to 300 mg/kg/day in the rat and 3 
mg/kg/day in the dog (approximately 6 times and similar to human exposure 
[AUC], at the recommended dose, respectively). 
 
The adverse effects of palbociclib on male reproductive function and fertility 
were observed in the repeat-dose toxicology studies in rats and dogs and a male 
fertility study in rats. In repeat-dose toxicology studies, palbociclib-related 
findings in the testis, epididymis, prostate, and seminal vesicle at ≥30 mg/kg/day 
in rats and ≥0.2 mg/kg/day in dogs included decreased organ weight, atrophy or 
degeneration, hypospermia, intratubular cellular debris, lower sperm motility and 


12 
ACCRU-GI-1618 
 
density, and decreased secretion. Partial reversibility of male reproductive organ 
effects was observed in the rat and dog following a 4- and 12-week non-dosing 
period, respectively. These doses in rats and dogs resulted in approximately ≥10 
and 0.1 times, respectively, the exposure [AUC] in humans at the recommended 
dose. In the fertility and early embryonic development study in male rats, 
palbociclib caused no effects on mating but resulted in a slight decrease in 
fertility at 100 mg/kg/day with projected exposure levels [AUC] of 20 times the 
exposure in humans at the recommended dose. 
 
1.42 
Clinical Experience with Palbociclib 
 
The most extensive clinical trials of palbociclib to date have been performed in 
combination with letrozole or fulvestrant in hormone receptor positive breast 
cancer patients. 
 
In a study of palbociclib 125 mg/day plus letrozole 2.5 mg/day versus letrozole 
alone, in which 83 out of 160 patients with ER-positive, HER2-negative 
advanced breast cancer received at least 1 dose of treatment with 
palbociclib/letrozole, the median duration of treatment for palbociclib was 13.8 
months while the median duration of treatment for letrozole on the letrozole- 
alone arm was 7.6 months. Dose reductions due to an adverse reaction of any 
grade occurred in 36% of patients receiving palbociclib plus letrozole. Permanent 
discontinuation associated with an adverse reaction occurred in 7 of 83 (8%) 
patients receiving palbociclib plus letrozole and in 2 of 77 (3%) patients 
receiving letrozole alone. Adverse reactions leading to discontinuation for those 
patients receiving palbociclib plus letrozole included neutropenia (6%), asthenia 
(1%), and fatigue (1%). The most common adverse reactions (≥10%) of any 
grade reported in patients in the palbociclib plus letrozole arm were neutropenia, 
leukopenia, fatigue, anemia, upper respiratory infection, nausea, stomatitis, 
alopecia, diarrhea, thrombocytopenia, decreased appetite, vomiting, asthenia, 
peripheral neuropathy, and epistaxis. The most frequently reported serious 
adverse reactions in patients receiving palbociclib plus letrozole were pulmonary 
embolism (3 of 83; 4%) and diarrhea (2 of 83; 2%). An increased incidence of 
infections was observed in the palbociclib plus letrozole arm (55%) compared to 
the letrozole alone arm (34%). Febrile neutropenia has been reported in the 
palbociclib clinical program, although no cases were observed in this study. 
Grade ≥3 neutropenia was managed by dose reductions and/or dose delay or 
temporary discontinuation consistent with a permanent discontinuation rate of 
6% due to neutropenia. 
 
In another study of palbociclib 125 mg/day plus fulvestrant 500 mg versus 
placebo plus fulvestrant, in which 345 out of 517 patients with HR-positive, 
HER2-negative advanced or metastatic breast cancer received at least 1 dose of 
treatment with palbociclib/fulvestrant, dose reductions due to an adverse reaction 
of any grade occurred in 36% of patients receiving palbociclib plus fulvestrant. 
Permanent discontinuation associated with an adverse reaction occurred in 19 of 
345 (6%) patients receiving palbociclib plus fulvestrant, and in 6 of 172 (3%) 
patients receiving placebo plus fulvestrant. Adverse reactions leading to 
discontinuation for those patients receiving palbociclib plus fulvestrant included 
fatigue (0.6%), infections (0.6%), and thrombocytopenia (0.6%). The most 
common adverse reactions (≥10%) of any grade reported in patients in the 


13 
ACCRU-GI-1618 
 
palbociclib plus fulvestrant arm were neutropenia, leukopenia, infections, fatigue, 
nausea, anemia, stomatitis, headache, diarrhea, thrombocytopenia, constipation, 
vomiting, alopecia, rash, decreased appetite, and pyrexia. The most frequently 
reported serious adverse reactions in patients receiving palbociclib plus 
fulvestrant were infections (3%), pyrexia (1%), neutropenia (1%), and pulmonary 
embolism (1%). 
 
1.5 
Control Agent Trifluridine/Tipiracil (TAS-102) 
 
1.51 
Preclinical pharmacology and toxicity 
 
TAS-102 is an orally administered chemotherapeutic drug comprised of the 
combination of trifluridine, a cytotoxic thymidine-based nucleic acid analogue, 
and tipiracil, a thymidine phosphorylase inhibitor that prevents overly rapid 
degradation of trifluridine to allow for therapeutic plasma concentrations for 
longer durations. No long-term studies evaluating the carcinogenic potential of 
trifluridine/tipiracil in animals have been performed. Trifluridine/tipiracil was 
genotoxic in a reverse mutation test in bacteria, a chromosomal aberration test in 
mammalian-cultured cells, and a micronucleus test in mice. Animal studies did 
not indicate an effect of trifluridine/tipiracil on male fertility in rats. Dose-related 
increases in the corpus luteum count and implanted embryo count were observed, 
but female fertility was not affected. 
 
1.52 
Clinical experience with TAS-102 
 
TAS-102 is currently FDA approved for the treatment of metastatic CRC after 
prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based 
chemotherapy, an anti-VEGF biologic therapy, and an anti-EGFR therapy if 
wild-type in RAS. In a randomized (2:1), double-blind, placebo-controlled trial, 
533 patients (median age 63 years; 61% men; 57% White, 35% Asian, 1% Black) 
with previously treated metastatic colorectal cancer received TAS-102 as a single 
agent at a dose of 35 mg/m2/dose administered twice daily on Days 1 through 5 
and Days 8 through 12 of each 28-day cycle. The mean duration of TAS-102 
therapy was 12.7 weeks. The median progression-free survival on this trial was 
2.0 months (95% confidence interval 1.9-2.1 months)[17]. These results were 
also true in the KRAS mutant subgroup (n=407), with median PFS of 1.9 mo [18]. 
The most common adverse drug reactions or laboratory abnormalities (all Grades 
and greater than or equal to 10% in incidence) in patients treated with TAS-102 
at a rate that exceeds the rate in patients receiving placebo were anemia, 
neutropenia, asthenia/fatigue, nausea, thrombocytopenia, decreased appetite, 
diarrhea, vomiting, abdominal pain, and pyrexia. In the study, 3.6% of patients 
discontinued TAS-102 for an adverse event and 13.7% of patients required a 
dose reduction. The most common adverse reactions leading to dose reduction 
were neutropenia, anemia, febrile neutropenia, fatigue, and diarrhea. 
 
2.0 
Goals 
 
2.1 
Primary Objective 
 
2.11 
The primary objective is to compare the progression-free survival (PFS) between 
those randomized to palbociclib/binimetinib and those randomized to TAS-102 


14 
ACCRU-GI-1618 
 
in patients with refractory KRAS- or NRAS-mutant metastatic CRC. 
 
2.2 
Secondary Objectives 
 
2.21 
To compare the overall response rate by RECIST 1.1 criteria between those 
randomized to palbociclib/binimetinib and those randomized to TAS-102 in 
patients with refractory KRAS- or NRAS-mutant metastatic CRC. 
 
2.22 
To compare the overall survival (OS) between those randomized to 
palbociclib/binimetinib and those randomized to TAS-102 in patients with 
refractory KRAS- or NRAS-mutant metastatic CRC. 
 
2.23 
To determine the safety and tolerability of the recommended phase II dose of 
palbociclib in combination with binimetinib in patients with refractory KRAS- or 
NRAS-mutant metastatic CRC. 
 
2.3 
Correlative Research 
 
2.31 
To determine the tumor mutational profiles that characterize groups of patients 
that predict for response or resistance to combination of palbociclib/binimetinib. 
 
2.32 
To determine the correlation between circulating tumor DNA and tumor response 
or resistance to therapy with palbociclib/binimetinib or TAS-102. 
 
2.33 
To determine the association between Consensus Molecular Subtype based on 
gene expression profiling and response or resistance to combination of 
palbociclib/binimetinib. 
 
3.0 
Patient Eligibility (Safety Run-In and Randomized Phase II) 
 
NOTE: Waivers to eligibility criteria are not allowed per ACCRU policy. 
 
For first 6-12 patients during Part 1 (Safety Run-In): Prior to discussing protocol entry 
with subjects, call the ACCRU Registration Office (507-284-4130) for dose level and to 
ensure that a place on the protocol is open to the patient. 
 
3.1 
Inclusion Criteria 
 
3.11 
Age ≥18 years. 
 
3.12 
Histological confirmation of colorectal cancer that is metastatic and/or 
unresectable. 
 
3.13 
Documented mutation in KRAS or NRAS (codon 12, 13, 59, 61, 117, or 146) in 
tumor tissue from primary or metastatic site, tested by a CLIA-certified 
laboratory. 
 
3.14 
Measurable disease as defined in Section 11.0. 
 
3.15 
ECOG Performance Status (PS) of 0 or 1. 


15 
ACCRU-GI-1618 
 
NOTE: Form is available on the ACCRU web site. 
 
3.16 
Previously treated with fluoropyrimidine, oxaliplatin, and irinotecan 
based chemotherapy, and an anti-VEGF biological therapy  
 
3.17 
The following laboratory values obtained ≤14 days prior to 
registration/randomization unless otherwise noted. 
 
• 
Absolute neutrophil count (ANC) ≥1.5 x 109/L 
• 
Platelet count 75 x 109/L without transfusions 
• 
Hemoglobin (Hgb) 9 g/dL 
• 
Total bilirubin ≤1.5 x upper limit of normal (ULN) 
• 
Aspartate transaminase (AST) and alanine aminotransferase (ALT) 2.5 x 
ULN; ≤5.0 x ULN if known liver metastases 
• 
Serum creatinine 1.5 mg/dL OR calculated creatinine clearance ≥50 
mL/min using the Cockcroft-Gault formula below: 
 
Cockcroft-Gault Equation: 
Creatinine clearance for males = 
Creatinine clearance for females = 
(140 - age)(weight in kg) 
(72)(serum creatinine in mg/dL) 
(140 - age)(weight in kg)(0.85) 
(72)(serum creatinine in mg/dL) 
 
3.18 
Negative serum β-HCG pregnancy test done ≤7 days prior to 
registration/randomization for women of childbearing potential only. 
 
3.19 a 
Able to swallow capsules with no surgical or anatomic conditions that would 
preclude the patient from swallowing and absorbing oral medications. 
 
3.19b Able and willing to provide informed written consent and able to comply with 
protocol requirements. 
 
3.19c 
Able and 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 
and observation), participants must be willing to return to the consenting 
institution for follow-up. 
 
3.19d Willing to provide blood and tissue samples for mandatory correlative research 


16 
ACCRU-GI-1618 
 
purposes (see Sections 6.0, 14.0, and 17.0). 
 
3.19e 
Patient is deemed by the Investigator to have the initiative and means to be 
compliant with the protocol (treatment and follow-up). 
 
3.2 
Exclusion Criteria 
 
3.21 
Prior treatment with drug targeting BRAF, MEK, ERK, or CDK family. 
 
NOTE: For the purpose of this protocol, prior treatment with regorafenib is 
allowed. 
 
3.22 
Prior treatment with trifluridine/tipiracil (TAS-102). 
 
3.23 
Pregnant or nursing (lactating women), where pregnancy is defined as the state of 
a female after conception and until the termination of gestation, confirmed by a 
positive hCG laboratory test. 
 
3.24 
Women of child-bearing potential. 
 
NOTE: defined as all women physiologically capable of becoming pregnant, 
unless they agree to use highly effective methods of contraception throughout the 
study and for 8 weeks after study drug discontinuation. Refer to Appendix III: 
Study Contraception Guidelines for acceptable forms of highly effective methods 
of contraception. 
 
NOTE: Women are considered post-menopausal and not of child bearing 
potential if they have had 12 months of natural (spontaneous) amenorrhea with 
an appropriate clinical profile (e.g. age appropriate, history of vasomotor 
symptoms) or have had surgical bilateral oophorectomy (with or without 
hysterectomy) or tubal ligation ≥42 days prior to registration/randomization. In 
the case of oophorectomy alone, only when the reproductive status of the woman 
has been confirmed by follow-up hormone level assessment is she considered not 
of child bearing potential. 
 
3.25 
Sexually active males. 
 
NOTE: unless they agree to use highly effective methods of contraception 
throughout the study and for 12 weeks after study drug discontinuation and 
should not father a child in this period. Refer to Appendix III: Study 
Contraception Guidelines for acceptable forms of highly effective methods of 
contraception. 
 
3.26 
Any symptomatic brain metastasis. 
 
NOTE: Patients previously treated or untreated for this condition who are 
asymptomatic in the absence of corticosteroid and anti-epileptic therapy are 
allowed. Brain metastases must be stable for ≥ 4 weeks prior to 
registration/randomization, with imaging (e.g., magnetic resonance imaging 
[MRI] or computed tomography [CT]) demonstrating no current evidence of 
progressive brain metastases at registration/randomization. 


17 
ACCRU-GI-1618 
 
 
3.27 
Prior treatment ≤21 days prior to registration/randomization with any other 
chemotherapy, small molecule inhibitor (e.g. regorafenib), monoclonal antibody, 
immunotherapy, or radiotherapy. 
 
NOTE: All toxicities from prior therapy must be ≤ Grade 1 (or ≤ Grade 2 for 
peripheral neuropathy or alopecia). 
 
3.28 
Impaired cardiovascular function or clinically significant cardiac diseases, 
including any of the following: 
 
• 
History of acute coronary syndromes (including myocardial infarction, 
unstable angina, coronary artery bypass grafting, coronary angioplasty, or 
stenting) <6 months prior to registration/randomization. 
• 
Symptomatic chronic heart failure (i.e. Grade 2 or higher), history or 
current evidence of clinically significant cardiac arrhythmia and/or 
conduction abnormality <6 months prior to registration/randomization 
except atrial fibrillation and paroxysmal supraventricular tachycardia. 
• 
Left ventricular ejection fraction (LVEF) <50% as determined by a 
multigated acquisition (MUGA) scan or echocardiogram ≤28 days prior to 
registration/randomization. 
 
3.29 a 
Uncontrolled hypertension, defined as persistent elevation of systolic blood 
pressure ≥150 mmHg or diastolic blood pressure ≥100mmHg despite current 
therapy. 
 
3.29b History of thromboembolic or cerebrovascular events ≤ 12 weeks prior 
registration/randomization. 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 emboli that does 
not result in hemodynamic instability are allowed to enroll as long as they are on 
a stable dose of anticoagulants for at least 4 weeks. 
Note: Patients with thromboembolic events related to indwelling catheters or 
other procedures may be enrolled. 
 
3.29c 
Known history of acute or chronic pancreatitis ≤ 6 months prior to 
registration/randomization. 
 
3.29d Known positive serology for HIV (human immunodeficiency virus), active 
hepatitis B, and/or active hepatitis C infection. 
 
3.29e 
Patients who have neuromuscular disorders that are associated with elevated 
CPK (e.g. inflammatory myopathies, muscular dystrophy, amyotrophic lateral 
sclerosis, spinal muscular atrophy). 
 
3.29f 
History of chronic inflammatory bowel disease or Crohn’s disease requiring 
medical intervention (immunomodulatory or immunosuppressive medications or 
surgery) ≤12 months prior to registration/randomization. 


18 
ACCRU-GI-1618 
 
3.29g Impaired GI function or disease that may significantly alter the absorption of 
binimetinib or palbociclib (e.g., ulcerative disease, uncontrolled vomiting, 
malabsorption syndrome, small bowel resection with decreased intestinal 
absorption) in the opinion of the investigator. 
 
3.29h History or current evidence of retinal vein occlusion (RVO) or current risk 
factors to RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of 
hyperviscosity or hypercoagulability syndromes). 
 
3.29i 
Leptomeningeal disease. 
3.29j 
Known hypersensitivity to the components of study drugs or its analogs. 
3.29k Known medical, psychiatric, substance abuse, or cognitive disorder that may 
compromise the patient's ability to understand the patient information, give 
informed consent, comply with the study protocol or complete the study. 
 
3.29l 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance 
with study requirements in the opinion of the investigator. 
 
3.29m Patients who have undergone major surgery ≤21 days prior to 
registration/randomization or who have not recovered from side effects of such 
procedures. 
 
3.29n Any other 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. 
 
3.29 o Previous or concurrent malignancy ≤3 years prior to registration/randomization 
with the following exceptions: 
 
• 
adequately treated basal cell or squamous cell carcinoma of the skin 
• 
superficial bladder cancer 
• 
prostate intraepithelial neoplasm 
• 
in situ carcinoma of the cervix 
• 
other solid tumors treated curatively without evidence of recurrence for ≥3 
years prior to registration/randomization 
 
NOTE: If there is a history or prior malignancy, must not be receiving other 
specific anti-cancer treatment such as anti-estrogen, anti-androgen, or other 
tyrosine kinase inhibitor therapy. 
 
3.3 
Re-Registration Procedure for Part 2 Optional Crossover Participants 
 
NOTE: Re-registration must occur ≤28 days from Part 2 TAS-102 disease 
progression (PD). 


19 
ACCRU-GI-1618 
 
Upon confirmation of progression for patients in Arm B (TAS-102) of randomized 
portion of the trial, patients may elect to cross-over to treatment with binimetinib + 
palbociclib as long as the following criteria are met: 
 
3.31 
Crossover Inclusion Criteria 
 
3.311 
Age ≥18 years. 
 
3.312 
Histological confirmation of colorectal cancer that is metastatic and/or 
unresectable. 
 
3.313 
Documented mutation in KRAS or NRAS (codon 12, 13, 59, 61, 117, or 
146) in tumor tissue from primary or metastatic site, tested by a CLIA- 
certified laboratory. 
 
3.314 
Measurable disease as defined in Section 11.0. 
 
3.315 
ECOG Performance Status (PS) of 0 or 1. 
 
3.316 
Previously treated with fluoropyrimidine, oxaliplatin, and 
irinotecan based chemotherapy, and an anti-VEGF biological 
therapy.  
 
 
3.317 
The following laboratory values obtained ≤28 days of Re-registration 
unless otherwise noted 
 
• 
Absolute neutrophil count (ANC ≥1.5 x 109/L) 
• 
Platelet count ≥75 x 109/L without transfusion 
• 
Hemoglobin (Hgb) ≥9 g/dL 
• 
Total bilirubin ≤1.5 x upper limit of normal (ULN) 
• 
Aspartate transaminase (AST) and alanine aminotransferase (ALT) 
≤2.5 x ULN; ≤5.0 x ULN if known liver metastases 
• 
Serum creatinine ≤1.5 mg/dL OR calculated creatinine clearance 
≥50 mL/min using the Cockcroft-Gault formula below: 
 
Cockcroft-Gault Equation: 
Creatinine clearance for males = 
Creatinine clearance for females = 
(140 - age)(weight in kg) 
(72)(serum creatinine in mg/dL) 
(140 - age)(weight in kg)(0.85) 
(72)(serum creatinine in mg/dL) 


20 
ACCRU-GI-1618 
 
 
 
3.318 
Negative serum β-HCG pregnancy test done ≤7 days prior to Re- 
registration for women of childbearing potential only. 
 
3.319 a 
Able to swallow capsules with no surgical or anatomic conditions that 
would preclude the patient from swallowing and absorbing oral 
medications. 
 
3.319b 
Able and willing to provide informed written consent and able to 
comply with protocol requirements. 
 
3.319c 
Able and 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 and observation), participants must be willing to return to the 
consenting institution for follow-up. 
 
3.319d 
Willing to provide blood samples for mandatory correlative research 
purposes (see Section 14.0). 
 
3.319e 
Patient is deemed by the Investigator to have the initiative and means 
to be compliant with the protocol (treatment and follow-up). 
 
3.32 
Crossover Exclusion Criteria 
 
3.321 
Prior treatment with drug targeting BRAF, MEK, ERK, or CDK 
family. 
 
NOTE: For the purpose of this protocol, prior treatment with 
regorafenib is allowed. 
 
3.322 
Pregnant or nursing (lactating women), where pregnancy is defined as 
the state of a female after conception and until the termination of 
gestation, confirmed by a positive hCG laboratory test. 
 
3.323 
Women of child-bearing potential. 
 
NOTE: Defined as all women physiologically capable of becoming 
pregnant, unless they agree to use highly effective methods of 
contraception throughout the study and for 8 weeks after study drug 
discontinuation. Refer to Appendix III: Study Contraception 
Guidelines for acceptable forms of highly effective methods of 
contraception. 
 
NOTE: Women are considered post-menopausal and not of child 
bearing potential if they have had 12 months of natural (spontaneous) 
amenorrhea with an appropriate clinical profile (e.g. age appropriate, 
history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy) or tubal ligation ≥42 


21 
ACCRU-GI-1618 
 
days of Re-registration. In the case of oophorectomy alone, only when 
the reproductive status of the woman has been confirmed by follow-up 
hormone level assessment is she considered not of child bearing 
potential. 
 
3.324 
Sexually active males. 
 
NOTE: unless they agree to use highly effective methods of 
contraception throughout the study and for 12 weeks after study drug 
discontinuation and should not father a child in this period. Refer to 
Appendix III: Study Contraception Guidelines for acceptable forms of 
highly effective methods of contraception. 
 
3.325 
Any symptomatic brain metastasis. 
 
NOTE: Patients previously treated or untreated for this condition who 
are asymptomatic in the absence of corticosteroid and anti-epileptic 
therapy are allowed. Brain metastases must be stable for ≥4 weeks, 
with imaging (e.g., magnetic resonance imaging [MRI] or computed 
tomography [CT]) demonstrating no current evidence of progressive 
brain metastases at Re-registration. 
 
3.326 
Impaired cardiovascular function or clinically significant cardiac 
diseases, including any of the following: 
 
• 
History of acute coronary syndromes (including myocardial 
infarction, unstable angina, coronary artery bypass grafting, 
coronary angioplasty, or stenting) <6 months prior to Re- 
registration 
• 
Symptomatic chronic heart failure (i.e., Grade 2 or higher), 
history or current evidence of clinically significant cardiac 
arrhythmia and/or conduction abnormality <6 months prior to 
Re-registration except atrial fibrillation and paroxysmal 
supraventricular tachycardia 
• 
Left ventricular ejection fraction (LVEF) <50% as determined 
by a multigated acquisition (MUGA) scan or echocardiogram. 
 
 
3.327 
Uncontrolled hypertension, defined as persistent elevation of systolic 
blood pressure ≥150 mmHg or diastolic blood pressure ≥100 mmHg 
despite current therapy. 
 
3.328 
History of thromboembolic or cerebrovascular events ≤ 12 weeks prior 
re-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 emboli 
that does not result in hemodynamic instability are allowed to enroll as 
long as they are on a stable dose of anticoagulants for at least 4 weeks. 
Note: Patients with thromboembolic events related to indwelling 
catheters or other procedures may be enrolled. 


22 
ACCRU-GI-1618 
 
 
3.329 a 
Known history of acute or chronic pancreatitis ≤ 6 months prior to re- 
registration. 
 
3.329b 
Known positive serology for HIV (human immunodeficiency virus), 
active hepatitis B, and/or active hepatitis C infection. 
 
3.329c Patients who have neuromuscular disorders that are associated with 
elevated CPK (e.g., inflammatory myopathies, muscular dystrophy, 
amyotrophic lateral sclerosis, spinal muscular atrophy). 
 
3.329d 
History of chronic inflammatory bowel disease or Crohn’s disease 
requiring medical intervention (immunomodulatory or 
immunosuppressive medications or surgery) ≤12 months prior to Re- 
registration. 
 
3.329e 
Impaired GI function or disease that may significantly alter the 
absorption of binimetinib or palbociclib (e.g., ulcerative disease, 
uncontrolled vomiting, malabsorption syndrome, small bowel resection 
with decreased intestinal absorption) in the opinion of the investigator. 
 
3.329f 
History of retinal vein occlusion (RVO) or current risk factors to RVO 
(e.g., uncontrolled glaucoma or ocular hypertension, history of 
hyperviscosity, or hypercoagulability syndromes). 
 
3.329g 
Leptomeningeal disease. 
 
3.329h 
Known hypersensitivity to the components of study drugs or its 
analogs. 
 
3.329i 
Known medical, psychiatric, substance abuse, or cognitive disorder 
that may compromise the patient’s ability to understand the patient 
information, give informed consent, comply with the study protocol, or 
complete the study. 
 
3.329j 
Uncontrolled intercurrent illness including, but not limited to, ongoing 
or active infection, symptomatic congestive heart failure, unstable 
angina pectoris, cardiac arrhythmia, or psychiatric illness/social 
situations that would limit compliance with study requirements in the 
opinion of the investigator. 
 
3.329k 
Patients who have undergone major surgery ≤21 days prior to Re- 
registration or who have not recovered from side effects of such 
procedures. 
 
3.329l 
Any other co-morbid, systemic illnesses or other severe concurrent 
disease which, in the judgement 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. 


23 
ACCRU-GI-1618 
 
3.329m 
Previous or concurrent malignancy ≤3 years prior to Re-registration 
with the following exceptions: 
 
• 
adequately treated basal cell or squamous cell carcinoma of the 
skin 
• 
superficial bladder cancer 
• 
prostate intraepithelial neoplasm 
• 
in situ carcinoma of the cervix 
• 
other solid tumors treated curatively without evidence of 
recurrence for ≥3 years prior to Re-registration 
 
NOTE: If there is a history or prior malignancy, must not be receiving 
other specific anti-cancer treatment such as anti-estrogen, anti- 
androgen, or other tyrosine kinase inhibitor therapy. 


24 
ACCRU-GI-1618 
 
4.0 
Test Schedule 
 
 
 
 
Tests and procedures 
Screening1 
Active Treatment Phase2 
≤28 days prior 
to Registration/ 
Randomization 
Cycle length = 28 days 
Optional 
Crossover at 
PD20 
(Arm B only) 
≤28 days prior 
to Re- 
Registration 
End of 
Treatment 
(30-37 
days from 
last dose) 
For off treatment 
reasons other than PD 
or alternative therapy 
(For Patients with PD, 
follow Section 13.3 
Event Monitoring) 
 
Observation† every 12 
weeks (±7 days) until 
PD or 24 months from 
Registration/ 
Randomization/ 
Re-Registration 
 
Cycle 1 
Cycle 2 
Cycles 3-24 
(until PD) 
Day 1 
(Prior to 
Treatment)3 
Day 15 
(Prior 
to Tx) 
Day 1 
(Prior 
to Tx) 
Day 15 
(Prior 
to Tx) 
Day 1 
(Prior 
to Tx) 
Day 15 
(Prior to 
Tx) 
Medical history 
X 
X 
Physical exam, vitals, 
weight, ECOG PS 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of 
concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
X 
Adverse event assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology: 
CBC with differential 
X4 
X 
X 
X 
X 
X 
X5,6 
X 
X 
X 
Chemistry: 
SGOT (AST), ALT, 
alkaline phosphatase, total 
bilirubin, creatinine, 
calcium, phos, glucose, 
sodium, potassium, 
glucose, albumin, total 
protein, chloride, 
bicarbonate, BUN, and 
magnesium 
X4 
X 
X 
X 
X 
X 
X 
Creatine phosphokinase 
(CK/CPK) 8, troponin I or 
troponin T 
X7 
X7 
X7 
X7 
X7 
X7 
X7 
Carcinoembryonic antigen 
(CEA) 
X 
X 
X 
X 
HIV Ab, HBsAg, HCV Ab 
X 


25 
ACCRU-GI-1618 
 
Serum β-HCG9 
X 
X 
X 
X 
X 
Urinalysis 
X7 
X7 
X7 
X7 


26 
ACCRU-GI-1618 
 
 
 
 
 
 
Tests and procedures 
Screening1 
Active Treatment Phase2 
≤28 days prior 
to Registration/ 
Randomization 
Cycle length = 28 days 
Optional 
Crossover at 
PD21 
(Arm B only) 
≤28 days prior 
to Re- 
Registration 
End of 
Treatment 
(30-37 
days from 
last dose) 
Observation† every 12 
weeks (±7 days) until 
PD or 24 months from 
Registration/ 
Randomization/ 
Re-Registration 
For off treatment 
reasons other than PD 
or alternative therapy 
Cycle 1 
Cycle 2 
Cycles 3-24 
(until PD) 
Day 1 
(Prior to 
Treatment)3 
Day 15 
(Prior 
to Tx) 
Day 1 
(Prior 
to Tx) 
Day 15 
(Prior 
to Tx) 
Day 1 
(Prior 
to Tx) 
Day 15 
(Prior to 
Tx) 
Tumor measurement10 
X 
X11 
X 
X12 
Ophthalmic exam 13 
XR 
2-D echocardiogram or 
MUGA14 
XR 
X7 
X7,15 
X7 
Mandatory archival tumor 
tissue sample (see Section 
17.1)16,R 
X 
Mandatory blood sample 
(see Section 14.1) 17, R 
X7 
X7,18 
X7 
X7,19 
Patient Medication Diaries 
X 
X 
X 
X 
X 
† Observation Phase: Part of the Active Monitoring Phase of a study; the time period following the active treatment phase when the participant continues to receive 
cycles of evaluation in compliance with the Test Schedule. Participants will be required to return to the consenting site for follow-up. 
 
1. Clinical testing may be used for screening purposes if within visit window. Patient must sign consent for any tests or procedures performed 
solely for the purpose of this research trial. 
2. Unless otherwise specified, may be performed ±3 days of the day indicated on the table. 
3. Protocol treatment must begin ≤21 days from Registration/Randomization/Re-Registration. 
4. Must be completed ≤14 days prior to Registration/Randomization 
5. Applicable to Arm B (TAS-102) patients ONLY 
6. Performed Day 15 (±3 days) on Cycle 3 and subsequent cycles. 
7. Not applicable to Arm B (TAS-102) patients. However, patients initially randomized to arm B who subsequently cross over to receive 
binimetinib/palbociclib do need to undergo the listed assessments. 
8. Follow-up for total creatine phosphokinase (CPK) ≥3.0 X ULN will include weekly assessment of isoenzymes and myoglobin in blood or 
urine and troponin as applicable. 
9. For women of childbearing potential only. Must be done ≤7 days prior to registration/randomization/re-registration and ≤72 hours prior to 
EACH cycle. 
10. Tumor measurement must be performed using CT scan or MRI. The same imaging assessment method performed at baseline should be 
used at subsequent required timepoints. 


27 
ACCRU-GI-1618 
 
11. Performed on Day 1 (±3 days) on Cycles 3, 5, 7, 9, and subsequent odd cycles. 
12. In Observation, CT and/or MRI scans are required to obtain tumor measurements (every 12 weeks ±7 days after last on-treatment tumor 
assessment) until documented radiographic disease progression, death, withdrawal of consent, study closure, or 24 months from 
Registration/Randomization/Re-Registration, whichever occurs first. 
13. Full ophthalmic examination including slit lamp examination, visual acuity testing, intraocular pressure (IOP), and indirect fundoscopy with 
attention to retinal abnormalities, especially RPED-like events and RVO. For patients with clinical suspicion of retinal abnormalities (e.g., 
photopsia, metamorphopsia, impairment of visual acuity, etc.) or RVO, additional assessments of optical coherence tomography (for RPED) 
and fluorescein angiography (for RVO) is mandatory. For patients on Arm A, any new or worsening visual impairment requires repeat 
ophthalmic evaluation. 
14. Limited echocardiogram only to assess left ventricular ejection fraction is acceptable. MUGA scan is also permitted. Whichever modality was 
used at baseline should be continued throughout the study. 
15. Performed on Cycle 5 Day 1 (±3 days) and then every 12 weeks after Cycle 5 Day 1 (±7 days). 
16. Submission of tissue ≤60 days after registration/randomization. Refer to Section 17.0 for additional information. 
17. Collect tubes as defined in Section 14.1. Kits are required for this collection. 
18. Thymidine kinase activity assay only. Refer to Section 14.1 
19. Mandatory blood samples should be collected as soon as possible upon knowledge of treatment cessation for reasons including but not limited 
to disease progression, withdrawal, etc. This sample can be collected ≤37 days after progression. 
20. Re-registration for Arm B (TAS-102) patients interested in optional crossover must occur ≤28 days from documentation of progression. After 
re-registration, patients follow Test Schedule beginning with Cycle 1 Day 1. Crossover treatment will continue until progression for up to 24 
cycles. 
R Research funded 


27 
ACCRU-GI-1618 
 
5.0 
Stratification and Grouping Factors 
 
5.1 
Stratification Factors (In Randomized groups only) 
 
5.11 
Mutation in KRAS codon 12/13: Yes vs No 
 
5.12 
Previously received regorafenib: Yes vs No 
 
5.2 
Grouping Factors 
 
5.21 
Group: Safety Run-in vs. Randomized 
 
6.0 
Registration/Randomization Procedures 
 
6.1 
Registration Procedure for Part 1: Safety Run-in 
 
Prior to discussing protocol entry with subjects, call the ACCRU Registration Office (
 
 for dose level and to ensure that a place on the protocol is open to the patient. 
 
6.11 
To register a patient, fax (
) a completed Eligibility Checklist to the Academic 
and Community Cancer Research United (ACCRU) Registration Office between 8 a.m. 
and 4:30 p.m. central time Monday through Friday. 
 
6.2 
Randomization Procedure for Part 2: Phase II 
 
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). 
 
Instructions for the registration/randomization application are available on the above web page 
under the Study Resources section, “Application Training.” 
 
Prior to initiation of protocol study intervention, this process must be completed in its entirety 
and a ACCRU subject ID number must be available as noted in the instructions. It is the 
responsibility of the individual and institution 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 fully 
registered, the ACCRU Registration Office staff can access the information from the 
centralized database and confirm the registration. 
• 
Refer to “Application Training” at www.ACCRU.org; click on “Registration, 
Installation & Entry Instructions”. 
 
6.22 
Randomization Procedures: Phase II 
 
6.221 
The factors defined in Section 5.0 will be used as stratification factors. 
 
6.222 
After the patient has been registered into the study, the values of the stratification 
factors will be recorded, and the patient will be assigned to one of the following 
treatment groups using the Pocock and Simon dynamic allocation procedure which 


28 
ACCRU-GI-1618 
 
balances the marginal distributions of the stratification factors between the 
treatment groups [21]. 
 
Arm A: 
Binimetinib 30 mg twice daily + Palbociclib using recommended dose as 
determined in Part 1 component 
 
Arm B: 
TAS-102 35 mg/m2 twice daily for days 1-5 and 8-12; off days 6-7 and 13-28 
 
6.3 
Safety Run-In and Phase II 
 
6.31 
Correlative Research 
 
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). 
 
6.32 
Prior to accepting the registration, the following will be verified: 
 
• 
IRB approval at the registering institution 
• 
Patient eligibility 
• 
Existence of a signed consent form 
• 
Existence of a signed authorization for use and disclosure of protected health 
information 
 
6.33 
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. 
 
6.34 
At the time of registration, the following will be recorded: 
 
• 
Patient has/has not given permission to store and use his/her leftover 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 leftover 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 to store and use his/her leftover 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 leftover 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 for ACCRU to give his/her leftover tissue 
sample(s) to outside researchers. 


29 
ACCRU-GI-1618 
 
• 
Patient has/has not given permission for ACCRU to give his/her leftover blood 
sample(s) to outside researchers. 
 
6.35 
Treatment cannot begin prior to registration and must begin 21 days after registration. 
 
6.36 
Pretreatment tests/procedures (see Section 4.0) must be completed within the guidelines 
specified on the test schedule. 
 
6.37 
All required baseline symptoms (see Section 10.0) must be documented and graded. 
 
6.38 
Treatment on this protocol must commence at an ACCRU institution under the supervision 
of a medical oncologist. 
 
6.39 
Blood draw kit is available on site. 
 
6.4 
Re-Registration Procedure for Part 2 Optional Crossover 
 
NOTE: Re-registration must occur ≤28days from Part 2 TAS-102 disease progression (PD). 
 
Upon confirmation of progression for patients in Arm B (TAS-102) of randomized portion of the 
trial, patients may elect to cross-over to treatment with binimetinib + palbociclib as long as the 
following criteria are met: 
 
6.41 
To re-register a patient, fax (
) or email (
) a completed 
crossover eligibility checklist to the Academic and Community Cancer Research United 
(ACCRU) Registration Office between 8 a.m. and 4:30 p.m. central time Monday through 
Friday. 
 
6.42 
Correlative Research 
 
A mandatory correlative research component is part of this study, the patient will be 
automatically registered onto this component (see Sections 3.0 and 14.0). 
 
6.43 
Prior to accepting the registration, the following will be verified: 
 
• 
IRB approval at the registering institution 
• 
Patient eligibility 
• 
Existence of a signed consent form 
• 
Existence of a signed authorization for use and disclosure of protected health 
information 
 
6.44 
At the time of re-registration, the following will be recorded: 
 
• 
Patient has/has not given permission to store and use his/her leftover 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 leftover 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 for ACCRU to give his/her leftover blood 
sample(s) to outside researchers. 
 
6.45 
Crossover treatment cannot begin prior to re-registration and must begin ≤21 days after 
crossover re-registration. 


30 
ACCRU-GI-1618 
 
 
6.46 
Treatment on this protocol must commence at an ACCRU institution under the supervision 
of a medical oncologist. 
 
6.47 
Blood draw kit is available on site. 
 
7.0 
Protocol Treatment 
 
This is a Phase II, open-label, multicenter study designed to evaluate the safety, tolerability, and efficacy of 
the combination of binimetinib and palbociclib in patients with metastatic KRAS or NRAS mutant colorectal 
adenocarcinoma. 
 
This study consist of two parts: Part 1 is a safety run-in to confirm the safety and tolerability of the doses of 
binimetinib and palbociclib determined in a preceding independent Phase I study; and Part 2 is a 1:1 
randomized, open-label, Phase II clinical trial. The primary aim is to determine the clinical efficacy of the 
combination of palbociclib and binimetinib administered at the confirmed safe and tolerable dose as 
confirmed in Part 1, compared to the efficacy of standard of care therapy TAS-102 (trifluridine/tipiracil). 
Subjects randomized to the TAS-102 arm will have the option of crossing over to therapy with the 
combination of palbociclib and binimetinib upon progression. 
 
7.1 
Part 1: Safety Run-In 
 
In Part 1, an initial cohort of 6 patients will receive palbociclib orally once daily on days 1-21 out 
of a 28 day cycle and binimetinib orally twice per day continuously per Dose Cohort 1 in the table 
below. The starting dose of palbociclib will be 100 mg orally once daily on days 1-21 out of a 28 
day cycle (Dose Cohort 1; see Table 7.1). 
 
Dose Cohort 
Binimetinib Dose 
Palbociclib Dose** 
-1 
30 mg BID daily 
75 mg daily Days 1-21 
1* 
30 mg BID daily 
100 mg daily Days 1-21 
* 
Starting dose level 
** Dose levels as listed in Table 1 are provisional, and actual dose levels will be determined per 
discussion with participating investigators during dose escalation teleconferences and may 
differ from those presented in Table 1. If the starting dose is not well tolerated, with 2 or more 
subjects experiencing excessive toxicity as defined in Section 7.15, then dose de-escalation will 
be studied to determine a safe and tolerable dose in this population of colorectal cancer 
patients. 
 
7.11 
Rules for Dose De-escalation 
 
Dose de-escalation will be considered if Dose Cohort 1 per Table 7.1 proves excessively 
toxic, with 2 or more subjects having excessive toxicity as defined in Section 7.15. If this is 
the case, an additional 6 patients will be enrolled at Dose Cohort -1 with dose de- 
escalation. 
 
Dose de-escalation will proceed per the tables below: 
Dose Cohort 1 
If there are… 
Then… 
0-1/6 subjects with excessive 
toxicity per Section 7.15 
Proceed to Part II 
≥2/6 subjects with excessive 
toxicity per Section 7.15 
Enroll 6 subjects at Dose 
Cohort -1 


31 
ACCRU-GI-1618 
 
 
Dose Cohort -1 
If there are… 
Then… 
0-1/6 subjects with excessive 
toxicity per Section 7.15 
Proceed to Part II 
≥2/6 subjects with excessive 
toxicity per Section 7.15 
STOP. Will need to 
reconsider dosing scheme 
 
7.12 
Patient Cohorts 
 
Six patients will be treated at each dose level and observed for a minimum of 28 days from 
the day that treatment is initiated with binimetinib and palbociclib (Cycle 1 Day 1 to Cycle 
1 Day 28), to assess toxicities, before new patients are treated. Doses will not be escalated 
in any individual patient. 
 
All patients who receive the assigned treatment will be considered evaluable for toxicities 
to make a dose escalation decision. 
 
If any patient in Part 1 withdraws from the study for any reason other than study drug 
toxicity or adverse event prior to completing one 28-day cycle of treatment with the study 
drugs, then he/she may be replaced. Otherwise, patients will not be replaced on study. 
 
7.13 
Reporting of Excessive Toxicities 
 
Whenever a patient experiences toxicity that fulfills the criteria for excessive toxicity per 
Section 7.15 treatment with the study drugs will be interrupted and the toxicity will be 
followed up. 
 
Investigators are to contact the ACCRU Operations Office (507-266-0800) as soon as any 
event comprising excessive toxicity per Section 7.15 occurs. 
 
7.14 
Re-Starting Patients on Treatment Following Excessive Toxicity event 
 
For all toxicity grades, if the toxicity resolves to Grade 1 or baseline within 1 week of 
onset, treatment may be resumed at the same or a lower dose level at the investigator’s 
discretion and following discussion with the study chair. For toxicities that result in 
treatment delays of more than 7 but not more than 21 days, treatment may be resumed at a 
lower dose level. 
 
If a patient requires a dose interruption of >21 days from the intended day of the next 
scheduled dose, then the patient must be discontinued from the study. In this event, more 
frequent follow up as outlined in cycle 1 to monitor this toxicity may be appropriate. 
 
7.15 
Definitions of Excessive Toxicity during Safety Run-In 
 
Definitions of excessive toxicity events reflect the known and expected toxicities of 
binimetinib and palbociclib. Events meeting criteria for excessive toxicity during the safety 
run-in will be defined as an adverse event or abnormal laboratory value assessed as at least 
possibly related to binimetinib and/or palbociclib that occurs during the first 28 days of 
treatment and fulfills any of the criteria in the table below. Toxicity is evaluated according 
to the NCI CTCAE v4.03.Whenever a patient experiences toxicity that fulfills the criteria 
for an excessive toxicity event, treatment with the study drug will be interrupted and the 
toxicity will be followed up. 


32 
ACCRU-GI-1618 
 
 
For this protocol, excessive toxicity events will be defined as follows: 
 
• 
Grade 3+ Febrile Neutropenia 
• 
Grade 4 neutrophil count decreased > 7 consecutive days 
• 
Grade 4 platelet count decreased 
• 
Grade 4+ anemia 
• 
Non-hematologic AE: Any Grade ≥4; Grade 3 requiring dose modification (dose 
reduction per section 8.0) 
o In addition: 
▪ 
Ejection fraction decreased: Grade ≥2 
▪ 
Retinal vascular disorder if comprised of retinal vein occlusion as 
assessed by ophthalmologist: Grade ≥2 
 
If 2 or more patients (out of 6) experience any of the above, then we will a) de-escalate or 
b) temporarily stop the trial to re-assess the drug dose. 
 
7.2 
Part 2: Randomized Phase II Study and Optional Crossover 
 
After confirming the optimal safe and tolerable doses of combination binimetinib and palbociclib 
in Part 1, eligible patients will be enrolled in an open-label, 1:1 randomized clinical trial of 
binimetinib/palbociclib (arm A) vs. TAS-102 monotherapy (arm B). 
 
Subjects in arm B who discontinue study therapy due to disease progression per RECIST 1.1 
criteria may choose to undergo crossover to treatment with binimetinib and palbociclib as in arm 
A. Those subjects who elect to cross over will need to re-register ≤28 days from progression on 
TAS-102 and will undergo monitoring as per subjects in arm A. Up to 24 cycles of crossover 
treatment is allowed. 
 
Part 2 Treatment Schedule (Randomized) 
Arm Agent 
Dose Level 
Route 
Day 
Re-Rx# 
A 
Binimetinib 
30 mg twice daily 
Oral 
Daily 
Every 28 days 
A 
Palbociclib 
100 mg once daily 
Oral 
Days 1-21 
B 
TAS-102 
35 mg/m2 twice daily* 
Oral 
Days 1-5 and 
8-12 
* 
Based on trifluridine component. Doses should be rounded to the nearest 5-mg increment. 
Dose should be capped at 80 mg per dose of trifluridine component, consistent with standard 
practice and the label.  Use actual weight or estimated dry weight if fluid retention. No change 
in dose will be required for 
<10% weight change. 
# 
Plus or minus 3 days 
 
 
Part 2 Treatment Schedule (Optional Crossover) 
Agent 
Dose Level 
Route 
Day 
Re-Rx# 
Binimetinib 
30 mg twice daily 
Oral 
Daily 
Every 28 days 
Palbociclib 
100 mg once daily 
Oral 
Days 1-21 
 
# 
Plus or minus 3 days 
 
7.21 
Patients can be instructed in administration techniques and granted treatment independence 
with nursing staff approval. 
 
7.22 
Return to consenting institution 
 
For this protocol, the patient must return to the consenting institution for evaluation at least 


33 
ACCRU-GI-1618 
 
every 28 days during treatment and at 30-37 days after discontinuation of investigational 
therapy if in Arm A during observation (Active Monitoring Phase). 


34 
ACCRU-GI-1618 
 
 
7.23 
Treatment by a local medical doctor (LMD) is not allowed. 
 
7.24 
Missed/skipped/vomited doses will not be made up (i.e. the patient should not double their 
dose if the previous dose was missed). 
 
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 to treatment 
given are based on adverse events observed in the preceding cycle. 
 
If a subject experiences more than one toxicity, dose reduction should be according to the toxicity with the 
highest grade. 
 
In the case of two or more toxicities of the same grade, the investigator may dose reduce according to that 
deemed most causally related to study treatment. 
 
ALERT: 
ADR reporting may be required for some adverse events (See Section 10.0) 
 
8.1 
Binimetinib Dose Levels (Based on Adverse Events) 
 
Patients will be monitored for adverse events at each visit with the NCI CTCAE version 4.03 used 
for all grading. All AEs should be followed at each visit until resolution or stabilization of the 
event, whichever comes first. 
 
Appropriate clinical experts such as an ophthalmologist, cardiologist, or dermatologist should be 
consulted as deemed necessary. 
 
Doses of binimetinib should be adjusted for AEs throughout the study. In general, doses should not 
be reduced or interrupted for Grade 1 AEs unless the AE is a specific treatment-related ocular AE. 
Treatment to control symptoms should be provided as appropriate. All dose modifications should 
be based on the worst preceding toxicity (CTCAE version 4.03). 
 
An individual patient may have their dose of binimetinib reduced to the dose levels specified in 
Table 8.1 below. When the AE that resulted in a dose reduction improves to and remains stable at 
the patient’s Baseline for a minimum of 14 days, the dose can be re-escalated to the next dose level 
at the discretion of the Investigator, provided there are no other concomitant binimetinib-related 
toxicities that would prevent drug re-escalation. 
 
There is no limit to the number of times the patient can have their dose reduced or re-escalated (in 
15 mg increments); however, no dose re-escalation is allowed after a dose reduction due to LVEF 
dysfunction. 
 
Dose interruptions of more than 28 days are not allowed. 
 
Refer to the tables in Section 8.4 for specific dose adjustment recommendations for binimetinib- 
induced toxicities. 
 
Dose 
Level 
Drug 
Dose** 
0* 
Binimetinib (MEK 162) 
30 mg BID 




36 
ACCRU-GI-1618 
 
 
→ → Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.03* unless otherwise specified   
CTCAE 
System/Organ/ 
Class (SOC) 
ADVERSE 
EVENT 
GRADE 
ACTION** 
• 
Patient is 
asymptomatic 
If the LVEF does not 
recover within 4 weeks, 
permanently 
DISCONTINUE 
treatment 
Cardiac disorders 
Left ventricular 
systolic 
dysfunction 
Grade 3-4: 
Symptomatic due to 
drop in ejection 
fraction (either 
responsive to or 
refractory to 
intervention) 
Permanently 
DISCONTINUE 
Closely monitor LVEF 
until resolution or up to 16 
weeks 
Investigations 
Ejection fraction 
decreased 
Grade 3-4: 
Absolute decrease in 
left ventricular 
ejection fraction of 
>20% compared to 
baseline and below 
the institutional 
lower limit of 
normal (LLN) 
Eye disorders 
Retinopathy 
Grade 1 
• 
MAINTAIN dose 
level 
• 
Repeat ophthalmologic 
monitoring including 
visual acuity 
assessment and OCT 
within 10 (±3) days. 
If remains asymptomatic 
(Grade 1), maintain dose 
level and continue 
schedule of visual 
assessments established 
per protocol. 
If becomes symptomatic 
or visual acuity assessment 
shows grade 2, follow 
Grade 2 guidelines below 
Eye disorders 
Retinopathy 
Grade 2 
• 
Interrupt treatment 
• 
Repeat ophthalmologic 
monitoring including 
visual acuity 
assessment and OCT 


37 
ACCRU-GI-1618 
 
 
→ → Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.03* unless otherwise specified   
CTCAE 
System/Organ/ 
Class (SOC) 
ADVERSE 
EVENT 
GRADE 
ACTION** 
within 10 (±3) days. 
If resolved to baseline or 
Grade ≤1, within 10 
days, resume treatment 
at current dose level and 
continue schedule of 
visual assessments 
established per protocol. 
If not resolved to baseline 
or Grade ≤1, resume 
treatment at REDUCED 
dose level# and continue 
schedule of visual 
assessments established 
per protocol 
Eye disorders 
Retinopathy 
Grade 3 
• 
Interrupt treatment 
• 
Repeat ophthalmologic 
monitoring including 
visual acuity 
assessment and OCT 
within 10 (±3) days. 
If resolved to baseline or 
Grade ≤2, resume 
treatment at REDUCED 
dose level# and continue 
schedule of visual 
assessments established 
per protocol. 
If not resolved to baseline 
or Grade ≤2, continue to 
hold treatment and repeat 
ophthalmologic 
assessment in 10 (±3) days 
- 
If then resolves to 
baseline or Grade 
≤2, resume 
treatment at 
REDUCED dose 
level# and continue 
schedule of visual 
assessments 
established per 
protocol. 
- 
 If remains Grade 3, 
permanently 


38 
ACCRU-GI-1618 
 
 
→ → Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.03* unless otherwise specified   
CTCAE 
System/Organ/ 
Class (SOC) 
ADVERSE 
EVENT 
GRADE 
ACTION** 
discontinue and 
proceed with 
immediate follow- 
up with 
ophthalmologic 
monitoring 
Eye disorders 
Retinopathy 
Grade 4 
• 
Permanently 
DISCONTINUE 
treatment 
• 
Initiate immediate 
follow-up with 
ophthalmic monitoring 
until stabilization or 
resolution 
Eye disorders 
Retinal vascular 
disorder 
Retinal vein 
occlusion – ANY 
GRADE 
Permanently 
DISCONTINUE 
treatment 
Continue ophthalmologic 
monitoring 
Eye disorders 
Uveitis 
Grade 1 
Asymptomatic; 
clinical or diagnostic 
observations only 
• 
MAINTAIN dose 
level 
• 
Repeat ophthalmologic 
monitoring including 
visual acuity 
assessment and OCT 
within 10 (±3) days. 
If remains asymptomatic 
(Grade 1), maintain dose 
level and continue 
schedule of visual 
assessments established 
per protocol. 
If becomes symptomatic 
or visual acuity assessment 
shows grade 2, follow 
Grade 2 guidelines below 
Eye disorders 
Uveitis 
Grade 2 
Medical intervention 
indicated 
• 
Interrupt treatment 
• 
Repeat ophthalmologic 
monitoring including 
visual acuity 
assessment and OCT 
within 10 (±3) days. 
If resolved to baseline or 
Grade ≤1, resume 
treatment at current dose 
level and continue 


39 
ACCRU-GI-1618 
 
 
→ → Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.03* unless otherwise specified   
CTCAE 
System/Organ/ 
Class (SOC) 
ADVERSE 
EVENT 
GRADE 
ACTION** 
schedule of visual 
assessments established 
per protocol. 
If uveitis lasts >6 weeks, 
permanently discontinue. 
Eye disorders 
Uveitis 
Grade 3 
Posterior or pan- 
uveitis 
• 
Interrupt treatment 
• 
Repeat ophthalmologic 
monitoring including 
visual acuity 
assessment and OCT 
within 10 (±3) days. 
If resolved to baseline or 
Grade ≤2, resume 
treatment at REDUCED 
dose level# 
If not resolved to baseline 
or Grade ≤2, continue to 
hold treatment and repeat 
ophthalmologic 
assessment in 10 (±3) days 
If remains Grade 3, 
permanently discontinue. 
Eye disorders 
Uveitis 
Grade 4 
Blindness (20/200 or 
worse) in the 
affected eye 
• 
Permanently 
DISCONTINUE 
treatment 
• 
Initiate immediate 
follow-up with 
ophthalmic monitoring 
until stabilization or 
resolution 
Eye disorders 
Eye disorders – 
Other, specify 
Grade 1-2 
• 
MAINTAIN dose 
level 
• 
Increase frequency of 
ophthalmologist 
monitoring to at least 
every 14 days until 
stabilization or 
resolution 
• 
Images/results of the 
ophthalmic 
examinations (at a 
minimum, OCT, color 
fundus photography 
and/or fluorescein 


40 
ACCRU-GI-1618 
 
 
→ → Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.03* unless otherwise specified   
CTCAE 
System/Organ/ 
Class (SOC) 
ADVERSE 
EVENT 
GRADE 
ACTION** 
angiography) must be 
made available upon 
Sponsor request. 
Eye disorders 
Eye disorders – 
Other, specify 
Grade 3 
• 
Interrupt treatment 
• 
Refer patient to 
ophthalmologist within 
1 week: 
o If resolved to ≤ 
Grade 1 in ≤21 days, 
REDUCE# dose 
level 
o If not resolved to ≤ 
Grade 1 in ≤21 days, 
permanently 
DISCONTINUE 
treatment and initiate 
close follow-up with 
ophthalmic 
monitoring until 
stabilization or 
resolution 
Images/results of the 
ophthalmic examinations 
(at a minimum, OCT, 
color fundus photography 
and/or fluorescein 
angiography) must be 
made available upon 
Sponsor request. 
Eye disorders 
Eye disorders – 
Other, specify 
Grade 4 
• 
Permanently 
DISCONTINUE 
treatment 
• 
Initiate immediate 
follow-up with 
ophthalmic monitoring 
until stabilization or 
resolution 
Gastrointestinal 
disorders 
Diarrhea 
Grade 1-2 (increase 
of up to 6 stools per 
day over baseline, or 
mild to moderate 
increase in ostomy 
output compared to 
baseline) 
IF uncomplicated 
(NO concomitant 
moderate to severe 
Consider temporary 
interruption of binimetinib 
until resolved to Grade ≤ 
1. Then resume treatment 
at current dose level of 
binimetinib. 


41 
ACCRU-GI-1618 
 
 
→ → Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.03* unless otherwise specified   
CTCAE 
System/Organ/ 
Class (SOC) 
ADVERSE 
EVENT 
GRADE 
ACTION** 
abdominal 
cramping, grade ≥2 
nausea/vomiting, 
decrease in 
performance status, 
fever, bleeding, or 
dehydration) 
Gastrointestinal 
disorders 
Diarrhea 
Grade 1-2 (increase 
of up to 6 stools per 
day over baseline, or 
mild to moderate 
increase in ostomy 
output compared to 
baseline) 
IF complicated (has 
concomitant 
moderate to severe 
abdominal 
cramping, grade ≥2 
nausea/vomiting, 
decrease in 
performance status, 
fever, bleeding, or 
dehydration) 
Interrupt dosing of 
binimetinib until resolved 
to Grade ≤ 1. Then resume 
treatment at reduced dose 
Gastrointestinal 
disorders 
Diarrhea 
Grade 3-4 
Interrupt dosing of 
binimetinib until resolved 
to Grade ≤ 1. Then resume 
treatment at reduced dose# 
Gastrointestinal 
disorders 
Nausea OR 
Vomiting 
Grade 1-2 
Maintain dose of 
binimetinib. 
Promptly initiate 
antiemetics 
Gastrointestinal 
disorders 
Nausea OR 
Vomiting 
Grade 3 
Ensure patient is taking 
optimal antiemetics. 
If optimal antiemetics do 
not control grade 3 
nausea/vomiting, interrupt 
dosing with binimetinib 
until resolved to Grade ≤1. 
May resume treatment at 
same dose level if toxicity 
is unrelated to binimetinib, 
or else resume at reduced 
dose 
Gastrointestinal 
disorders 
Nausea OR 
Vomiting 
Grade 4 
Permanently discontinue 
Investigations 
Alanine 
aminotransferase 
increased 
AST or ALT > ULN 
Continue treatment with 
maintained dose level 


42 
ACCRU-GI-1618 
 
 
→ → Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.03* unless otherwise specified   
CTCAE 
System/Organ/ 
Class (SOC) 
ADVERSE 
EVENT 
GRADE 
ACTION** 
OR 
Aspartate 
aminotransferase 
increased 
to 3 × ULN if 
baseline was normal, 
or 1.5-3 x baseline 
value if had abnormal 
baseline) 
Investigations 
Alanine 
aminotransferase 
increased 
OR 
Aspartate 
aminotransferase 
increased 
 (AST or ALT > 
3 to 5 × 
ULN, or > 3 to 5 x 
baseline value if had 
abnormal baseline) 
 
Maintain dose level of 
binimetinib 
Reassess within ≤ 14 days. 
If no improvement within 
14 days, interrupt dosing 
of binimetinib until 
resolved to Grade ≤ 1 or to 
pretreatment/ baseline 
levels. Then resume 
treatment at current dose 
level binimetinib 
 
 
 
 
Investigations 
Alanine 
aminotransferase 
increased 
OR 
Aspartate 
aminotransferase 
increased 
 (AST or ALT > 
5 to 20 × ULN if 
baseline was 
normal, or >5 to 
20 × baseline if 
had abnormal 
baseline 
 
1st occurrence: 
Interrupt dosing of 
binimetinib for up to 28 
days until resolved to 
Grade ≤ 1. If improves to 
Grade 0-1 or to 
pretreatment/baseline 
levels, resume at 1 
reduced dose level of 
binimetinib. If no 
improvement, 
PERMANENTLY 
DISCONTINUE 
binimetinib 
2nd occurrence: 
Consider permanently 
discontinuing 
binimetinib 
 


43 
ACCRU-GI-1618 
 
 
Investigations 
Alanine 
aminotransferase 
increased 
OR 
Aspartate 
aminotransferase 
increased 
AST or ALT 
>20 × ULN if 
baseline was 
normal, or >20 × 
baseline if had 
abnormal 
baseline 
 
PERMANENTLY 
DISCONTINUE 
binimetinib 
 
 
 
 
 
→ → Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.03* unless otherwise specified   
CTCAE 
System/Organ/ 
Class (SOC) 
ADVERSE 
EVENT 
GRADE 
ACTION** 
Investigations 
CPK increased 
Grade 1-2 (CPK > 
ULN – 5x ULN) 
Maintain dose of 
binimetinib. Ensure patient 
is adequately hydrated. 
Closely monitor CK and 
serum creatinine. 
If total CK ≥ 3 × ULN, 
measure CK isoenzymes 
and myoglobin in blood or 
urine. 
Investigations 
CPK increased 
Grade 3 (CPK >5 – 
10 x ULN) 
WITHOUT renal 
impairment (serum 
creatinine <1.5x 
ULN or 1.5 x 
If asymptomatic, maintain 
dose of binimetinib. 
Ensure patient is 
adequately hydrated. 
Monitor and measure 
isoenzymes and 
 
 


44 
ACCRU-GI-1618 
 
 
 
 
 
 
 
 
 
 
 
 
 
→ → Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.03* unless otherwise specified   
CTCAE 
System/Organ/ 
Class (SOC) 
ADVERSE 
EVENT 
GRADE 
ACTION** 
baseline) 
myoglobin in blood or 
urine and serum 
creatinine. 
If symptomatic (muscle 
pain/spasms/muscle 
weakness), interrupt 
dosing of binimetinib until 
resolved to CTCAE Grade 
≤ 1 and monitor closely, 
then: 
• If resolved in ≤ 28 days, 
resume treatment at 1 
reduced dose level of 
binimetinib# 
• If not resolved in ≤ 28 
days permanently 
discontinue binimetinib. 
Investigations 
CPK increased 
Grade 4 (CPK >10 x 
ULN) 
WITHOUT renal 
impairment (serum 
creatinine <1.5x 
ULN or 1.5 x 
baseline) 
If asymptomatic, interrupt 
dosing of binimetinib. 
Ensure patient is 
adequately hydrated. 
Monitor and measure 
isoenzymes and 
myoglobin in blood or 
urine and serum creatinine 
• If resolved in ≤ 28 days, 
resume treatment at 1 
reduced dose level of 
binimetinib# 
• If not resolved in ≤ 28 
days, permanently 
discontinue binimetinib. 
If symptomatic (muscle 
pain/spasms/muscle 
weakness), interrupt 
dosing of binimetinib until 
resolved to CTCAE Grade 
≤ 1 and monitor closely, 
then: 
• If resolved in ≤ 28 days, 


45 
ACCRU-GI-1618 
 
 
resume treatment at 1 
reduced dose level of 
binimetinib# 
If not resolved in ≤ 28 
days permanently 
discontinue   
Investigations 
CPK increased 
Grade 3-4 
WITH renal 
impairment (serum 
creatinine ≥1.5x 
ULN or 1.5 x 
baseline) 
Interrupt dosing of 
binimetinib until resolved 
to Grade ≤ 1 or baseline 
level. Ensure patient is 
adequately hydrated. 
Monitor closely and 
measure isoenzymes and 
myoglobin in blood or 
urine and serum 
creatinine, then: 
• If resolved in ≤ 28 days, 


46 
ACCRU-GI-1618 
 
 
→ → Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.03* unless otherwise specified   
CTCAE 
System/Organ/ 
Class (SOC) 
ADVERSE 
EVENT 
GRADE 
ACTION** 
resume treatment at 1 
reduced dose level of 
binimetinib# 
• If not resolved in ≤ 28 
days, permanently 
discontinue binimetinib. 
2nd occurrence: 
Permanently discontinue 
binimetinib. 
Skin and 
subcutaneous 
tissue disorders 
Any 
Grade 1 
Maintain dose level of 
binimetinib. 
Initiate Initial Rash 
Treatment Regimen and 
closely monitor rash 
Skin and 
subcutaneous 
tissue disorders 
Any 
Grade 2 
1st occurrence: 
• Maintain dose level of 
binimetinib 
• Initiate Initial Rash 
Treatment Regimen if it 
was not already started 
and rash should be closely 
monitored 
•Reassess within ≤ 14 
days. If rash worsens or 
does not improve, 
interrupt dosing of 
binimetinib until resolved 
to Grade ≤ 1. Then resume 
treatment at current dose 
level binimetinib. 
2nd occurrence: 
• Maintain dose level of 
binimetinib 
• Continue Initial Rash 
Treatment Regimen and 
rash should be closely 
monitored 
• Reassess within ≤ 14 
days. If rash worsens or 
does not improve, 
interrupt dosing of 
binimetinib until resolved 
to Grade ≤ 1. Then resume 
treatment with a dose 
reduction#. 
Skin and 
subcutaneous 
Any 
Grade 3 
1st occurrence: 
• Interrupt dosing of 


47 
ACCRU-GI-1618 
 
 
→ → Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.03* unless otherwise specified   
CTCAE 
System/Organ/ 
Class (SOC) 
ADVERSE 
EVENT 
GRADE 
ACTION** 
tissue disorders 
binimetinib until resolved 
to Grade ≤ 1. Reassess 
weekly. Then resume 
treatment at current dose 
level of binimetinib. 
• Consider referral to 
dermatologist and manage 
rash per dermatologist’s 
recommendation. 
2nd occurrence: 
• Interrupt dosing of 
binimetinib until resolved 
to Grade ≤ 1. Then resume 
treatment at 1 reduced 
dose level of binimetinib#. 
• Consider referral to 
dermatologist and manage 
rash per dermatologist’s 
recommendation. 
Skin and 
subcutaneous 
tissue disorders 
Any 
Grade 4 
DISCONTINUE 
permanently 
Vascular 
disorders 
Thromboembolic 
event 
Grade 2 or 3: 
Uncomplicated DVT 
or PE 
WITHHOLD for up to 3 
weeks 
• 
If improved to Grade 0 
or 1 and is 
symptomatic, 
RESUME at same 
dose#. 
• 
If not improved, resume 
at reduced dose level or 
permanently 
DISCONTINUE 
Vascular 
disorders 
Thromboembolic 
event 
Grade 4: Life- 
threatening 
pulmonary 
embolism 
Permanently 
DISCONTINUE 
Respiratory, 
thoracic, and 
mediastinal 
disorders 
Pneumonitis 
Grade 1 
MAINTAIN dose level of 
binimetinib and monitor 
weekly 
Respiratory, 
thoracic, and 
mediastinal 
disorders 
Pneumonitis 
Grade 2 
WITHHOLD for up to 4 
weeks 
• 
If improved to Grade 
0 or 1, RESUME at 
DECREASED dose#. 
• 
If not resolved within 
4 weeks, 
permanently 


48 
ACCRU-GI-1618 
 
 
→ → Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.03* unless otherwise specified   
CTCAE 
System/Organ/ 
Class (SOC) 
ADVERSE 
EVENT 
GRADE 
ACTION** 
DISCONTINUE 
Respiratory, 
thoracic, and 
mediastinal 
disorders 
Pneumonitis 
Grade 3-4 
Permanently 
DISCONTINUE 
* 
Located at 
 
** 
Use the following to describe actions in the Action column: 
➢ Omit = Treatment is not given for thiscycle 
➢ Hold/Delay = Treatment can be made up as part of this cycle 
➢ Discontinue = Treatment is totally stopped 
# 
Do not re-escalate. 
 
For adverse events NOT otherwise identified above that are suspected to be related to binimetinib, 
the following general recommendations should be used as guidelines for clinically significant 
dose modifications: 
 
GRADE 
ACTION 
Recurrent 
Grade 2  
Withhold BINIMETINIB for up to 4 weeks. 
If improved to Grade 0 or 1, or pretreatment/baseline level, 
resume at reduced dose *. 
*NOTE: dose reduction below 15 mg BID is not allowed. Dose 
may be re-escalated when AE improves and remains stable at ≤ 
Grade 1 for ≥14 days. There is no limit to the number of times 
dose can be reduced or re-escalated in 15-mg increments. 
Grade 3 or 4 
Withhold BINIMETINIB for up to 4 weeks. 
• 
If improved to Grade 0 or 1 or pretreatment/baseline level, 
resume at reduced dose*. 
If not improved, permanently discontinue. 
*NOTE: dose reduction below 15 mg BID is not allowed. 
Grade 4 
Permanently discontinue binimetinib 
 
NOTE: If the patient experiences a significant adverse event requiring a dose reduction at the start 
of the next cycle, then the dose will remain lowered for that entire subsequent cycle. If that cycle is 
completed with no further adverse events > Grade 2, then the dose may be increased, at the 
investigator’s discretion, one level at a time, in the following cycles, for the adverse events that are 
not marked with # in the table above (Section 8.4). 
 




50 
ACCRU-GI-1618 
 
 
→ → Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03* 
unless otherwise specified   
CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE 
EVENT 
GRADE 
ACTION** 
Investigations 
Neutrophil count 
decreased 
Grade 4: <500/mm3 
• 
OMIT treatment and 
initiation of next cycle 
until recovery to ≤ Grade 
2 
• 
Resume at next lower 
dose. 
Investigations 
Platelet count 
decreased 
Grade 3: 25,000/ 
mm3 - <50,000/mm3 
• 
No dose adjustment is 
required. 
• 
Consider repeating 
complete blood count 
monitoring one week 
later. 
• 
Withhold initiation of 
next cycle until recovery 
to ≤ Grade 2. 
Investigations 
Platelet count 
decreased 
Grade 4: <25,000/ 
mm3 
• 
OMIT treatment and 
initiation of next cycle 
until recovery to ≤ Grade 
2 
• 
Resume at next lower 
dose. 
Respiratory, thoracic, 
and mediastinal 
disorders 
Pneumonitis 
Grade 3 
• 
Omit treatment and 
initiation of next cycle 
until recovery to ≤ Grade 
2 
Respiratory, thoracic, 
and mediastinal 
disorders 
Pneumonitis 
Grade 4 
• 
Permanently 
Discontinue 
* 
Located at 
 
** 
Use the following to describe actions in the Action column: 
➢ Omit = Treatment is not given for this cycle 
➢ Hold/Delay = Treatment can be made up as part of this cycle 
➢ Discontinue = Treatment is totally stopped 
 
For clinically relevant adverse events that are suspected to be related to palbociclib NOT 
otherwise identified above, the following general recommendations should be used as 
guidelines for dose modifications: 
 
GRADE 
AGENT 
ACTION 
Grade ≥3 Non- 
hematologic 
toxicity (if 
persisting despite 
medical 
treatment) 
PALBOCICLIB 
• 
OMIT treatment until symptoms 
resolve to Grade ≤1 or ≤2 if not 
clinically significant. 
• 
Resume at next lower dose. 
NOTE: If the patient experiences a significant adverse event requiring a dose reduction at the start 


51 
ACCRU-GI-1618 
 
of the next cycle, then the dose will remain lowered for that entire subsequent cycle. If that cycle is 
completed with no further adverse events > Grade 2, then the dose may be increased, at the 
investigator’s discretion, one level at a time, in the following cycles. 
NOTE: Adverse events requiring a dose-reduction step for any or all drugs beyond the two dose- 
reduction steps (levels –1 and –2) will be at the discretion of the treating physician, if the decision 
is made for the patient to be kept on study. These dose reductions must be clearly recorded in 
reported clinical data. 
NOTE: Asymptomatic lab abnormalities that is not clinically significant ( i.e. electrolyte abnormalities, 
ALC decrease. 






54 
ACCRU-GI-1618 
 
 
→ → Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.03* unless otherwise specified   
CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE 
EVENT 
GRADE 
ACTION** 
Investigations 
Platelet count 
decreased 
Grade 3: 25,000/ 
mm3 - <50,000/mm3 
OMIT treatment until 
platelets ≥75,000/mm3. 
Reinitiate treatment at 
SAME dose level 
Investigations 
Platelet count 
decreased 
Grade 4: <25,000/ 
mm3 
• OMIT treatment until 
resolved to ≤ Grade 1 
o If recovery ≤1 
week, reinitiate at 
SAME dose level 
o If recovery >1 
week, reinitiate at 
REDUCED dose 
level 
* 
Located at 
 
** 
Use the following to describe actions in the Action column: 
➢ Omit = Treatment is not given for this cycle 
➢ Hold/Delay = Treatment can be made up as part of this cycle 
➢ Discontinue = Treatment is totally stopped 
 
For clinically significant adverse events that are suspected to be related to TAS-102 NOT otherwise 
identified above, the following general recommendations should be used as guidelines for dose 
modifications at all points within a cycle: 
 
GRADE 
ACTION 
Grade ≥3 Non- 
hematologic toxicity 
• 
OMIT treatment until resolved to ≤ Grade 1 
• 
For Grade 3 nausea/vomiting controlled by 
antiemetics, reinitiate at SAME dose level 
• 
For Grade 3 diarrhea responsive to antidiarrheal 
medication, reinitiate at SAME dose level 
• 
For all other, reinitiate at REDUCED dose level 
 
9.0 
Ancillary Treatment/Supportive Care 
 
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. 
 
9.1 
Permitted concomitant therapy requiring caution and/or action with binimetinib therapy 
 
Binimetinib potently inhibits CYP2B6 (Ki of 1.67 µM). Based on these in vitro findings, 
binimetinib may inhibit the metabolic clearance of co-medications metabolized by CYP2B6 if 
sufficiently high concentrations are achieved in vivo. At 45 mg BID, the maximum concentrations 
achieved in plasma are normally <1.5 µM so the risk of drug interaction is limited. Caution should 
be used in patients receiving concomitant treatment with other drugs that are substrates of this 
enzyme. 
 
Binimetinib induced CYP3A4 in vitro; however no clinically relevant inhibition or induction was 


55 
ACCRU-GI-1618 
 
observed in a clinical midazolam-based drug interaction study [CMEK162A2105] following 14 
days of repeat dosing of binimetinib. 
 
Binimetinib is primarily metabolized via glucuronidation by UGT1A1. It is advised that inhibitors 
or inducers of UGT1A1 should be taken with caution when co-administered with binimetinib. 
 
In vitro data showed that binimetinib is a substrate of P-gp as well as a substrate of BCRP. Thus, 
the use of drugs that are known to inhibit or induce P-gp and BCRP should be used with caution. 
 
The solubility of binimetinib is pH-dependent, and a 10-fold decrease in solubility is observed 
between pH 1 and 2. However, the extent of binimetinib exposure (AUC) was not altered in the 
presence of a gastric acid reducing agent (rabeprazole) [Clinical Study ARRAY-162-105]. 
 
Drugs with a conditional, possible, or known risk to induce Torsade de Pointes (TdP) should be 
used with caution. Patients receiving such medications must be carefully monitored for potentiating 
of toxicity due to any individual concomitant medication, and may require dose titration of the drug 
substance. Investigators should use caution when prescribing co-medications, as clinical experience 
with these compounds in patients with cancer is often limited. 
 
Refer to Appendix I for list of medications to be used with caution when administered with 
binimetinib. 
 
9.2 
Management of nausea and/or vomiting (on binimetinib arm) 
 
Because nausea and vomiting have been reported for binimetinib, it is recommended that patients 
are educated on the possibility of occurrence of these side effects prior to starting study treatment. 
Patient education as well as proper management of nausea and/or vomiting at the first sign is 
important. 
 
Clinical judgment and experience of the treating physician should guide the management plan of 
each patient. Patients experiencing nausea and/or vomiting ≥ Grade 1 by CTCAE v4.03 will 
receive antiemetics at the discretion of the treating physician (as per local guidelines). It is 
recommended that patients be provided a prescription for antiemetics, and are instructed on the use 
of antiemetics on the first day of study drug treatment. Prophylactic antiemetics such as 
dexamethasone 8 mg, prochlorperazine, or metoclopramide may be administered to patients on an 
"as needed" basis. 
 
Dose interruption/reduction decisions for nausea and/or vomiting should be based on the CTCAE 
grade of the toxicity and the guidelines provided in Section 8.4. 
 
As a guidance for recommendations on supportive measures for the prevention and/or management 
of nausea and/or vomiting, the published recommendation from American Society of Clinical 
Oncology (ASCO), the European Society of Medical Oncology (ESMO) and Multinational 
Association of Supportive Care (MASCC) can be used [19, 20]. 
 
9.3 
Diarrhea (on binimetinib arm) 
 
9.31 
Proactively investigate for occurrence of diarrhea and educate patients 
 
• 
Remind patients at each visit to contact the Investigator immediately upon the first 
sign of loose stool or symptoms of abdominal pain. Additionally, at each study 
visit, each patient should be asked regarding occurrence of diarrhea or diarrhea- 
related symptoms. If the patient had symptoms, the patient should be asked 
regarding the actions taken for these symptoms and re-instruct if indicated. 


56 
ACCRU-GI-1618 
 
 
• 
The patients should be instructed on dietary modifications and on early warning 
signs of diarrhea and potentially life-threatening illnesses (e.g. severe cramping 
might be a sign for severe diarrhea, fever with diarrhea might be a sign for 
infection, fever and dizziness on standing might be a sign for shock). 
 
• 
Patients should be educated about what to report to the Investigator (i.e., number of 
stools, stool composition, stool volume). 
 
9.32 
Anti-diarrheal therapy 
 
• 
In order to effectively manage diarrhea and mitigate the escalation in severity or 
duration of diarrhea, patient education as outlined above as well as proper 
management of diarrhea is important. 
 
• 
Management of diarrhea should be instituted at the first sign of abdominal 
cramping, loose stools or overt diarrhea. All concomitant therapies used for 
treatment of diarrhea must be recorded on the Concomitant Medications section of 
the patient record. It is recommended that patients be provided loperamide tablets 
and are instructed on the use of loperamide at on the first day of binimetinib 
treatment. In addition to the binimetinib induced-diarrhea dosing guidelines, these 
instructions should be provided at each visit and the site should ensure that the 
patient understands the instructions. 
 
• 
Explain the frequency of diarrhea and its relationship to NCI CTCAE grading. 
 
• 
Determine if diarrhea is complicated or uncomplicated. 
 
9.33 
Rule out other or concomitant causes 
These may include: 
• 
Infection with Candida, Salmonella, Clostridium difficile, Campylobacter, Giardia, 
Entamoeba and Cryptosporidium species can lead to severe infections in 
immunosuppressed patients 
• 
Medication-induced diarrhea 
• 
Malabsorption/lactose intolerance 
• 
Fecal impaction, partial bowel obstruction 
 
9.34 
For uncomplicated Grade 1/2 diarrhea 
 
• 
Stop all lactose-containing products, alcohol and eat frequent small meals that 
include bananas, rice, applesauce or toast 
 
• 
Stop laxatives, bulk fiber (i.e. Metamucil®) and stool softeners (e.g. docusate 
sodium; Colace®) 
 
• 
Stop high-osmolar food supplements such as Ensure® Plus and Jevity® Plus (with 
fiber) 
 
• 
Drink 8 to 10 large glasses of clear liquids per day (e.g. water, Pedialyte®, 
Gatorade® or broth) 


57 
ACCRU-GI-1618 
 
• 
Consider administration of standard dose of loperamide: initial administration 4 
mg, then 2 mg every 4 hours (maximum of 16 mg/day) or after each unformed 
stool. 
 
• 
Discontinue loperamide after 12-hours diarrhea-free (Grade 0) interval. 
 
• 
If uncomplicated Grade 1 to 2 diarrhea persists for more than 24 hours, escalate to 
high dose loperamide: 2 mg every 2 hours (max. of 16 mg/day) or after each 
unformed stool. 
 
NOTE: Oral antibiotics may be started as prophylaxis for infections under the discretion of 
the physician. 
 
• 
If uncomplicated Grade 1 to Grade 2 diarrhea persists after 48 hours of treatment 
with loperamide, discontinue loperamide and begin a second-line agent which can 
be an opiate (opium tincture or paregoric), octreotide acetate or steroid 
(budesonide) 
 
9.35 
For complicated Grade 1/2 diarrhea or any Grade 3 to 4 diarrhea 
 
• 
The patient must call the investigator immediately 
 
• 
If loperamide has not been initiated, initiate loperamide immediately. Initial 
administration 4 mg, then 2 mg every 4 hours (maximum of 16 mg/day) or after 
each unformed stool 
 
• 
Administer IV fluids and electrolytes as needed. In case of severe dehydration, 
replace loperamide by octreotide. 
 
• 
Monitor/continue IV fluids and antibiotics as needed. Intervention should be 
continued until the patient is diarrhea free for at least 24 hours. 
 
• 
Hospitalization may need to be considered. 
 
9.4 
Skin Toxicity (on binimetinib arm) 
 
Clinical judgment and experience of the treating physician should guide the management plan of 
each patient. In general, the following interventions are in addition to the rash dosing guidelines in 
Section 8.4: 
 
• 
Prophylaxis of skin toxicity to be initiated 24 hours prior to the first treatment with study 
drug or later as needed 
 
• 
Application of topical agents to the most commonly affected skin areas such as face, scalp, 
neck, upper chest and upper back 
 
Topical agents include non-oily sunscreen (PABA free, SPF ≥30, UVA/UVB protection), topical 
steroids (preferably mometasone cream i.e. Elocon®) and topical erythromycin evening (i.e. 
Eryaknen® or topical pimocrolimus) 
 
NOTE: Topical agents should be applied on a daily basis starting on Day 1 of study treatment or 
24 hours prior to the first dose, and more often as needed. 


58 
ACCRU-GI-1618 
 
• 
Possibly oral doxycycline (100 mg twice daily) for the first 2-3 weeks of study drug 
administration. 
 
Other effective medications are antihistamines, other topical corticosteroids, other topical 
antibiotics and low-dose systemic corticosteroids. 
 
The treatment algorithm based on CTCAE grade is as follows: 
 
9.41 
Mild rash (CTCAE Grade 1) 
 
• 
Consider prophylactic rash treatment if not already started 
 
• 
Topical or other topical corticosteroid (i.e. mometasone cream) and/or topical 
antibiotic (i.e. erythromycin 2%) are recommended. 
 
• 
The patient should be reassessed within a maximum of 2 weeks or as per 
investigator opinion. 
 
9.42 
Moderate rash (CTCAE Grade 2) 
 
• 
Use of topical erythromycin or clindamycin (1%) plus topical mometasone or 
pimecrolimus cream (1%) plus oral antibiotics such as: doxycycline (100 mg BID) 
or minocycline (50 to 100 mg QD). 
 
• 
Although there has been no evidence of phototoxicity or photosensitivity in 
patients being treated with binimetinib, doxycycline (or minocycline as second- 
line) should be used with thorough UV protection (i.e., avoidance of direct 
exposure to sunlight, use of sunscreen and sunglasses, etc.). 
 
• 
Use of acitretin is not recommended 
 
9.43 
Severe rash (CTCAE Grade 3) 
 
• 
In addition to the interventions recommended for moderate rash, consider oral 
prednisolone at a dose of 0.5 mg/kg. Upon improvement, taper the dose in a 
stepwise manner (25 mg for 7 days, subsequently decreasing the dose by 5 mg/day 
every day). 
 
• 
Alternatively, in addition to the interventions recommended for moderate rash, 
consider oral isotretinoin (low doses, i.e. 0.3 to 0.5 mg/kg) (Lacouture et al 2011) 
 
• 
Use of acitretin is not recommended 
 
9.44 
Severe rash (CTCAE Grade 4) 
 
• 
Immediately discontinue the patient from study drug and treat the patient with oral 
and topical medications (see recommendation CTCAE Grade 3). 
 
9.45 
Symptomatic treatment 
 
It is strongly recommended that patients who develop rash/skin toxicities receive 
symptomatic treatment 


59 
ACCRU-GI-1618 
 
• 
For pruritic lesions, use cool compresses and oral antihistaminic agents 
 
• 
For fissuring, use Monsel’s solution, silver nitrate, or zinc oxide cream. If not 
sufficient use mild steroid ointments or combinations of steroids and antibiotics 
such as Fucicort® 
 
• 
For desquamation, use emollients with mild pH 5/neutral (best containing urea 
10%) 
 
• 
For paronychia, antiseptic bath and local potent corticosteroids, use oral antibiotics 
and if no improvement is seen, refer to a dermatologist or surgeon 
 
• 
For infected lesions, obtain bacterial and fungal cultures and treat with topical or 
systemic antibiotics based on sensitivity of culture 
 
9.5 
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. 
 
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 4.03 will be 
utilized for AE reporting. All appropriate treatment areas should have access to a copy of the 
CTCAE version 4.03. A copy of the CTCAE version 4.03 can be downloaded from the CTEP web 
site: (
 
 
a. Adverse event monitoring and reporting is a routine part of every clinical trial. 


60 
ACCRU-GI-1618 
 
 
b. Identify the grade and severity of the event using the CTCAE version 4.03. 
 
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 10.5 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)/treatment. 
Probable - The adverse event is likely related to the agent(s)/treatment. 
Possible - The adverse event may be related to the agent(s)/treatment. 
Unlikely - The adverse event is doubtfully related to the agent(s)/treatment. 
Unrelated - The adverse event is clearly NOT related to the agent(s)treatment. 
 
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. 
 
10.31 Protocol-Specific Exceptions to Expedited Reporting 


61 
ACCRU-GI-1618 
 
10.311 The following hospitalizations are not considered to be SAEs because there is no 
“adverse event” (i.e., there is no untoward medical occurrence) associated with the 
hospitalization: 
 
• 
Hospitalizations for respite care 
• 
Hospitalization planned before informed consent (where the condition 
requiring the hospitalization has not changed post study drug administration) 
• 
Hospitalization for routine maintenance of a device (e.g., battery replacement) 
that was in place before study entry 
 
10.312 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. 
 
• 
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 should be reported as Grade  5 
“Neoplasms benign, malignant and unspecified (including 
cysts and polyps) – Other (Progressive Disease)” under the 
system organ class (SOC) of the same name. 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. 
 
10.313 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: 


62 
ACCRU-GI-1618 
 
o Leukemia secondary to oncology chemotherapy (e.g., AcuteMyeloctyic 
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. 
10.314 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. 
 
10.315 Pregnancy 
 
To ensure patient safety, pregnancies or lactation (both those of female patients 
and female partners of male patients) occurring while the patient is on study 
treatment must be reported to ACCRU within 24 hours of learning of its 
occurrence. The pregnancy should be followed up to determine outcome, including 
spontaneous or voluntary termination, details of the birth, and the presence or 
absence of any birth defects, congenital abnormalities, or maternal and/or newborn 
complications. 
 
Pregnancy should be recorded on the MedWatch Form 3500A and reported by the 
investigator to ACCRU. Pregnancy follow-up should be recorded on the same 
form and should include an assessment of the possible relationship to the study 
treatment any pregnancy outcome. Any SAE experienced during pregnancy must 
be reported on the MedWatch Form 3500A. 
 
If a pregnancy occurs while on study treatment, the newborn will be followed for 
at least 3 months following the expected delivery date. 
 
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. 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 MedWatch Form 3500A reports for “Pregnancy”, 
“Pregnancy loss”, or “Neonatal loss”, 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. 
 
10.4 
Expedited Reporting Requirements for Commercial Agent(s) – Palbociclib + Binimetinib or TAS-102 
 
Expedited Reporting Requirements for or Adverse Events that Occur within 28-30 Days of the 
Last Administration of a Commercial Agent 1,2 




64 
ACCRU-GI-1618 
 
4. The ACCRU SAE Coordinator will forward to 
 as appropriate. The 
ACCRU IND Coordinator will assist the sponsor-investigator in notifying the FDA if required. 
 
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. 


65 
ACCRU-GI-1618 
 
 
10.52 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 v4.03 grading. 
 
System Organ 
Class (SOC) 
Adverse event/Symptoms 
Baseline 
Each 
evaluation 
Blood and 
lymphatic 
symptom 
disorders 
Anemia 
Febrile neutropenia 
X 
X 
X 
X 
Eye disorders 
Blurred vision 
Flashing lights 
Floaters 
Retinal vascular disorder 
X 
X 
X 
X 
X 
X 
X 
X 
Investigations 
Ejection fraction decreased 
X 
X 
CPK increased 
X 
X 
Neutrophil count decreased 
X 
X 
Platelet count decreased 
White blood cell decreased 
X 
X 
X 
X 
Musculoskeletal 
and connective 
tissue disorders 
Arthralgia 
Myalgia 
X 
X 
X 
X 
Skin and 
subcutaneous 
tissue disorders 
Photosensitivity 
Rash acneiform 
Rash maculo-papular 
X 
X 
X 
X 
X 
X 
 
 
10.53 Case Report Forms - Academic and Community Cancer Research United (ACCRU) 
 
Submit via appropriate ACCRU Case Report Forms (i.e., paper or electronic as applicable) 
the following AEs experienced by a patient and not specified in Section 10.5: 
 
10.531 Grade 1 and 2 AEs deemed possibly, probably, or definitely related to the study 
treatment or procedure. 
 
10.532 Grade 3 and 4 AEs regardless of attribution to the study treatment or procedure. 
 
10.533 Grade 5 AEs (Deaths) 
 
10.5331Any death within 30 days of the patient’s last study treatment or procedure 
regardless of attribution to the study treatment or procedure. 
 
10.5332Any 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. 
 
10.54 
Follow-up for Toxicities 
 
Patients whose treatment is interrupted or permanently discontinued due to an adverse 


66 
ACCRU-GI-1618 
 
event or clinically significant laboratory value must be followed up at least once a week (or 
more frequently if required by institutional practices, or if clinically indicated) for 4 weeks, 
and subsequently at approximately 4-week intervals, until resolution or stabilization of the 
event, whichever comes first. Appropriate clinical experts should be consulted as deemed 
necessary. 
 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has been registered on the trial and until at least 30 days after the patient has 
stopped study treatment must be reported to ACCRU as per timeframe outlined in protocol 
sections 10.4 and 10.5. 
 
Any SAEs experienced after this 30-day period should only be reported to ACCRU if the 
investigator suspects a causal relationship to the study treatment. Recurrent episodes, 
complications, or progression of the initial SAE must be reported as follow-up to the 
original episode within 24 hours of the investigator receiving the follow-up information. 
An SAE occurring at a different time interval or otherwise considered completely unrelated 
to a previously reported one should be reported separately as a new event. 
 
Information about all SAEs is collected and recorded on the MedWatch 3500A Form; all 
applicable sections of the form must be completed in order to provide a clinically thorough 
report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the 
MedWatch 3500A Form, and send the completed form to ACCRU. 
 
Follow-up information is sent to the same contact(s) to whom the original SAE Report 
Form was sent, using a new MedWatch 3500A Form stating that this is a follow-up to the 
previously reported SAE and giving the date of the original report. Each re-occurrence, 
complication, or progression of the original event should be reported as a follow-up to that 
event regardless of when it occurs. 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. 
 
 
10.55 Late-Occurring Adverse Events 
 
Refer to the instructions in the Forms Packet (or electronic data entry screens, as 
applicable) regarding the submission of late occurring AEs following completion of the 
Active Monitoring Phase (i.e., compliance with Test Schedule in Section 4.0). 
 
10.56 Quarterly Report: Research Coordinating Center will provide Pfizer with accrual and 
a toxicity report on a quarterly 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. 


67 
ACCRU-GI-1618 
 
 
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) (26). Changes 
in the largest diameter (unidimensional measurement) of the tumor lesions and the short axis measurements 
in the case of lymph nodes are used in the RECIST guideline. 
 
11.1 
Schedule of Evaluations 
 
For the purposes of this study, patients should be reevaluated every 8 weeks while on study 
treatment, per schedule of events in Section 4.0. 
 
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 2.0 cm with chest x-ray, or 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. 
 
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. 
 
11.22 
Non-Measurable Disease 
 
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. 
 
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. 


68 
ACCRU-GI-1618 
 
• 
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. If CT scans 
have slice thickness >5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness. 
 
o 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. 
 
11.33 
Measurement at Follow-up Evaluation 
 
• 
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 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. 
 
• 
Cytologic and histologic techniques can be used to differentiate between PR and CR 
in rare cases (e.g., residual lesions in tumor types such as germ cell tumors, where 
known residual benign tumors can remain.) 
 
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 and 
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, there is 
no reason to perform additional studies beyond those specified in the protocol to 
discover new lesions. 


69 
ACCRU-GI-1618 
 
• 
Target lesions and target lymph nodes should be selected on the basis of their size, 
be representative of all involved sites of disease, and 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. 
 
• 
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 Section 11.43. 
 
11.43 
Response Criteria 
 
All target lesions and target lymph nodes followed by CT/MRI/PET-CT/Chest X- 
ray/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. 
 
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. 


70 
ACCRU-GI-1618 
 
 
• 
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. 
 
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. 
 
c. Normalization of tumor biomarkers (i.e. CEA) 
 
• 
Non-CR/Non-PD - Persistence of one or more non-target lesions or non- 
target lymph nodes and/or maintenance of tumor marker level above the 
normal limits. 
 
• 
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. 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 








74 
ACCRU-GI-1618 
 
14.0 
Body Fluid Biospecimens 
 
14.1 
Body Fluid Biospecimen Submission 
 
14.11 Summary Table of Body Fluid Biospecimens for This Protocol 
Type of 
biospecimen to 
submit 
Mandatory 
or optional 
When to submit 
Reason for submission 
(background/methodology 
section) 
Where to 
find specific 
details for 
specimen 
submission 
Blood/blood 
products 
(STRECK whole 
blood) 
Mandatory 
Refer to kit 
instructions 
Defined translational 
studies (Section 14.41) 
Section 
14.411 
Blood/blood 
products (no 
additive whole 
blood) 
Mandatory 
Refer to kit 
instructions 
Defined translational 
studies (Section 14.41) 
Section 
14.412 
Blood/blood 
products (SST 
whole blood) 
Mandatory 
Refer to kit 
instructions 
Defined translational 
studies (Section 14.41) 
Section 
14.411 
 
 
14.2 
Blood/Blood Products Handling 
 
14.21 
Kits are required for this study. 
 
14.211 
The kit contains supplies and instructions for collecting, processing, and 
shipping specimens. 
 
14.212 
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. 
 
14.213 
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. 
 
14.214 
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. 
 
14.22 
All samples must be collected Monday-Friday. 
 
14.23 
Label specimen tube(s) with protocol number, ACCRU patient ID number, and time and 
date blood was drawn. 
 
14.24 
Collect and process all blood/blood products according to specific kit instructions and table 
below. 


 
72 
ACCRU-GI-1618 
 
14.241 
Summary Table of Research Blood/Blood Products to Be Collected for This Protocol 
Applicable Arm 
Mandatory 
or Optional 
Collection tube 
description 
and/or additive 
Volume to 
collect per tube 
(number of 
tubes to be 
collected) 
Blood product 
being submitted 
Cycle 1 
Day 1 
(+/- 3 
days) 
Cycle 1 
Day 15 
(+/- 3 
days) 
Cycles 
2 
Day 1 
(+/- 3 
days) 
≤37 days 
after 
progression 
Additional 
processing 
required at 
site 
after 
blood draw? 
Storage 
/shipping 
conditions1 
▪ Safety Run-In 
▪ Arm A 
▪ Crossover 
Mandatory 
Streck 
10 ml (2) 
Whole blood for 
Platelet Poor 
Plasma 
X 
X 
X 
No 
Ambient/ 
room 
temperature 
▪ Safety Run-In 
▪ Arm A 
▪ Crossover 
Mandatory 
Na Heparin 
10 ml (1) 
Whole blood for 
Peripheral blood 
mononuclear 
cells 
X 
X 
X 
No 
Ambient 
▪ Safety Run-In 
▪ Arm A 
▪ Crossover 
Mandatory 
SST 
10 ml 
Serum for TK 
assay 
X 
X 
X 
X 
No 
Refrigerated 
/ cold pack 
 
1. After all samples have been processed according to kit instructions, ship all specimens according to shipping 
instructions (see Section 14.3 for detailed shipping instructions.) 
 
14.3 
Shipping 
 
14.31 Verify ALL sections of the Blood Specimen Submission Form (see Forms Packet), BAP Requisition Form (provided in kit) and 
specimen collection labels are completed and filled in correctly. 
 
14.32 Specimens must be shipped the same day they are drawn. 
 
14.33 
Ship SST tubes via Priority Overnight service refrigerated/on cold packs. 
 
Ship STRECK and Na Heparin tubes via Priority Overnight service ambient/room temperature. 
 
14.34 Ship specimens via Priority Overnight service, Monday – Friday, to BAP Receiving according to kit instructions. Do not send 
samples on weekends or just prior to federal holidays. 


73 
ACCRU-GI-1618 
 
 
 
14.35 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. 
 
Ship samples to: 
 
 
 
 
 
 
At study completion, samples will be shipped by BAP to The University of Texas MD 
Anderson Cancer Center: 
 
 
 
 
 
 
 
14.4 
Study Methodology and Storage Information 
 
14.41 Blood/blood product samples will be collected for the following research 
 
14.411 A portion of the plasma will initially be analyzed for the presence of circulating 
free tumor DNA using standard laboratory protocols. We will utilize digital PCR 
or ultra-deep sequencing technology to assay patient serum for circulating free 
tumor DNA, which can be assayed for mutations longitudinally. This analysis will 
be useful in determining whether resistant clones harboring mutations undergo 
expansion over the course of treatment, as detected by increasing allele frequency 
of mutations predicted to contribute to resistance. The analysis will take place at 
the laboratory of 
 located at The University of Texas MD 
Anderson Cancer Center. According to patient consent information (see Section 
6.14), remaining serum/plasma will be stored frozen at -70ºC at The University of 
Texas MD Anderson Cancer Center, 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. 
 
14.412 Peripheral blood mononuclear cells (PBMCs) will be analyzed to determine 
pharmacodynamic effects of palbociclib/binimetinib in PBMCs as a surrogate. 
PBMCs may also be analyzed for evaluation of immune response to therapy. The 
analysis will take place at the laboratory of 
 located at The 
University of Texas MD Anderson Cancer Center. According to patient consent 
information (see Section 6.14), remaining specimens will be stored frozen at -70ºC 
at The University of Texas MD Anderson Cancer Center, 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. 
 
14.5 
Return of Genetic Testing Research Results 
 
Because the results generated by the genetic testing included in this section are not currently 


74 
ACCRU-GI-1618 
 
 
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. 
 
15.0 
Drug Information 
 
 Refer to the package insert for complete, up-to-date information. 
 
 
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. 
 
Binimetinib oral suspension prepared from 15 mg binimetinib tablets should not be stored 
above 25°C and should not be refrigerated. The suspension should be used within 30 days 
after preparation. 
 
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. 
 
Binimetinib oral suspension is intended for oral administration as prepared. 
 
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%). 


75 
ACCRU-GI-1618 
 
 
 
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: Results of a human ADME study indicated 62% of the dose was eliminated in 
feces, and 31% was eliminated in the urine. The T1/2 range was 8.1-13.6 hours, median 8.66 
hours. 
 
Results from a hepatic impairment study indicate the exposure of binimetinib in mild 
hepatic impairment is similar compared to that of subjects with normal liver function; 
study results indicate exposures patients with moderate and severe hepatic impairment may 
be increased up to approximately 2-fold [Clinical Study CMEK162A2104]. 
 
Results from a renal impairment study indicate the exposure of binimetinib in subjects with 
severe renal impairment is 14-29% higher compared to that in healthy subjects [Clinical 
Study ARRAY-162-106]. 
 
15.16 
Potential Drug Interactions: 
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%) - anemia, chorioretinopathy, dry eye, macular edema, retinal 
detachment, retinal vein occlusion, retinopathy, serous retinal damage, blurred vision, 
reduced visual acuity, visual impairment, abdominal pain, constipation, dry mouth, 
dyspepsia, gastroesophageal reflux disease, stomatitis, mouth ulceration, asthenia, facial 
edema, generalized 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, 
upper gastrointestinal hemorrhage, general physical health deterioration, infection, skin 
infection, cellulitis, erysipelas, irregular heart rate, increased troponin I, hypoglycemia, 
musculoskeletal pain, myositis, rhabdomyolysis, dropped head syndrome, ageusia, renal 
failure, pneumonitis, pulmonary embolism, xeroderma, follicular rash, pruritic rash, deep 
vein thrombosis, hypertensive crisis, hypotension 


76 
ACCRU-GI-1618 
 
 
15.18 
Drug procurement 
 
Pfizer will supply commercial supply of binimetinib (Mektovi) to RxCossroads by 
McKesson Clinical Research Services. Each participating ACCRU treating location 
will order the drug from RxCrossroads by McKesson Clinical Research Services. 
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. 
 
15.181 Temperature excursions that occur at the site should be reported by the site to RxCrossroads by McKesson Clinical 
Research Services via email 
Any shipment deviations (those not occurring at 
the site) should be reported to RxCrossroads by McKesson Clinical Research Services via email to: 
 RxCrossroads by McKesson Clinical Research Services will report any 
temperature and shipment deviations (those not occurring at the site) to Pfizer via email to:  globalmedicalgrants@pfizer.com 
15.1811When reporting a temperature excursion to RxCrossroads by McKesson, please 
include the following information as required by Pfizer: 
• 
Study/protocol number 
• 
Name and contact information 
• 
Site location and address 
• 
Pfizer 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 a temperature deviation, the affected material should be 
physically quarantined by the site until a response is received from Pfizer 
regarding the disposition of the affected materials. 
 
15.19 
Nursing Guidelines 
 
15.191 
Instruct patient to take binimetinib twice daily approximately 12 hours apart. 
Agent may be taken with or without food. 
 
15.192 
MEK inhibitors can have significant cardiac side effects including cardiac 
failure, tachycardia, myocarditis, and decreased ejection fraction. Instruct 
patients to report any side effects concerning for heart failure (SOB, peripheral 
edema, chest, pain, etc) to the study team immediately. 
 
15.193 
Warn patient of eye disorders, which can be severe and lead to permanent loss of 
eyesight. Instruct patient to report any eye pain, dryness, itching, etc. to study 


77 
ACCRU-GI-1618 
 
 
team. Refer patient to ophthalmologist for treatment. 
 
15.194 
Binimetinib may cause gastrointestinal side effects (diarrhea, nausea, vomiting, 
GI bleeding, etc). Treat symptomatically and/or premedicate as necessary and 
monitor for effectiveness. 
 
15.195 
Monitor LFT’s. Patients have experienced acute hepatic failure. Instruct patients 
to report any acute and or worsening RUQ pain and/or any jaundice to study 
team immediately. 
 
15.196 
Patients may experience pruritus and/or rash. Rash is generally acneiform in 
nature. Manage symptomatically and monitor for effectiveness. 
 
15.197 
Patients may experience generalized edema, including the face and the limbs. 
Instruct patient to report any edema and rule out any allergic and/or cardiac 
component. 
 
15.198 
Monitor creatinine levels. 
 
15.199 a Patients may experience myositis or rarely rhabdomyolysis.. Patients should be 
instructed to report generalized muscle pain to the study team. 
 
15.199b Agent may cause pneumonitis. Instruct patients to report any cough, SOB, or 
chest pain to study team. 
 
15.199c Monitor any new skin lesions. Patients may develop secondary skin cancer or 
cysts. Refer to dermatology as necessary. 
 
15.199d Patients may experience palmar-plantar erythrodysaesthesia (hand-foot 
syndrome). Instruct patients to report any redness, pain, or skin changes of the 
hands or feet to the study team immediately. Encourage good hand and foot care 
and the use of moisturizers. 
 
15.2 
Palbociclib (Ibrance®, PD-0332991, NSC 772256) for Oral Administration 
 
Refer to the package insert for complete, up-to-date information. 
 
15.21 
Background 
 
Palbociclib, an orally active pyridopyrimidine, is a potent and highly selective reversible 
inhibitor of cyclin-dependent kinase (CDK) 4 and CDK6. The compound prevents cellular 
DNA synthesis by prohibiting progression of the cell cycle from G1 into the S phase, as 
demonstrated in laboratory models and early clinical trials. 
 
15.22 
Formulation 
 
125 mg tablets: Oval, light purple, film-coated tablets debossed with “Pfizer” on one side 
and “PBC 125” on the other side. 
100 mg tablets: Oval, green, film-coated tablets debossed with “Pfizer” on one side and 
“PBC 100” on the other side. 
75 mg tablets: Round, light purple, film-coated tablets debossed with “Pfizer” on one side 
and “PBC 75” on the other side. 
 
Capsule: PD-0332991-00 (free-base formulation) will be provided as the active ingredient 
with precedented excipients filled in hard gelatin capsules composed of gelatin and 
precedented colorants. Capsules contain 75 mg, 100 mg, or 125 mg equivalents of 
palbociclib free base. 


78 
ACCRU-GI-1618 
 
15.23 
Preparation and storage 
Store at 20C to 25 C (68F to 77F); excursions permitted between 15C to 30C (59F to 86F). Store 
in the original blister pack. 
 
Store capsules at controlled room temperature, 15-30°C, in their original containers. 
15.24 
Administration 
Caution: Capsules containing the free base formulation of palbociclib should be given once 
daily with food. Palbociclib capsules must not be opened and/or emptied into any vehicle 
for oral ingestion; capsules must be swallowed whole. 
 
Palbociclib tablet may be taken with or without food. Patients should be instructed to take 
the dose of palbociclib at approximately the same time each day. Palbociclib tablets should 
be swallowed whole (do not chew, crush, or split them prior to swallowing). 
 
15.25 
Pharmacokinetic information 
Absorption: Median Tmax values ranged between 4-12 hours after oral dosing 
Bioavailability: Mean absolute oral bioavailability 46% 
Distribution: Mean volume of distribution 2583 L 
Metabolism: Extensively hepatically metabolized. The major primary metabolic 
pathways are comprised of oxidation and sulfonation, with glucuronidation and 
acylation contributing as minor pathways. 
Half-life elimination: Mean T½ 28.8 hours 
Excretion: Median 17.5% recovered in urine, 74.1% recovered in feces 
 
15.26 
Potential Drug Interactions 
 
The effect of multiple dosing of palbociclib on the single dose PK of midazolam 
showed that palbociclib is a weak time-dependent inhibitor of CYP3A. 
 
Concomitant use of strong CYP3A inhibitors (e.g. boceprevir, clarithromycin, 
conivaptan, delavirdine, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, 
mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, 
telithromycin, voriconazole, and grapefruit or grapefruit juice) and inducers (e.g. 
carbamazepine, enzalutamide, felbamate, nevirapine, phenobarbital, phenytoin, 
primidone, rifabutin, rifampin, rifapentin, and St. John’s wort) should be avoided. 
 
Moderate CYP3A inducers (e.g. bosentan, efavirenz, etravirine, modafinil, and 
nafcillin) can be used concurrently with palbociclib if it cannot be avoided. 
 
15.27 
Known potential toxicities 
See the current version of the palbociclib Investigator’s Brochure for complete toxicity 
information. 
 
Very Common (≥ 10%): 
Infections, neutropenia, leukopenia, anemia, thrombocytopenia, decreased appetite, 
stomatitis, nausea, diarrhea, vomiting, rash, alopecia, fatigue, fever 
 
Common: (≥1% - 10%) 
Blurred vision, increased lacrimation, dry eyes, dysgeusia, epistaxis, dry skin, asthenia, 
pyrexia, increased ALT 
 
Interstitial lung disease (ILD)/non-infectious pneumonitis has been reported as a 
potential known adverse reaction. This toxicity has been identified during post- 
approval use of palbociclib. Because these reactions are reported voluntarily from a 
population of uncertain size, it is not always possible to reliably estimate their 
frequency or establish a causal relationship to drug exposure. 


79 
ACCRU-GI-1618 
 
 
 
 
 
 
15.28 
Drug procurement 
 
Pfizer will provide commercial formula of palbociclib to RxCrossroads by McKesson 
Clinical Research Services for investigational use in this study. The product will be 
labeled, “For Investigational Use.” Each participating ACCRU treating location will order 
the drug from RxCrossroads by McKesson Clinical Research Services. It will take 1- 
business days to receive the palbociclib. 
 
Fax 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 palbociclib and will use the appropriate 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. 
 
15.281 Temperature excursions that occur at the site should be reported by the site to 
RxCrossroads by McKesson Clinical Research Services via email to: 
 Any shipment deviations (those not 
occurring at the site) should be reported to RxCrossroads by McKesson Clinical 
Research Services via email to: 
 
RxCrossroads by McKesson Clinical Research Services will report any 
temperature and shipment deviations (those not occurring at the site) to Pfizer via 
email to: 
 
 
15.2811When reporting a temperature excursion to RxCrossroads by 
McKesson, please use the Pfizer Site Temperature Excursion Report 
Form found on the ACCRU web site. RxCrossroads by McKesson 
will report all temperature excursions to Pfizer. 
 
15.29 
Nursing Guidelines 
 
15.291 
Please refer to section 15.24 for administration guidelines. 
 
15.292 
Monitor CBC w/diff as cytopenias are common and require dose reductions. 
Instruct patients to report signs or symptoms of infection and/or any unusual 
bruising or bleeding to the study team. 
 
15.293 
GI symptoms are common, including nausea/vomiting, stomatitis and diarrhea. 
Treat symptomatically and monitor for effectiveness. Some side effects may 
require dose reductions. 
 
15.294 
Patients should avoid grapefruit and grapefruit juice, due to possible increase in 
the serum concentration of palbociclib. 
 
15.295 
There are drug to drug interactions with CYP3A4 substrates. Obtain a complete 
list of patient medications including OTC and herbal products. Instruct patients 
to report any new medications to the study team immediately. 


80 
ACCRU-GI-1618 
 
15.296 
Warn patient of risk of thromboembolic events, specifically pulmonary 


81 
ACCRU-GI-1618 
 
embolism. 
 
15.297 
Warn patients of possibility of alopecia. 
 
15.298 
Patients may experience upper respiratory infection. Instruct patients to report 
URI symptoms to study team. 
 
15.299 
Rarely patients may experience peripheral neuropathy. Monitor patients closely 
who may have preexisting CIPN from previous therapy. 
 
 
15.3 
Trifluridine (FTD)/Tipiracil (TPI) (TAS-102, Lonsurf®) 
 
Refer to the package insert for complete, up-to-date information. 
 
15.31 
Background 
 
FTD/TPI is an orally available combination drug of an antineoplastic thymidine-based 
nucleoside analogue, 1M trifluridine (FTD), and 0.5 M tipiracil hydrochloride (TPI). FTD 
is incorporated into deoxyribonucleic acid (DNA) of tumor cells following 
phosphorylation. TPI inhibits degradation of FTD by thymidine phosphorylase (TPase). 
 
15.32 
Formulation 
 
FTD/TPI contains trifluridine (FTD) and tipiracil (TPI as active ingredients with a molar 
ratio of 1:0.5. TAS-102 drug products are immediate-released film coated tablets, with two 
strengths of 15 mg and 20 mg (expressed as FTD). The inactive ingredients of the 
FTD/TPI 15 mg and 20 mg tablets are lactose monohydrate, pregelatinized starch, stearic 
acid, hypromellose, polyethylene glycol, titanium dioxide, red ferric oxide (only 20 mg 
tablet), and magnesium stearate. 
• 
FTD/TPI (TAS-102) tablet (15 mg) contains 15 mg trifluridine and 6.14 mg 
tipiracil as active ingredients. The appearance is white round tablet. 
• 
FTD/TPI (TAS-102) tablet (20 mg) contains 20 mg trifluridine and 8.19 mg 
tipiracil as active ingredients. The appearance is pale red round tablet. 
 
15.33 
Preparation and storage 
 
Store at 20°C to 25°C (68°F to 77°F); excursions are permitted from 15°C to 30°C (59°F to 
86°F). If stored outside of original bottle, discard after 30 days. 
 
15.34 
Administration 
 
Recommended to take within 1 hour after completion of the morning and evening meals. 
 
15.35 
Pharmacokinetic information 
 
Protein Binding: Trifluridine: >96% (primarily to albumin); Tipiracil: <8% 
Metabolism: Trifluridine and tipiracil are not metabolized by cytochrome P450 (CYP) 
enzymes. Trifluridine is mainly eliminated by metabolism via thymidine phosphorylase to 
form an inactive metabolite, 5-(trifluoromethyl) uracil (FTY) 
Half-life elimination: Trifluridine: 2.1 hours (at steady state); Tipiracil: 2.4 hours (at 
steady state) 
Time to peak, plasma: ~2 hours 
Excretion: Trifluridine: Urine (<2% [as unchanged drug]; ~19% [as inactive metabolite 
FTY]); Tipiracil: Urine (~29% [as unchanged drug] 


82 
ACCRU-GI-1618 
 
15.36 
Potential Drug Interactions 
 
Caution is required when using drugs that are human thymidine kinase substrates, e.g., 
zidovudine. Such drugs, if used concomitantly with FTD/TPI, may theoretically compete 
with the effector of FTD/TPI, i.e., FTD, for activation via thymidine kinases. Therefore, 
when using antiviral drugs that are human thymidine kinase substrates, monitor for 
possible decreased efficacy of the antiviral agent, and consider switching to an alternative 
antiviral agent that is not a human thymidine kinase substrate such as: lamivudine, 
zalcitabine, didanosine, abacavir, etc. 
 
15.37 
Known potential toxicities 
 
Very common known potential toxicities, ≥ 10%: 
Blood and lymphatic: Anemia, leukopenia, neutropenia, thrombocytopenia 
Gastrointestinal: Diarrhea, nausea, vomiting 
General: Fatigue 
Metabolism and nutrition: Decreased appetite 
 
Common known potential toxicities, ≥1% - <10%: 
Blood and lymphatic: Febrile neutropenia, lymphopenia, monocytosis 
Dermatologic: Alopecia, dry skin, Palmar-plantar erythrodysesthesia syndrome, pruritis, 
rash 
Gastrointestinal: Abdominal pain, constipation, oral disorder, stomatitis 
General: Malaise, mucosal inflammation, edema, pyrexia 
Hepatobiliary: Hyperbilirubinemia 
Infections: Lower respiratory tract infection, upper respiratory tract infection 
Investigations: Blood alkaline phosphatase increased, hepatic enzyme increased, weight 
decreased 
Metabolism and nutrition: Hypoalbuminemia 
Nervous System: Dizziness, dysgeusia, headache, peripheral neuropathy 
Psychiatric: Insomnia 
Renal and urinary: Proteinuria 
Respiratory: Cough, dyspnea 
Vascular: Flushing 
 
Uncommon known potential toxicities, <1% (Limited to important or life- 
threatening): 
Blood and lymphatic: Pancytopenia 
Gastrointestinal: Ascites, colitis, ileus, acute pancreatitis, subileus 
General: General physical health deterioration 
Infections: Bacterial infection, biliary tract infection, enteritis infection, urinary tract 
infection 
Investigations: Blood lactate dehydrogenase increased 
Metabolism and nutrition: Dehydration 
Respiratory: Pulmonary embolism 
 
15.38 
Drug procurement 
 
Each participating ACCRU treating location will be responsible for procuring the supply of 
TAS-102. 
 
15.39 
Nursing Guidelines: 
 
15.391 Instruct patients that agent should be taken within 1 hour after completion of 
morning and evening meal. 
 
15.392 Patients may experience fatigue. Instruct patients in energy conserving lifestyle. 


83 
ACCRU-GI-1618 
 
15.393 GI side effects are common, including nausea, decreased appetite, diarrhea, 
vomiting, and abdominal pain. 
 
15.394 Cytopenias are common. Monitor CBC w/diff and instruct patients to report any 
signs or symptoms of infection and/or unusual bruising or bleeding to the study 
team. 
 
15.395 Rarely Pulmonary embolism has been reported with this agent. Instruct patient to 
report any shortness of breath or chest pain to study team and/or seek out 
emergency medical attention. 
 
15.396 Although uncommon, warn patients of the possibility of alopecia. 
 
16.0 
Statistical Considerations and Methodology 
 
16.1 
Study Overview / Rationale 
 
This randomized Phase II trial is designed to primarily compare the progression-free survival (PFS) 
between patients randomized to palbociclib/binimetinib and those randomized to TAS-102 in 
patients with refractory KRAS or NRAS mutant metastatic colorectal cancer. We will also conduct 
a safety run-in, which consists of a thorough review of adverse event data within the initial 6-12 
patients enrolled on the experimental arm (palbo+bini) before randomization. (details see Section 
16.62). Other endpoints of interest that will be evaluated are adverse events, overall survival, and 
overall response rate. 
 
16.2 
Statistical Design 
 
16.21 
Primary Endpoint 
 
The primary endpoint for this study will compare PFS between palbociclib/binimetinib vs. 
TAS-102 in patients with refractory KRAS or NRAS mutant metastatic CRC. PFS is defined 
as the time from randomization date to either disease progression or death from any cause, 
whichever occurs first. Patients who are still alive and progression-free at the time of 
analysis will be censored at the time of their last disease assessment. Disease progression 
will be determined based on RECIST 1.1 and will be documented at each enrolling site 
with no central review planned. 
 
16.211 Analysis Plan 
 
PFS will be compared between treatment arms using the stratified log rank test at 
one-sided level 0.05. The stratification factors listed in Section 5.1 will be used for 
the analysis. The HR for PFS will be estimated using a stratified Cox proportional 
hazards model and the 95% CI for the HR will be provided. Results from an 
unstratified analysis will also be provided. Kaplan-Meier methodology will be 
used to estimate the median PFS for each treatment arm, and Kaplan-Meier curves 
will be produced. 
 
16.22 
Decision Rule 
 
The primary goal is to compare PFS between those randomized to palbociclib/binimetinib 
and those randomized to TAS-102. The alternative hypothesis is that the combination of 
palbociclib and binimetinib has improvement in PFS compared to TAS-102. 
 
16.221 Interim Analysis Decision Rule 
 
One interim analysis for futility will be conducted when 37 events have occurred. 
PFS will be used as the endpoint for interim analysis. The interim futility boundary 
was selected using EAST v6.4 software. The trial will continue accrual while 


84 
ACCRU-GI-1618 
 
 
interim analysis is being conducted. To reject the alternative hypothesis at the 
interim (i.e. reject palbociclib/binimetinib as effective), the HR will need to be ≥ 
1.043 for palbociclib/binimetinib compared to TAS-102, which corresponds to a 1- 
sided p-value of 0.551 or larger. Otherwise, if the HR is < 1.043 (1-sided p-value 
<0.551), the study will continue to full accrual, and the final analysis will be 
conducted as discussed below. 
 
16.222 Final Analysis Decision Rule 
 
The primary efficacy analysis will be conducted when at least 73 patients across 
both arms combined have provided documentation of either disease progression or 
death without progression of disease, which will take place approximately 3 
months after last patient enrollment. To reject the alternative hypothesis at the final 
analysis (i.e. reject palbociclib/binimetinib as effective), the HR will need to be ≥ 
0.68 for palbociclib/binimetinib compared to TAS-102, which corresponds to a 1- 
sided p-value of 0.05 or larger. Otherwise, if the HR is < 0.68 (1-sided p-value < 
0.05), the palbociclib/binimetinib treatment will be considered effective. All 
eligible patients who sign the consent form, are randomized, and receive any 
protocol treatment will be considered evaluable for this endpoint. 
 
16.23 
Power and Significance Level 
 
If we enter 45 evaluable patients to each arm of the study using a 1:1 randomization 
scheme (90 evaluable patients in total), then with a total of 73 observed events, we have 
90% power to detect an improvement in the median PFS from 2 to 4 months (hazard ratio 
(HR) = 0.5), assuming a 1-sided significance level of 0.05 and an accrual rate of 8 patients 
per month. The trial has a single interim analysis for futility, adopting Rho family (Rho = 
3) beta spending function, for controlling the overall type II error rate. 
 
The operating characteristics of current design are tabulated below. Probabilities reported 
in the table are calculated based on simulation study with 50,000 replicates. 
 
Scenario 
Median PFS 
in TAS-102 
(months) 
Median PFS in 
Palbo/ 
Binimetinib 
(month) 
Hazard 
Ratio (HR) 
Probability of declaring 
that Palbo/ Binimetinib 
warrants further studies 
is… 
Probability of 
stopping at the 
interim analysis 
due to futility is… 
1 
2 
1.5 
1.333 
0.0021 
0.7686 
2 
2 
2 
1 
0.0506 
0.4478 
3 
2 
2.5 
0.8 
0.2426 
0.2152 
4 
2 
3 
0.667 
0.5229 
0.0909 
5 
2 
3.5 
0.571 
0.7588 
0.0368 
6 
2 
4 
0.5 
0.8982 
0.0143 
 
16.24 
Secondary Endpoints 
 
16.241 Overall Response Rate 
 
Assessment of response data will be performed on the basis of definitions of 
responses according to RECIST v1.1. For patients that elect to crossover, only 
responses that occur prior to crossover will be considered for this endpoint. 
Objective response is defined as a complete or partial response by RECIST v1.1. 
Subjects with missing or no response assessments will be classified as non- 
responders. This will be reported as a proportion with a 95% confidence interval 
for the true proportion. 


85 
ACCRU-GI-1618 
 
 
 
 
16.242 Overall Survival 
 
Overall survival is defined as the time from first dose of study treatment to death 
from any cause. Patients who are still alive at the time of analysis will be censored 
at the time of their last study assessment (if still actively on study) or at last known 
date alive (if on survival follow-up). Due to the crossover component of this trial, 
all analyses relating to OS will be descriptive in nature. No formal statistical tests 
will be performed. We will use Kaplan-Meier methods to evaluate time to event 
endpoints, and will report median OS and its 95% confidence interval. 
 
16.243 Adverse Events 
 
Adverse events (AEs) will be described by grade for Grade 1 and above with and 
without attribution considered. 
 
All eligible patients that have initiated treatment will be considered evaluable for 
assessing adverse event rate(s). For patients that elect to crossover, only AEs that 
occur prior to crossover will be considered for this endpoint. AEs after crossover 
will be described independently. The maximum grade for each type of adverse 
event will be recorded for each patient, and described using frequency tables. The 
adverse events will be compared by arm to determine any differences. 
Additionally, the relationship of the adverse event(s) to the study treatment will be 
taken into consideration. 
 
16.25 
Exploratory analyses of correlative studies 
 
As correlative studies will be performed as an exploratory analysis, we do not have formal 
statistical power testing. Analyses that are planned for correlative studies are described in 
Section 17.3. 
 
16.3 
Sample Size 
 
The study design to be utilized is fully described in Section 16.2 and includes a planned interim 
analysis. There will be 45 evaluable patients randomized to each arm of this study (total of 90 
patients). We anticipate accruing an additional 5 patients in each arm (10 total) to account for 
ineligibilities, cancellations, major violations, or other reasons. Including 6-12 patients for early 
adverse event assessment in the experimental arm, thus the maximum accrual is 112 patients in 
total. 
 
16.4 
Accrual Time and Study Duration 
 
We conservatively estimated the accrual rate at about 8 patients per month, as enrollment of 
KRAS/NRAS mutant refractory metastatic CRC on clinical trials at each site is at least 1-2 per 
month. We make the same assumption for the accrual rate for the current study. Therefore, 
following the safety run-in we anticipate that the study will take approximately 14 months to 
accrue. Assuming an accrual period of 11.25 months, we anticipate that the study will take just 
over a year to complete. 
 
16.5 
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 processes; however, they will be 


86 
ACCRU-GI-1618 
 
 
included in final point estimates, confidence intervals, and secondary endpoints. 
 
16.6 
Adverse Events Stopping Rule 
 
16.61 Data Safety Monitoring Board 
 
This study will be monitored by the Mayo Clinic Data Safety Monitoring Board (DSMB). 
Reports containing patient characteristics, toxicity and administrative information will be 
provided to the DSMB every six months, with the first report due at the first reporting 
period after study initiation. 
 
16.62 Early Adverse Assessment in Experimental Arm (Safety Run-In) 
 
To ensure safety before randomization, the first 6 patients entered onto this study will be 
only enrolled in the experimental arm. This phase of early adverse event assessment will be 
open throughout ACCRU. For this phase of the study, patients will be deemed evaluable 
for toxicity assessment if they initiate any protocol treatment. As mentioned previously in 
Section 7.12, a patient may only be replaced if the patient withdraws from the study for 
any reason other than study drug toxicity or adverse event prior to completing one cycle. 
For evaluation of the toxicity rule, we will consider AE data for all evaluable patients in 
the first cycle. When the last of these 6 patients is enrolled, accrual will be halted. When 
the last of these 6 patients becomes evaluable for toxicity (started protocol treatment and 
either: 1, completed one cycle of AE assessments or 2. went off treatment prior to one 
cycle), the data from these first 6 patients will be reviewed. If there are 0-1 excessive 
toxicities (as defined in Section 7.15) among the first 6 patients, we will consider start to 
randomize patients to both Arms A and B. If there are 2 or more excessive toxicities 
among the first 6 patients, we will pursue dose de-escalation as described in Section 7.11. 
We acknowledge that the final decision to open randomization will rest in the clinical 
judgment of the investigative team and that mitigating factors may impact the decision- 
making process. 
 
Patients in Arm A enrolled before randomization for early toxicity assessment (Safety 
Run-In Cohort) 
 
i. 
will not be used to evaluate the efficacy stopping rule or used in any decision 
making processes; 
ii. will not be included in the primary and secondary efficacy comparison; will be 
included in the descriptive analysis of adverse events and analyses in translational 
study. 
 
16.63 Adverse Events Stopping Rule 
 
The monitoring rule specified below is based on the knowledge available at the time of 
study development. We note that the Adverse Event Monitoring Rule may be adjusted in 
the event of either (1) the study re-opening to accrual after any temporary suspension 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 also 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 at least possibly related to study treatment (i.e., an adverse event with attribute 
specified as “possible,” “probable,” or “definite”) that satisfy any of the following criteria 
for each arm separately: 


87 
ACCRU-GI-1618 
 
 
 
• 
If at any time 3 of the initial 10 treated patients or ≥30% of all patients on the 
experimental arm (i.e., when accrual is greater than 10 patients) have experienced 
at least one grade 4 adverse event at least possibly related to protocol treatment at 
any point during treatment, excluding lymphocytopenia, uncomplicated 
neutropenia <7 days, and uncomplicated leukopenia <7 days. 
• 
If at any time 2 patients on the experimental arm have experienced a grade 5 
adverse event at least possibly related to protocol treatment (not due to progressive 
disease). 
 
NOTE: For evaluation of the AE Stopping Rule above, we will only consider patients that 
are included in the randomized portion of the trial. 
 
17.0 
Pathology Considerations/Tissue Biospecimens 
 
17.1 
Tissue Biospecimen Submission 
 
NOTE: Patients must have consented to submission of the tissue(s) listed in the following table. 
 
17.11 Summary Table of Tissue Biospecimens for This Protocol 
 
Section 
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 
17.111 
Archival tissue: 
Formalin-fixed 
paraffin-embedded 
(FFPE) tissue blocks 
with corresponding 
H&E from surgical 
resection or biopsy 
(primary or 
metastatic; in cases 
where both 
available primary 
preferred) (OR at 
least 10 unstained 
slides with 
corresponding H&E) 
Mandatory 
≤60 days after 
registration/ 
randomization
, shipped prior 
to C1d1 
Correlative studies 
(Section 17.31) 
Section 17.2 
 
17.2 
Archival Paraffin Embedded Tissue Blocks/Slides 
 
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 and/or recurrent surgery or biopsy. 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 11 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 


88 
ACCRU-GI-1618 
 
 
slides will be processed as described in 17.51. For samples containing less than 7 square 
millimeters of tumor tissue, multiple sections should be mounted onto each slide to ensure 
that the appropriate amount of tumor tissue is available. 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. Do not place sticky labels on the slides. 
 
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 10 unstained 
slides with corresponding H&E(s)). 
• 
Specimen Submission: Tissue form 
• 
Surgical Pathology Report 
• 
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. 
 
17.25 Tissue specimens must be shipped ≤ 60 days after registration/randomization and 
shipped before Cycle 1, Day 1. 
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: 
 
 
 
 
 
 
 
17.28 If a corresponding H&E wasn’t submitted with the block/slides, the ACCRU Operations 
Office will request a slide to be processed (i.e., cut and H&E stained) from the tumor tissue 
block at the IHC core facility at Mayo Clinic Rochester. 
 
17.3 
Study Methodology and Storage Information 
Submitted tissue samples will be analyzed as follows: 
17.31 
Archival formalin-fixed paraffin-embedded tissue will be collected for the following 
research: 
 
17.311 We will perform whole-exome or hotspot sequencing for a panel of relevant 
oncogenes and tumor suppressors to assay for mutations. This data will be utilized 
to determine whether specific mutations in KRAS or NRAS predict differential 
response to combination palbociclib/binimetinib. In addition, we will investigate 
whether alterations in the PI3K/AKT/MTOR pathway predict for differential 


89 
ACCRU-GI-1618 
 
 
responses to combination palbociclib/binimetinib. 
 
17.312 We will perform gene expression profiling to determine gene expression subtypes 
via the Consensus Molecular Subtypes (CMS subtypes). Distinct CMS subtypes 
are associated with distinct clinicopathologic characteristics, differential prognosis, 
and activation of distinct signaling pathways.[21] We will investigate whether 
CMS subtypes are associated with efficacy of therapy withpalbociclib/binimetinib. 
 
17.313 We will perform immunohistochemistry to confirm staining with retinoblastoma 
protein is present at baseline. Additional immunohistochemical stains may be 
considered as well. 
 
17.314 ACCRU will batch ship blocks/slides to The University of Texas MD Anderson 
Cancer Center at the end of the study. 
 
17.32 
At the completion of the study, any unused/remaining material will be stored at the The 
University of Texas MD Anderson Cancer Center for future research according to the 
patient consent permission (see Section 6.15). 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. 
 
17.33 
The institutional pathologist will be notified by the Pathology Coordinator if the block may 
be depleted. 
 
17.34 
Blocks requested to accommodate individual patient management will be returned 
promptly upon request. 
 
17.35 
Return of Genetic Testing Research Results: No genetic specimens will be collected from 
tissue biospecimens for this study. If future genetic testing is being requested for stored 
tissue, patient reconsent is required. 
 
18.0 
Records and Data Collection Procedures 
 
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 
 
Initial Material(s) 
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
Institutional Contacts 
 2 weeks after registration 
On-Study Form 
On-Study: Prior Surgery 
On-Study: Prior Radiation 
On-Study: Prior Systemic Therapy 
Adverse Events: Baseline 


90 
ACCRU-GI-1618 
 
 
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
RECIST Measurements: Baseline 
Supporting Documentation: Baseline 
Laboratory Tests and Results: Baseline 
Specimen Submission: Tissue (Baseline)2 
Patient Status: Baseline 
OP and Path Reports (see Section 17.0)3 
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 and observation) 
1. Submit only if applicable. 
2. After registration/randomization, but prior to C1D1. 
3. Attach an electronic copy in RAVE on the Supporting Documentation Form. This is in addition to 
the pathology material requirements for tissue submission (Section 17.0). 
 
 
Test Schedule Material(s) 
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
At each evaluation 
during treatment 
At end of 
treatment 
Observation 
Treatment (Intervention) Form 
X1 
X 
Treatment (Intervention):Dose 
modifications, Omissions, and Delays2 
X 
X 
Adverse Events: Solicited 
X 
X 
Adverse Events: Other2 
X 
X 
RECIST Measurements 
X 
X 
X 
RECIST Measurements: Crossover 
(Baseline)3 
X 
RECIST Measurements: Crossover3 
X 
X 
X 
Supporting Documentation2 
X 
X1 
Specimen Submission: Blood 
X 
X 
Laboratory Tests and Results 
X 
X 
X 
Patient Status: Treatment (Intervention) 
X 
X 
Off Treatment 
X 
End of Initial Treatment3 
X 
Patient Status: Clinical Follow- 
up/Observation 
X 
Adverse Event: Late2 
X 
Notice of New Primary2 
X 
X 
X 
Consent Withdrawal2 
X 
X 
X 
Consent Withdrawal: Specimen Only2 
X 
X 
X 


91 
ACCRU-GI-1618 
 
 
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
At each evaluation 
during treatment 
At end of 
treatment 
Observation 
Consent Withdrawal: Clinical Follow- 
Up Only2 
X 
X 
X 
Consent Withdrawal: All Follow-Up2 
X 
X 
X 
ACCRU Deviation Form2 
X 
X 
X 
 
1. Attach a copy of documentation of response or progression in RAVE on the Supporting 
Documentation form if disease is evaluated. NOTE: All reports must be de-identified, and labeled 
with study number, ACCRU patient ID number, and initials. 
2. Submit only if applicable. 
3. For optional crossover only 
 
Follow-up Material(s) 
CRF 
Event Monitoring Phase/Survival Follow-Up1,4 
q. 6 
months 
until PD2 
At 
PD2 
After 
PD q. 
6 mos. 
Death 
At Each Event 
Occurrence 
Patient Status: Survival and 
Disease Status Follow- 
up/Event Monitoring 
X 
X 
X 
X 
Supporting Documentation2 
X 
Adverse Events: Late3 
X 
X 
Consent Withdrawal (choose 
appropriate form)3 
• 
Consent 
Withdrawal: 
Specimen Only 
• 
Consent 
Withdrawal: Clinical 
Follow-Up Only 
• 
Consent 
Withdrawal: All 
Follow-up 
X 
X 
ACCRU Deviation Form3 
X 
Notice of New Primary3 
X 
1. 
Patients are followed in Event Monitoring for a maximum of 3 years from registration. 
2. 
Attach a copy in RAVE for documentation of progression on the Supporting 
Documentation Form. 
3. 
Submit only if applicable. 
4. 
Event monitoring evaluations may occur via telephone 
 
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 


92 
ACCRU-GI-1618 
 
 
well as any additional invoiceables that may be allowed. 
 
19.2 
Tests to be research funded: 
 
• 
Mandatory archival tumor tissue submission 
• 
Mandatory blood sample 
 
19.3 
Other budget concerns: 
 
 
19.31 
Pfizer will provide palbociclib and binimetinib free of charge to patients while they are 
participating in this study. 


93 
ACCRU-GI-1618 
 
 
20.0 
References 
 
1. 
Howlader, N., et al. SEER Cancer Statistics Review, 1975-2011. 2014 based on November 2013 SEER data 
submission, posted to the SEER web site, April 2014. [cited 2014; Available from: 
http://seer.cancer.gov/csr/1975 2011/. 
2. 
Kopetz, S., et al., Improved survival in metastatic colorectal cancer is associated with adoption of hepatic 
resection and improved chemotherapy. J Clin Oncol, 2009. 27(22): p. 3677-83. 
3. 
Chong, C.R. and P.A. Janne, The quest to overcome resistance to EGFR-targeted therapies in cancer. Nat 
Med, 2013. 19(11): p. 1389-400. 
4. 
Pylayeva-Gupta, Y., E. Grabocka, and D. Bar-Sagi, RAS oncogenes: weaving a tumorigenic web. Nat Rev 
Cancer, 2011. 11(11): p. 761-74. 
5. 
The Cancer Genome Atlas Network, Comprehensive molecular characterization of human colon and rectal 
cancer. Nature, 2012. 487(7407): p. 330-7. 
6. 
Janakiraman, M., et al., Genomic and biological characterization of exon 4 KRAS mutations in human 
cancer. Cancer Res, 2010. 70(14): p. 5901-11. 
7. 
Messersmith, W.A., et al., Clinical activity of the oral MEK1/MEK2 inhibitor GSK1120212 in pancreatic 
and colorectal cancer. J Clin Oncol, 2011. 29(s4): p. suppl; abstr 246. 
8. 
Migliardi, G., et al., Inhibition of MEK and PI3K/mTOR suppresses tumor growth but does not cause tumor 
regression in patient-derived xenografts of RAS-mutant colorectal carcinomas. Clin Cancer Res, 2012. 
18(9): p. 2515-25. 
9. 
Yamamoto, H., et al., Paradoxical increase in retinoblastoma protein in colorectal carcinomas may protect 
cells from apoptosis. Clin Cancer Res, 1999. 5(7): p. 1805-15. 
10. 
Collins, M.J., et al., Loss of Rb cooperates with Ras to drive oncogenic growth in mammalian cells. Curr 
Biol, 2012. 22(19): p. 1765-73. 
11. 
Guan, R.J., et al., Association of K-ras mutations with p16 methylation in human colon cancer. 
Gastroenterology, 1999. 116(5): p. 1063-71. 
12. 
Esteller, M., et al., K-ras and p16 aberrations confer poor prognosis in human colorectal cancer. J Clin 
Oncol, 2001. 19(2): p. 299-304. 
13. 
Halilovic, E., et al., PIK3CA mutation uncouples tumor growth and cyclin D1 regulation from MEK/ERK 
and mutant KRAS signaling. Cancer Res, 2010. 70(17): p. 6804-14. 
14. 
Kwong, L.N., et al., Oncogenic NRAS signaling differentially regulates survival and proliferation in 
melanoma. Nat Med, 2012. 18(10): p. 1503-10. 
15. 
Lee, M.S., et al., Efficacy of the combination of MEK and CDK4/6 inhibitors in vitro and in vivo in KRAS 
mutant colorectal cancer models. Oncotarget, 2016. 
16. 
Ziemke, E.K., et al., Sensitivity of KRAS Mutant Colorectal Cancers to Combination Therapy that Co- 
Targets MEK and CDK4/6. Clin Cancer Res, 2015. 
17. 
Mayer, R.J., et al., Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med, 
2015. 372(20): p. 1909-19. 
18. 
Van Cutsem, E., et al., The subgroups of the phase III RECOURSE trial of trifluridine/tipiracil (TAS-102) 
versus placebo with best supportive care in patients with metastatic colorectal cancer. Eur J Cancer, 2018. 
90: p. 63-72. 
19. 
Basch, E., et al., Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J 
Clin Oncol, 2011. 29(31): p. 4189-98. 
20. 
Roila, F., et al., Guideline update for MASCC and ESMO in the prevention of chemotherapy- and 
radiotherapy-induced nausea and vomiting: results of the Perugia consensus conference. Ann Oncol, 2010. 
21 Suppl 5: p. v232-43. 
21. 
Guinney, J., et al., The consensus molecular subtypes of colorectal cancer. Nat Med, 2015. 21(11): p. 1350- 
6. 




ACCRU-GI-1618 
Appendix II 
Page 1 of 4 
 
 
Appendix II: Patient Medication Diary: Binimetinib and Palbociclib 
 
Patient Initials:  
 
Patient Study ID:  
 
 
MEDICATION DIARY 
 
Patient Instructions 
 
• 
Please use an ink pen when completing the Medication Diary as these will be retained in our research record. To correct an error or 
mistake, please make a single line through that entry and write your initials and date next to the error or mistake. 
• 
Please record each dose as soon as you take it and fill in the date as directed. 
• 
Please indicate on the calendar below every day that you take your study medication by placing the time the dose was 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. 
• 
Please bring your Medication Diary and all bottles and any unused study medication with you to every appointment. 
• 
Please contact your physician and study coordinator any time you go into the hospital. Your physician can advise if you should stop 
taking your medication or continue it. 
• 
Binimetinib is taken twice daily with water, approximately 12 hours apart. 
• 
Binimetinib can be taken with our without food 
• 
Palbociclib is taken once daily with food. 
• 
Your study team should enter your dose of each drug in the table below. 
 
 
Medication 
Dose 
Binimetinib A.M. 
MG 
Binimetinib P.M. 
MG 
Palbociclib 
MG 
 
Study Drug 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Date: 
Binimetinib A.M. 
Binimetinib P.M. 
Palbociclib 








ACCRU-GI-1618 
Appendix 
IIIV Page 1 
 
Appendix III: Study Contraception Guidelines 
 
Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, 
must agree to use highly effective methods of contraception throughout the study and for 12 weeks after 
study drug discontinuation. 
 
Highly effective contraception methods include: 
 
• 
Total abstinence when this is in line with the preferred and usual lifestyle of the patient. Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are 
NOT acceptable methods of contraception 
• 
Double barrier methods 
o Condom with spermicide in conjunction with use of an intrauterine device 
o Condom with spermicide in conjunction with use of a diaphragm 
• 
Birth control patch or vaginal ring 
• 
Oral, injectable, or implanted contraceptives 
• 
Surgical sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or 
tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, 
only when the reproductive status of the woman has been confirmed by follow up levels of 
luteinizing hormone (LH), follicle-stimulating hormone (FSH), and/or estradiol. 
• 
Male sterilization (at least 6 months prior to registration). For female patients on the study, the 
vasectomized male partner should be the sole partner for that patient 
 
NOTE: Women are considered post-menopausal and not of child bearing potential if they have had 12 
months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, 
history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without 
hysterectomy) or tubal ligation ≥42 days of registration. In the case of oophorectomy alone, only when 
the reproductive status of the woman has been confirmed by follow-up hormone level assessment is she 
considered not of child bearing potential. 
 
Sexually active males must use highly effective methods of contraception throughout the study and for 12 
weeks after study drug discontinuation and should not father a child in this period. 
 
Highly effective contraception methods include: 
 
• 
Total abstinence when this is in line with the preferred and usual lifestyle of the patient. Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are 
NOT acceptable methods of contraception 
• 
Double barrier methods 
o Condom with spermicide in conjunction with use of an intrauterine device 
o Condom with spermicide in conjunction with use of a diaphragm 
• 
Surgical sterilization (vasectomy) at least 6 weeks prior to registration 


ACCRU-GI-1618 
Appendix 
IVV Page 
 
Appendix IV: Patient Lifestyle Guidelines 
 
Patients should not embark on a new, strenuous exercise regimen after first dose of study treatment. 
 
NOTE: Muscular activities, such as strenuous exercise, that can result in significant increases in plasma 
CPK levels should be avoided while on binimetinib treatment. 


 
 
 
 
Appendix V: Snellen Equivalence visual acuity conversion chart 
ACCRU-GI-1618 
Appendix V 
Page 1 of 1 
Visual Acuity Conversion Chart* 
Distance 
LogMAR Acuity Chart 
Near 
Snellen 
Feet 
20/ 
Equivalent 
Meter 
6/ 
Decimal 
Line 
Number 
LogMAR† 
Spatial 
Frequency 
(cyc/deg) 
% Central 
Visual 
Efficiency 
Jaeger 
Standard
Inches 
(14/) 
Centimeters 
(35/) 
Revised 
American 
Point-Type 
“M” 
Notation 
10 
3.0 
2.00 
-3 
-0.30 
60.00 
100 
— 
7.0 
17.5 
— 
0.20 
12.5 
3.8 
1.60 
-2 
-0.20 
48.00 
100 
— 
8.8 
21.9 
— 
0.25 
16 
4.8 
1.25 
-1 
-0.10 
37.50 
100 
— 
11.2 
28.0 
— 
0.32 
20 
6.0 
1.00 
0 
0.00 
30.00 
100 
1 
14.0 
35.0 
3 
0.40 
25 
7.5 
0.80 
1 
0.10 
24.00 
95 
2 
17.5 
43.8 
4 
0.50 
30 
9.0 
0.67 
— 
0.18 
20.00 
91 
3 
21.0 
52.5 
5 
0.60 
32 
9.6 
0.63 
2 
0.20 
18.75 
90 
4 
22.4 
56.0 
6 
0.64 
40 
12.0 
0.50 
3 
0.30 
15.00 
85 
5 
28.0 
70.0 
7 
0.80 
50 
15.0 
0.40 
4 
0.40 
12.00 
75 
6 
35.0 
87.5 
8 
1.0 
60 
18.0 
0.33 
— 
0.48 
10.00 
67 
7 
42.0 
105.0 
9 
1.2 
63 
18.9 
0.32 
5 
0.50 
9.52 
65 
8 
44.1 
110.3 
10 
1.3 
70 
21.0 
0.29 
— 
0.54 
8.57 
63 
— 
49.0 
122.5 
— 
1.4 
80 
24.0 
0.25 
6 
0.60 
7.50 
60 
9 
56.0 
140.0 
11 
1.6 
100 
30.0 
0.20 
7 
0.70 
6.00 
50 
10 
70.0 
175.0 
12 
2.0 
114 
34.2 
0.18 
— 
0.76 
5.26 
44 
11 
79.8 
199.5 
13 
2.3 
125 
37.5 
0.16 
8 
0.80 
4.80 
40 
12 
87.5 
218.8 
14 
2.5 
150 
45.0 
0.13 
— 
0.88 
4.00 
32 
— 
105.0 
262.5 
— 
3.0 
160 
48.0 
0.13 
9 
0.90 
3.75 
30 
13 
112.0 
280.0 
21 
3.2 
200 
60.0 
0.10 
10 
1.00 
3.00 
20 
14 
140.0 
350.0 
23 
4.0 
*Courtesy Jack Holladay, MD, modified from full Holladay table. For full table, visit 
www.journalofrefractivesurgery.com 
†Log minimum angle of resolution; bold values are standard logMAR progression. 
Note: 20/2000 is equivalent to count fingers @ 2 feet; 20/20000 is equivalent to hand motion @ 2 feet 
Resources 
1. Sloan LL. New test charts for the measurement of visual acuity. Am J Ophthalmol. 1959;48:808-813. 
2. Report of Working Group 39, Committee of Vision, National Academy of Sciences. Recommended standard 
procedures for the clinical measurement and specification of visual acuity. Adv Ophthalmol. 1980;41:103- 
143. 
3. Keeney AH. Durerson HL Jr. Collated near-vision test card. Am J Ophthalmol. 1958;46:592-594. 
4. Keeney AH. Ocular Examination: Basis and Techniques. 2nd ed. St Louis, MO: CV Mosby Co; 1976. 
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Revised Visual Acuity Abbreviations* 
UDVA 
uncorrected distance visualacuity 
UIVA 
uncorrected intermediate visualacuity 
UNVA 
uncorrected near visual acuity 
CDVA 
corrected distance visualacuity 
CIVA 
corrected intermediate visualacuity 
CNVA 
corrected near visual acuity 
DCNVA 
distance-corrected near visualacuity 
*Kohnen T. New abbreviations for visual acuity values (editorial). 
J Cataract Refract Surg. 2009;35:1145.