MATCH Treatment Subprotocol U: VS-6063 (Defactinib) in Patients With Tumors With NF2 Loss
Phase: PHASE2
Conditions: Advanced Lymphoma, Advanced Malignant Solid Neoplasm, Hematopoietic and Lymphoid Cell Neoplasm, Refractory Lymphoma, Refractory Malignant Solid Neoplasm, Refractory Multiple Myeloma
Sponsor: National Cancer Institute (NCI)

i
28 State Street, Suite 1100, Boston, MA 02109
p: 857.504.2900
f:617. 589.0914
ecog-acrin.org
July 10, 2019
Martha Kruhm, MS RAC
Head, Protocol and Information Office
Quality Assurance Section
CTEP, DCT, NCI
6130 Executive Blvd, EPN Room 7000
Bethesda, MD   20892
Dear Ms. Kruhm:
Enclosed is Addendum #21 to EAY131-U, VS-6063 (defactinib) in Patients with Tumors with 
NF2 Loss.
Please replace your current copy of the protocol and Informed Consent document (if ICD 
changed) with this (these) updated version(s).  We recommend that each institution maintain a 
file containing the original protocol, Informed Consent, and all subsequent revisions/versions.
IRB Review Requirements:
This addendum has been reviewed and approved by the Central IRB which is the sole 
IRB of record for this study.
Implementation of this addendum must occur on the activation date. Sites are not 
permitted to conduct the study utilizing outdated versions of any MATCH protocol documents 
after the activation date of this addendum.]
This addendum is in response to Dr. Charles Kunos June 19, 2019 Request for Amendment for
Defactinib. 
The following revisions to EAY131-U protocol have been made in this addendum:
Section
Change
1.
Cover Page
Updated Version date.
2.
3.3
Updated the VS-6063 (defactinib hydrochloride) CAEPR list with version 
2.3, April 5, 2019.
The following revisions to EAY131-U Informed Consent Document have been made in this 
addendum:
Section
Change
1.
Page 1
Updated Version Date.
2.
What possible risks 
can I expect from 
taking part in this 
study?
Updated the VS-6063 (defactinib hydrochloride) possible risks risk list 
with version 2.3 April 5, 2019.

ii
If you have any questions regarding this addendum, please contact aagu@ecog-acrin.org or
857-504-2900.
We request review and approval of this addendum to EAY131-U so ECOG-ACRIN may activate 
it promptly.  
Thank you.
Sincerely,
Pamela Cogliano
Senior Director of Protocol Development
Enclosure
CC:
David M. Jackman, MD
Marjorie G. Zauderer, MD
Alice Chen, MD
Keith Thomas Flaherty, MD
Lyndsay N. Harris. MD
Peter O’Dwyer, MD
Mickey Williams, PhD
James V. Tricoli, PhD
Stanley Hamilton, MD
Lisa McShane, PhD 
Larry Rubinstein, PhD
Robert Gray, PhD
Shuli Li, PhD
Lalitha Shankar, MD
Susanna Lee, MD, PhD
Constantine Gastonis, PhD
Paolo Caimi, MD
Shaji Kumar, MD
Carlos Arteaga, MD
Edith Mitchell, MD
John J. Wright, MD, PhD
Bruce Giantonio, MD
Donna Marinucci
Kerry Higgins
Gayle Ipock
Jean MacDonald
Carol Chami, R.N.
Juanita Andrews
Melinda Flood
Kelly Redmond
Becky Fillingham
Kevin Pollard
Abuchi Agu
Elanna Radomyshelsky
Camilla Abreu 
Michael T. Balco
Lauren Lambert
Cayden Maican
Margaret Cavenagh
Ben Kim
Alexandra Sachs

EAY131-U
1
Molecular Analysis for Therapy Choice (MATCH)
MATCH Treatment Subprotocol U: VS-6063 (defactinib)
in Patients with Tumors with NF2 Loss
VS-6063 (DEFACTINIB) TREATMENT 
SUBPROTOCOL CHAIR:
David Jackman, MD
VS-6063 (DEFACTINIB) TREATMENT 
SUBPROTOCOL CO-CHAIR:
Marjorie Zauderer, MD
Version Date: July 10, 2019
NCI Update Date: August 12, 2015
NOTE: This subprotocol (EAY131-U) should 
be used in conjunction with the
MATCH Master Protocol (EAY131)
SUBPROTOCOL ACTIVATION DATE
August 12, 2015 (incorporated in Addendum #1)
Update #2 – 8/15
Addendum #2 – 2/16
Addendum #3 – 5/16
Addendum #4 – 7/16
Addendum #5 – 12/16
Addendum #7 – 3/17
Addendum #11 – 8/17
Addendum #21
Agent
IND#
NSC#
Supply
VS-6063 (defactinib)
IND Sponsor: DCTD, NCI IND#: 
781450
NCI Supplied

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NCI Update Date: August 12, 2015
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Table of Contents
Molecular Analysis for Therapy Choice (MATCH) ...................................................... i 
MATCH Treatment Subprotocol U: VS-6063 (defactinib) in Patients with Tumors 
with NF2 Loss ...................................................................................................... 1 
Table of Contents ...................................................................................................... 2 
Schema ...................................................................................................................... 4 
1. Introduction ........................................................................................................ 5 
1.1 
The Potential Role of FAK Inhibition in Human Cancers ........................... 5 
1.2 
VS-6063 (defactinib) .................................................................................. 6 
1.3 
Non-Clinical Data ....................................................................................... 6 
1.4 
Previous Human Experience ..................................................................... 9 
2. Selection of Patients ......................................................................................... 12 
2.1 
Eligibility Criteria ..................................................................................... 12 
3. VS-6063 (defactinib) Treatment Plan ............................................................... 14 
3.1 
Administration Schedule ......................................................................... 14 
3.2 
Adverse Event Reporting Requirements ................................................. 14 
3.3 
Comprehensive Adverse Events and Potential Risks List (CAEPR) for VS-
6063 (defactinib hydrochloride, NSC 781450) ........................................ 17 
3.4 
Dose Modifications ................................................................................. 19 
3.5 
Supportive Care ....................................................................................... 21 
3.6 
Duration of Agent-specific treatment ..................................................... 21 
3.7 
Duration of Follow-Up ............................................................................. 21 
4. Study Parameters .............................................................................................. 22 
4.1 
Therapeutic Parameters for VS-6063 (defactinib) Treatment ................ 22 
5. Drug Formulation and Procurement ................................................................. 24 
5.1 
VS-6063 (defactinib hydrochloride) (NSC #781450) ............................... 25 
6. Translational Studies ......................................................................................... 27 
7. References ........................................................................................................ 27 
Appendix I  Patient Pill Calendar ............................................................................. 28 
Appendix II   Information on Possible Drug Interactions ........................................ 30 
Appendix III  Actionable Mutations for Sub-Protocol EAY131-U ............................ 32 
Appendix IV  CYP3A4 Inducers and Inhibitors ......................................................... 33 
 

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TREATMENT SUBPROTOCOL CHAIR
David M. Jackman, MD
Dana-Farber Cancer Institute
450 Brookline Ave.
Boston, MA 02215
Phone: 617-632-3468
Fax: 617-632-5786
Email: David Jackman@dfci.harvard.edu
TREATMENT SUBPROTOCOL CO-CHAIR 
Marjorie G. Zauderer, MD
Memorial Sloan-Kettering Cancer Center
1275 York Ave
New York, NY 10065
Phone: 646-888-4656
Fax:646-888-4261
Email: zauderem@mskcc.org

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Schema
Long-Term Follow-Up
VS-6063 (defactinib) 400 mg BID
Until progression or unacceptable 
toxicity
Cycle = 28 days
Accrual Goal: 35

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1.
Introduction
1.1
The Potential Role of FAK Inhibition in Human Cancers
High expression of the cytoplasmic protein tyrosine kinase focal adhesion kinase 
(FAK) has been frequently demonstrated to be associated with invasive and 
metastatic malignancies, implicating FAK in malignant progression of multiple 
epithelial tumors.1 FAK localizes to focal adhesions and mediates physical 
attachment of cells to the extracellular matrix (ECM), integrating signals from 
growth factor receptors and integrins. FAK is known to promote tumor cell 
survival and resistance to anoikis (induction of apoptosis upon loss of contact 
with the ECM), via the ADRB2/Src signaling pathway. The ability to survive 
without ECM contact is a hallmark of metastatic cells, allowing them to leave the 
parent tumor and migrate to and colonize distant tissues. This ability is also 
characteristic of cancer stem cells (CSC) and suggests that FAK modulation may 
be a new therapeutic target in cancer.
In some malignancies, the neurofibromatosis type 2 gene (NF2) may be mutated 
or otherwise inactivated. NF2 is a tumor suppressor gene that encodes the 
protein Merlin (moesin-exrin-radixin-like protein).  Bi-allelic inactivation of NF2
through mutation and/or deletion is known to occur in several malignancies, 
including mesothelioma, vestibular Schwannomas, and meningiomas, resulting in 
inactive Merlin. Merlin has been demonstrated to play a role in regulation of the 
FAK pathway. Increased activation of FAK has been demonstrated in NF2-
mutated Merlin-negative mesothelioma cells, resulting in increased cell motility, 
spreading, and invasiveness. Restoration of Merlin expression in these cells both 
attenuated FAK phosphorylation and decreased invasiveness,2 indicating that 
FAK may be an important therapeutic target for diseases in which NF2 mutations 
occur.
NF2 mutations have been demonstrated in several tumor types as well as cell 
lines, as shown in the figure below from cBioPortal:

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1.2
VS-6063 (defactinib)
VS-6063 (also known as defactinib, and previously known as PF-04554878) is a 
small molecule, orally available potent adenosine-5'-triphosphate (ATP)-
competitive, reversible inhibitor of FAK and proline-rich tyrosine kinase-2 (Pyk2), 
each with half maximal inhibitory concentration (IC50) < 0.6 nM.
VS-6063 (defactinib) is formulated as a white to off-white oval tablet for oral 
administration and supplied in single unit dose strength of 200 mg. In addition to 
VS-6063 (defactinib), formulation components include microcrystalline cellulose, 
lactose monohydrate, sodium starch glycolate, and magnesium stearate.
More information is available in the investigator’s brochure for VS-6063.
1.3
Non-Clinical Data
1.3.1
Primary Pharmacology
To determine the in vitro activity of VS-6063 against mesothelioma 
cell lines and to test whether low Merlin expression correlates with 
sensitivity to VS-6063 (defactinib), the mesothelioma tumor 
microenvironment was modeled using 3-dimentional culture. 
Mesothelioma cell lines were initially characterized by Western blot 
analysis for Merlin expression. MSTO-211H, H226 and MM692 cell 
lines had high levels of Merlin expression, while MM129 and MM690 
had no detectable Merlin expression. The Merlin status of the cell 
lines was found to correlate with sensitivity to VS-6063 (defactinib),
with a dramatic bifurcation between the Merlin-negative and Merlin-
positive cell lines. Mutant NF2 MPM cells were found to be especially 
sensitive to the FAK inhibitor VS-6063 (defactinib) with EC50 values 

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below 800 nM, in contrast to wild-type NF2 MPM cell lines which were 
less sensitive with EC50 values above 3 μM. Ectopic expression of a 
non-phosphorylatable artificial mutant of NF2 (NF2-S518A) in NF2-
mutant MPM cells abolished the enhanced sensitivity to FAK 
inhibitors. The reactivation of the FAK pathway with the introduction of 
a non-phosphorylatable form of NF2 that is resistant to FAK inhibition 
further supports the potential importance of this pathway and its 
targeted inhibition.
In addition to its antiproliferative activity against mesothelioma cell 
lines, VS-6063 (defactinib) may have an effect on cancer stem cells 
(CSCs). Using multiple cancer stem cell assays, both in vitro and in
vivo, Verastem has observed that FAK inhibitors, including VS-6063
(defactinib), effectively kill CSCs. CSCs are a subset of tumor cells 
that are both resistant to standard therapies and capable of seeding 
new tumors, resulting in tumor recurrence and metastasis. This 
increase in CSCs following standard-of-care treatment is thought to 
limit the ability of standard cancer drugs to confer durable clinical 
responses for patients. This hypothesis is supported by in vitro 
experiments with human mesothelioma cell lines, which show that 
chemotherapeutic agents such as pemetrexed and cisplatin enrich for 
cells testing positive to the Aldefluor assay (a marker of cancer stem 
cells). FAK inhibitors, including VS-6063 (defactinib), effectively 
reduced the proportion of Aldefluor-positive cells, suggesting that 
targeting FAK might reduce the CSC population and reverse the 
resistance that develops to standard chemotherapy.
In light of these data, inhibition of FAK by compounds like VS-6063
(defactinib), may represent an important therapeutic approach in
appropriate patients. Moreover, given the preferential sensitivity of 
Merlin-low cell lines to VS-6063 (defactinib), it is additionally 
hypothesized that VS-6063 (defactinib) may be especially beneficial in 
those subjects whose tumors have reduced or absent Merlin 
expression.
1.3.3
Summary of Pharmacokinetics, Metabolism, and Pharmacodynamics
VS-6063 (defactinib) is a potent and selective ATP-competitive, 
reversible inhibitor of recombinant human FAK and Pyk2 in 
biochemical and cell-based assays. A comprehensive evaluation of 

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selectivity against a large panel of other kinases in enzyme assays 
demonstrated that VS-6063 (defactinib) is highly selective for FAK 
and Pyk2, strongly suggesting that its predominant pharmacologic 
activity is mediated by inhibition of FAK and Pyk2.
VS-6063 (defactinib) demonstrated antitumor efficacy in multiple 
human tumor xenograft models in nude mice including mesothelioma, 
glioma, ovarian, colon, and pancreatic carcinoma models. In these 
studies, oral administration of VS-6063 (defactinib) was demonstrated 
to result in significant growth inhibition or regression of established 
tumors at well-tolerated dose levels. In addition, studies investigating 
the dose- and time-dependent inhibition of FAK activity following oral 
administration of VS-6063 (defactinib) provided insight towards the 
relationship of inhibition of FAK to antitumor efficacy and the 
PK/pharmacodynamic relationship for this compound. The 
PK/pharmacodynamic relationship and subsequent target Ceff was 
determined by measuring VS-6063 (defactinib) in plasma samples 
isolated from the same individual mice in which target inhibition data 
was generated.

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1.4
Previous Human Experience
The safety and tolerability of VS-6063 (defactinib) have been tested in a first-in-
human Phase I study in subjects with solid tumors. A total of 46 subjects 
received oral doses of VS-6063 (defactinib) ranging from 12.5 to 750 mg BID, 36 
subjects in a fasted state and 10 in a fed state. Overall VS-6063 (defactinib) was 
safe and well tolerated. Exposure did not increase significantly above 425 mg 
BID; therefore the maximum tolerated dose (MTD) was not established. On the 
basis of both the Phase I data and the nonclinical pharmacodynamic studies, the 
recommended Phase 2 dose has been established as 400 mg BID.
1.4.1
Potential Risk
Evidence from in vitro and in vivo toxicological assessments of VS-
6063 (defactinib) and from the Phase I first-in-human (FIH) study 
suggests VS-6063 (defactinib) has a safety profile supportive of its 
development as an anticancer therapeutic.
In the Phase I FIH study, VS-6063 (defactinib) was safe and well 
tolerated. The most frequently reported adverse events (AEs) were 
from the system organ classes (SOCs) of GI disorder and nervous 
system disorder. A total of 10 subjects experienced 15 serious AEs 
(SAEs) during this study. All 15 SAEs were considered not related to 
the study drug.
Dose-limiting toxicities (DLTs) were observed in 5 subjects; 
hyperbilirubinemia was considered a DLT for 2 subjects in the fasting 
cohort (300 mg BID [n=1] and 425 mg BID [n=1]) and 1 subject in the 
fed cohort (425 mg BID]). Other DLTs observed were headache in the 
200 mg BID fasting cohort [n=1] and fatigue in the 425 mg BID fed 
cohort [n=1].
The most frequently reported treatment-emergent AEs (TEAEs) in the 
Phase I FIH study were nausea (19 of 46 [41.3%] subjects) followed 
by fatigue (18 of 46 [39.1%] subjects), vomiting (15 of 46 [32.6%] 
subjects), and hyperbilirubinemia (15 of 46 [32.6%] subjects). Most 
AEs were grade 1 or 2 in severity and resolved without sequelae.
1.4.2
Other Potential Risks
1.4.2.1
Hyperbilirubinemia
Includes data up to 28 days after last dose of study drug 
Highest grade reported for each subject. Overall, 15 
subjects (32.6%) reported hyperbilirubinemia. In all these 
cases, aspartate aminotransferase (AST) and alanine 
aminotransferase (ALT) were within normal limits. This 
unconjugated hyperbilirubinemia was generally 
asymptomatic and reversible with dosing holiday or 
continued treatment.

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1.4.2.2
Blood Pressure
A total of 9 (19.6%) subjects had a maximum increase 
from Baseline ≥ 30 mmHg in supine systolic blood 
pressure (BP), and 9 (19.6%) subjects had a maximum 
increase from Baseline ≥ 30 mmHg in standing systolic BP. 
A total of 8 (17.4%) subjects had maximum increase from 
Baseline ≥ 20 mmHg in supine diastolic BP, and 5 (10.9%) 
subjects had maximum increase from Baseline ≥ 20 mmHg 
in standing diastolic BP.
1.4.2.3
Phototoxicity
VS-6063 (defactinib) exhibits an absorbance peak in the 
range of UV-A/UV-B light, specifically at 290 nm. Clinical 
studies of other drugs that modulate mitogen-activated 
protein kinase pathway components have exhibited skin 
phototoxicity.
Beyond dermatological monitoring, potential risks of direct 
phototoxicities induced by VS-6063 (defactinib) will be 
further minimized by advising that subjects minimize sun 
exposure, use broad-spectrum sunscreens, and wear 
sunglasses. Subjects will be informed that relevant sun 
exposure may occur even through glass, such as while 
driving.
1.4.2.4
Reproductive
On the basis of extrapolations from nonclinical toxicities, 
potential manifestations in humans may also include 
impaired fertility. The effect of VS-6063 (defactinib) on a 
developing fetus is unknown. Therefore, men and women 
of childbearing potential will be required to agree to use 
adequate contraception (double barrier birth control or
abstain from all sexual activity) for the duration of study 
therapy and for 3 months after the last dose of VS-6063
(defactinib).
1.4.3
Clinical Efficacy
In the Phase I FIH study in subjects with solid tumors, best response 
of SD was achieved in 16 of 46 (34.8%) subjects. These responses 
appeared to be related to dose since SD was not achieved any of the 
9 subjects (0/9) who received doses of < 100 mg BID (12.5, 25, and 
50 mg in the 9 subjects BID). However, 16 of 37 (43%) subjects who 
received doses of ≥ 100 mg BID experienced SD as their best 
response to treatment.
1.4.4
Summary of Clinical Pharmacokinetics
In the previously conducted Phase I clinical study, maximum serum 
VS-6063 (defactinib) concentrations were generally achieved 1 to 2 
hours post-dose following single (Day 1) or multiple-dose 
administration (Day 15) under fasted and fed conditions. Peak and 

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total exposure (Cmax and AUC) generally increased with increasing 
dose across the entire dose range (12.5 to 750 mg) following a single 
dose on Day 1, and up to 425 mg BID on Day 15. With multiple-
dosing exposure was found to be less than proportional with dose 
above 425 mg BID. Consequently, dose escalation in the fasting 
cohort was stopped at the 750 mg BID dose and the MTD was not 
attained. After a single 425 mg dose (recommended phase 2 dose) 
the Cmax and AUC were determined to be 552.6 ng/mL and 3314 
ng.hr/mL, respectively. Terminal t1⁄2 following a single dose averaged 
about 9 hours across all treatment groups.
The measured mean free plasma concentration that corresponded to 
the plasma median effective concentration (EC50) for inhibition of 
FAK phosphorylation was used as Ceff for human dose projection. 
Based on this PK/PD modeling, the total blood Ceff of VS-6063
(defactinib) which will cause 50% inhibition of FAK phosphorylation 
was estimated at a concentration of 160 ng/mL total (95% CI 93.2 to 
228 ng/mL) in mice. Taking into account differences in blood to 
plasma partitioning with VS-6063 (defactinib), the human plasma 
efficacious free concentration (Ceff or Css,ave) is 13.3 ng/mL or 26 
nM to produce 50% inhibition of FAK phosphorylation. Based on 
estimates from the Phase 1 PK data, the concentration of free and 
total drug at the end of a 12 hour dosing interval were 25 ng/mL (50 
nM) and 250 ng/mL, respectively, for fasted patients at 400 mg BID 
(the dose used in this study).
Administration of VS-6063 (defactinib) with food at 300 and 425 mg 
BID delayed time of Cmax (Tmax) to about 4 hours but did not change 
exposure significantly.

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2.
Selection of Patients
Each of the criteria in the checklist that follows must be met, along with the eligibility in 
the main screening study, in order for a patient to be considered eligible for this study. 
Use the checklist to confirm a patient’s eligibility. For each patient, this checklist must be 
photocopied, completed and maintained in the patient’s chart. 
In calculating days of tests and measurements, the day a test or measurement is 
done is considered Day 0. Therefore, if a test is done on a Monday, the Monday 
four weeks later would be considered Day 28. 
ECOG-ACRIN Patient No. ____________________________
Patient’s Initials (L, F, M) _______________________
Physician Signature and Date ___________________
NOTE:
CTEP Policy does not allow for the issuance of waivers to any protocol 
specified criteria 
(http://ctep.cancer.gov/protocolDevelopment/policies deviations.htm).
Therefore, all eligibility criteria listed in Section 2 must be met, without 
exception. The registration of individuals who do not meet all criteria listed in 
Section 2 can result in the participant being censored from the analysis of the 
study, and the citation of a major protocol violation during an audit. All 
questions regarding clarification of eligibility criteria must be directed to the 
Group's Executive Officer (EA.Execofficer@jimmy.harvard.edu) or the 
Group's Regulatory Officer (EA.RegOfficer@jimmy.harvard.edu).
NOTE:
Institutions may use the eligibility checklist as source documentation if it has 
been reviewed, signed, and dated prior to registration/randomization by the 
treating physician.
NOTE:
All patients must have signed the relevant treatment consent form
2.1
Eligibility Criteria
2.1.1
Patients must fulfill all eligibility criteria outlined in Section 3.1 of 
MATCH screening protocol (excluding Section 3.1.6) at the time of 
registration to treatment step (Step 1, 3, 5, 7).
2.1.2
Patients must have a tumor that harbors an inactivating mutation in 
NF2. See Appendix III of this sub-protocol for a list of the NF2
mutations and corresponding Levels of Evidence.
2.1.3
Patients must have an electrocardiogram (ECG) within 8 weeks prior 
to treatment assignment and must have no clinically important 
abnormalities in rhythm, conduction or morphology of resting ECG 
(e.g. complete left bundle branch block, third degree heart block).
Date of ECG:  _______________
2.1.4
Patients with known left ventricular dysfunction must have ECHO or a 
nuclear study (MUGA or First Pass) within 4 weeks prior to 
registration to treatment and must not have left ventricular ejection 
fraction (LVEF) < institutional lower limit of normal (LLN). If the LLN is 
Rev.2/16
Rev.2/16

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not defined at a site, the LVEF must be > 50% for the patient to be 
eligible.
Date of ECHO/Nuclear Study:  _______________
NOTE:
Pre-treatment LVEF determination in patients without 
known left ventricular dysfuction is NOT otherwise 
required.
2.1.5
Patients must not have known hypersensitivity to VS-6063 (defactinib)
or compounds of similar chemical or biologic composition.
2.1.6
Patients must not have a history of upper GI bleeding, ulceration, or 
perforation within 12 months prior to the first dose of study drug.
2.1.7
Patients must not have known history of Gilbert's Syndrome.
2.1.8
Patient must not have a known history of stroke or cerebrovascular 
accident within 6 months prior to the first dose of VS-6063
(defactinib).
2.1.9
Patients with history of hypertension should be adequately controlled 
(BP < 140/90) with appropriate anti-hypertensive therapy or diet.
2.1.10
Patients must not have prior treatment with a FAK inhibitor (eg. VS-
6063 (defactinib) or GSK2256098) and must not be participating or 
have participated in the COMMAND trial of maintenance therapy of 
VS-6063 (defactinib) vs. placebo, for mesothelioma.
2.1.11
Patients must not be using drugs or foods that are known potent 
CYP3A4 or CYP2C9 inhibitors or inducers (See Appendix II and
Appendix IV of this subprotocol). Substrates of CYP 3A4, 2C9, 
UGT1A1, P-gp, OATP1B1, and OATP1B3 should be used with 
caution.
Physician Signature
Date
OPTIONAL:
This signature line is provided for use by institutions wishing to 
use the eligibility checklist as source documentation.
Rev.2/16
Rev. 5/16

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3.
VS-6063 (defactinib) Treatment Plan
3.1
Administration Schedule
In this study, the dosing regimen for VS-6063 (defactinib) is 400 mg BID. Take 
VS-6063 immediately following a meal with a full glass of water (approximately 8 
ounces). VS-6063 (defactinib) will be administered in continuous 28 day cycles. 
The dosing regimen is based on the findings of the Phase I FIH study and 
supporting nonclinical data.
Patients will undergo restaging scans following the completion of every 2 cycles.   
See Section 3.6 regarding the duration of therapy and procedures for 
discontinuing treatment.
3.2
Adverse Event Reporting Requirements
The Adverse Event Reporting Requirements for all EAY131 subprotocols are 
outlined in the MATCH MASTER protocol.  Please refer to those guidelines when 
determining if an event qualifies as a Serious Adverse Event (SAE) and requires 
expedited reporting via CTEP’s Adverse Event Reporting System (CTEP-AERS). 
In addition, the following section outlines agent specific requirements and must 
be followed to ensure all reporting requirements are met.
3.2.1
Additional instructions, requirements and exceptions for protocol 
EAY131-U
Additional Instructions
For instructions on how to specifically report events that result in 
persistent or significant disability/incapacity, congenital anomaly, or 
birth defect events via CTEP-AERS, please contact the AEMD Help 
Desk at aemd@tech-res.com or 301-897-7497.  This will need to be 
discussed on a case-by-case basis.
EAY131-U specific expedited reporting requirements:
x
Pregnancies:  Pregnancies and suspected pregnancies 
(including a positive or inconclusive pregnancy test, regardless of 
age or disease state) occurring while the subject is on VS-6063
(defactinib), or within 28 days of the subject’s last dose of VS-
6063 (defactinib), are considered immediately reportable events. 
The pregnancy, suspected pregnancy, or positive/ inconclusive 
pregnancy test must be reported via CTEP-AERS within 24 hours 
of the Investigator’s knowledge.  Please refer to Appendix VIII in
the MATCH Master protocol for detailed instructions on how to 
report the occurrence of a pregnancy as well as the outcome of 
all pregnancies.
Rev. 5/16

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

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submitted for the most recent trial. ECOG-ACRIN must be 
provided with a copy of the form and the associated 
pathology report and cytogenetics report (if available) even 
if ECOG-ACRIN was not the patient's most recent trial.
NOTE:
Once data regarding survival and remission status are no 
longer required by the protocol, no follow-up data should 
be submitted via CTEP-AERS or by the Second Primary 
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1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail.
Adverse events reported on VS-6063 (defactinib hydrochloride) trials, but for which there 
is insufficient evidence to suggest that there was a reasonable possibility that VS-6063
(defactinib hydrochloride) caused the adverse event:
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Anemia
CARDIAC DISORDERS - Heart failure
EAR AND LABYRINTH DISORDERS - Ear pain
EYE DISORDERS - Blurred vision; Watering eyes
GASTROINTESTINAL DISORDERS - Abdominal distension; Dry mouth; Dyspepsia; 
Esophageal ulcer; Esophagitis; Flatulence; Gastroesophageal reflux disease; Mucositis oral
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Fever; Malaise; 
Non-cardiac chest pain
IMMUNE SYSTEM DISORDERS - Allergic reaction
INFECTIONS AND INFESTATIONS - Catheter related infection; Lung infection; Upper 
respiratory infection
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising; Fracture; Injury, 
poisoning and procedural complications - Other (laceration of scalp); Injury, poisoning and 
procedural complications - Other (limb injury)
INVESTIGATIONS - Alanine aminotransferase increased; Alkaline phosphatase increased; 
Electrocardiogram QT corrected interval prolonged; Neutrophil count decreased; Platelet count 
decreased
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hyperglycemia; 
Hypomagnesemia; Hyponatremia; Metabolism and nutrition disorders - Other (hypouricemia)
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Back pain; Chest 
wall pain; Myalgia; Pain in extremity
NERVOUS SYSTEM DISORDERS - Intracranial hemorrhage; Lethargy; Peripheral sensory 
neuropathy; Stroke; Syncope
PSYCHIATRIC DISORDERS - Confusion; Psychiatric disorders - Other (mental status changes)
RENAL AND URINARY DISORDERS - Acute kidney injury; Hematuria; Proteinuria
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Epistaxis; 
Pharyngolaryngeal pain; Respiratory failure
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Photosensitivity; 
Pruritus; Rash maculo-papular
VASCULAR DISORDERS - Flushing; Hypertension; Hypotension; Thromboembolic event
NOTE:
VS-6063 (defactinib hydrochloride) in combination with other agents could cause an 
exacerbation of any adverse event currently known to be caused by the other agent, 
or the combination may result in events never previously associated with either 
agent.

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3.4
Dose Modifications 
All toxicity grades below are described using the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0.
All appropriate treatment areas should have access to a copy of the CTCAE 
version 4.0. A copy of the CTCAE version 4.0 can be downloaded from the 
CTEP website (http://ctep.cancer.gov).
3.4.1
Dose Delays and Dose Modifications:
AEs assessed by the Investigator as exclusively related to underlying 
disease or medical condition or concomitant treatment will not be 
taken into consideration for treatment interruption and dose reduction. 
If treatment must be delayed for reasons other than toxicity, contact 
the Subprotocol Study Chair to discuss the reasons for delay and 
plans for resuming study therapy.
Treatment may be delayed up to 14 days (2 weeks) for toxicity 
resolution. If toxicity does not resolve to eligible levels after 2 weeks, 
the patient will be taken off study for unacceptable toxicity.
Subjects who experience a toxicity requiring reduction in dose level 
may continue treatment at the lower dose level until disease 
progression or unacceptable toxicity. Once the dose has been 
reduced it may not be re-escalated.
The table below details dosing delays and dose modifications for VS-
6063 (defactinib).
Toxicity Criteria
Dose Modification
Persistent grade 2 
nonhematological 
toxicities lasting > 7 
days (excluding 
alopecia, nausea, 
vomiting, or diarrhea)
Withhold study drug up to 2 weeks until toxicity decreases to ≤ grade 1 or returns 
to Baseline and resume dosing at current dose.
If on resumption of treatment, toxicity returns to ≥ grade 2, withhold treatment up 
to 2 weeks until toxicity decreases to ≤ grade 1 or returns to Baseline and 
decrease subsequent dose to 200 mg (1 tablet) BID.
If toxicity returns to ≥ grade 2 at reduced dose, permanently discontinue study 
drug.
Grade 3 and 4 non-
hematological events 
(except alopecia, 
nausea, vomiting, or 
diarrhea not already 
maximally medically 
managed)
Withhold study drug up to two weeks until toxicity decreases to ≤ grade 1 or 
returns to Baseline and resume dosing at current dose.
If on resumption of treatment, toxicity returns to ≥ grade 3, withhold treatment up 
to 2 weeks until toxicity decreases to ≤ grade 1 or returns to Baseline and 
decrease dose to 200 mg (1 tablet) BID.
If toxicity returns to ≥ grade 3 at reduced dose, permanently discontinue study 
drug.
Hematological toxicities have not been previously reported with VS-6063 (defactinib). The 
recommendations below are provided as guidance in the event of treatment-related hematological 
changes.
Grade 3 or 4 
neutropenia
Withhold study drug up to 2 weeks until ANC > 1.5x109 cells/L and fever 
resolved. Reduce dose to 200 mg (1 tablet) BID. If recurs at the reduced dose, 
permanently discontinue the study drug.
Grade 3 or 4 
thrombocytopenia
Withhold study drug up to 2 weeks until platelets > 100x109 cells/L. Reduce dose 
to 200 mg (1 tablet) BID.
If toxicity returns to ≥ grade 3 at reduced dose, permanently discontinue study 
drug. 
NOTE: See additional instructions regarding specific toxicities including hyperbilirubinemia in Section 3.4.2.1
below.

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3.4.2
Additional Toxicity Management Instructions
3.4.2.1
Increased Bilirubin
If the grade 3 or 4 increase in bilirubin is not associated 
with an increase in AST or ALT, the bilirubin value must 
return to ≤ grade 2 before resuming study therapy at the 
current dose level. If on retreatment bilirubin returns to 
≥ grade 3, withhold treatment until toxicity ≤ grade 2 or 
returns to Baseline and decrease dose to 1 tablet (200 
mg), BID.
If the bilirubin increases to ≥ grade 2 and is associated with 
an ≥ grade 2 increase in AST and/or ALT, permanently 
discontinue study drug.
3.4.2.2
Nausea
Take VS-6063 immediately following a meal with a full 
glass of water (approximately 8 ounces). However, 
subjects who experience nausea following dosing may 
benefit from eating a few crackers or other small amounts 
of food before or after taking the study drug. On the basis 
of Phase I data, initial use of prophylactic premedication 
was not required. However, prophylactic medications may 
be used as needed if nausea is found to occur with 
administration of study drug and cannot be managed with 
small amounts of food.
3.4.2.3
Hypertension
Minor, generally asymptomatic increases in blood pressure 
were observed in the Phase I study with VS-6063
(defactinib). Subjects experiencing recurrent, persistent, or 
symptomatic increase by > 20 mmHg (diastolic) or to 
> 150/100 mmHg if previously within normal limits, should 
be initiated on antihypertensive therapy according to 
institutional policies. Study drug should not be interrupted.
For subjects with persistent systolic BP >= 160 mm Hg or 
diastolic BP > = 100 mm Hg despite optimal 
antihypertensive therapy, study drug should be interrupted 
until < 150/100 mm Hg and the dose of study drug should 
be reduced.
3.4.2.4
Phototoxicity
VS-6063 (defactinib) may cause sensitivity to direct and 
indirect sunlight. The subjects should be warned to avoid 
direct sun exposure. When exposure to sunlight is 
anticipated for longer than 15 minutes, the subject should 
be instructed to apply factor 30 or higher sunscreen to 
exposed areas and wear protective clothing and 
sunglasses.
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3.4.2.5
Other
If the subject has requested that study treatment be
discontinued due to a toxicity that does not require dosing 
delays or dose reductions, contact the Subprotocol Study 
Chair to discuss options for clinical management that may 
be helpful to support continuation of study therapy.
3.5
Supportive Care 
3.5.1
All supportive measures consistent with optimal patient care will be 
given throughout the study. Subjects should receive full supportive 
care including transfusion of blood and blood products and antibiotics, 
etc., according to local standards and guidelines. Adequate treatment 
for nausea, vomiting, and diarrhea is permitted according to 
institutional guidelines. Take VS-6063 immediately following a meal 
with a full glass of water (approximately 8 ounces)
Nausea and emesis:
For nausea and vomiting, treat with standard anti-emetics such as 
prochloroperazine or ondansetron. Patients should be counseled that 
taking the medication with food may reduce nausea. The use of 
prophylactic antiemetics should be considered per standard clinical 
guidelines. Given the potential for ondansetron to increase QTc 
prolongation, review baseline QTc EKG prior to initiation of 
ondansetron and consider follow up EKGs on treatment.
Diarrhea:
For grade 1 diarrhea, symptomatic care such as loperamide 
(Imodium) or no intervention at investigator judgment. For grade 2 
diarrhea, loperamide (4 mg at first onset, then 2 mg every 2-4 hrs until 
symptom free for 12 hours).
3.6
Duration of Agent-specific treatment
VS-6063 (defactinib) will be administered daily by mouth as described in Section 
3.1.
In the absence of treatment delays due to adverse event(s), treatment may 
continue until one of the following criteria applies:
x
Extraordinary Medical Circumstances: If at any time the constraints of this 
protocol are detrimental to the patient's health, protocol treatment should be 
discontinued. In this event submit forms according to the instructions in the 
MATCH Forms Packet.
x
Patient withdraws consent.
x
Patient experiences unacceptable toxicity.
x
Non-protocol therapies are administered.
x
Disease progression
3.7
Duration of Follow-Up
Refer to the MATCH Master Protocol for specifics on the duration of follow-up.
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4.
Study Parameters
4.1
Therapeutic Parameters for VS-6063 (defactinib) Treatment
NOTE:
In addition to the study parameters listed in the main screening protocol, the below parameters must also be 
performed for patients receiving VS-6063 (defactinib) treatment.
NOTE:
All assessments required prior to registration to treatment should be done ≤4 weeks prior to registration to 
Steps 1, 3, 5, 7, excluding the radiologic evaluation and electrocardiogram (ECG).
Test/Assessment
Prior to 
Registration to 
Treatment
Treatment
End of Treatment
Follow UpF
Every Cycle, prior to 
treatment
Every 2 Cycles
H&P, Weight, Vital signsA
X
XH
X
Performance status
X
XH
X
CBC w/diff, pltsB
X
XH
X
Serum chemistryB
X
XH
X
Radiologic evaluationD
X
XD
XF
E-HCGC
X
Toxicity Assessment
XH
X
XF
Pill Count/DiaryG
X
X
Concomitant Medications
X
XH
ECG
XI
ECHO/Nuclear Study
XJ
Tumor biopsy and blood sample for MATCH Master ProtocolE
X
X
A. History and physical, including vital signs and weight at the start of each cycle (up to 3 days before start of new cycle).
B. Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, creatinine, glucose, phosphorus, potassium, SGOT[AST], SGPT[ALT], 
sodium, magnesium and serum tumor markers (including LDH, PSA if appropriate). For eligibility purposes, participants with creatinine levels 
above institutional normal, Cockcroft-Gault will be used to calculate creatinine clearance. CBC w/diff, platelets and serum chemistries should be 
performed on cycle 1, day 1 (or up to 7 days prior), and at the start of each subsequent cycle (up to 3 days before start of new cycle). CBC with 
differential will be performed more frequently in patients with grade 4 neutropenia or thrombocytopenia until resolution to ≤grade 3. CBC and 
serum chemistries are only required in follow-up until values return to pre-treatment levels or until progressive disease.
C. Blood pregnancy test (women of childbearing potential) required prior to beginning treatment.
D. Disease measurements are repeated every 2 cycles for the first 26 cycles, and every 3 cycles thereafter until PD or start of another MATCH 
treatment step. The baseline evaluation should be performed as closely as possible to the beginning of treatment and never more than 6 weeks 
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before registration to treatment step. For multiple myeloma patients, please refer to Section 6.4 of the MATCH Master Protocol for additional 
information on myeloma response criteria and the required disease assessments. Documentation (radiologic) must be provided for patients 
removed from study for progressive disease.
E. Additional blood specimens and/or biopsies are to be submitted from consenting patients per the MATCH Master Protocol. Submit at the following 
time points, as applicable:
x
Blood specimens are to be submitted at the end of Cycle 2 (prior to start of Cycle 3 treatment). If patient progresses or treatment is 
discontinued prior to Cycle 3, collect the blood at that time instead.  See Section 9.3.2.3 of MATCH Master Protocol. On-treatment kits for blood 
sample collections will be automatically shipped to sites upon registration to the treatment step.
x
Screening biopsies for additional aMOI assessments after registration to appropriate screening step, if applicable (Step 2 or Step 4).
x
At end of all MATCH study treatments, blood specimens and/or research biopsy after consent and registration to Step 8
Please refer to Section 4 of the MATCH Master Protocol to determine whether the patient proceeds to the next screening step or to follow-up (with 
a potential end of treatment biopsy for research purposes on Step 8). Samples are to be submitted as outlined in Section 9 of the MATCH Master 
Protocol. To order Step 2/4 Screening or Step 8 kits, complete the EAY131 Collection and Shipping Kit Order Form (See Appendix XII of the
MATCH Master Protocol) and fax to 713-563-6506.
F. Every 3 months if patient is < 2 years from study entry, and every 6 months for year 3. Toxicity assessments and radiologic evaluations are not
required to be done during Follow Up if progression has been previously reported; however if an adverse event occurs post treatment that meets 
the SAE reporting requirements, it still must be reported via CTEP-AERS, even if progression has occurred.
G. The pill calendar will be collected at the end of every cycle. The Pill Count/Diary is not required prior to Cycle 1, but is required every subsequent 
cycle.
H. For Cycle 1, if the following tests/assessments occurred within 7 days of Day 1, they do not need to be repeated at this timepoint: H&P, Weight, 
Vital signs; Performance Status; CBC w/diff, plts; Serum chemistry; Concomitant Medications.  The Toxicity Assessment is not required prior to 
Cycle 1, but required every subsequent cycle.
I. Within 8 weeks of treatment assignment.
J. As required per Section 2.1.4.
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5.
Drug Formulation and Procurement
This information has been prepared by the ECOG-ACRIN Pharmacy and Nursing 
Committees.
Availability
NO STARTER SUPPLIES MAY BE ORDERED. Subjects must be enrolled and assigned 
to the treatment subprotocol prior to submitting the clinical drug request to PMB.
Drug Ordering: NCI supplied agents may be requested by the Principal Investigator (or 
their authorized designees) at each participating institution. Pharmaceutical 
Management Branch (PMB) policy requires that drug be shipped directly to the institution 
where the patient is to be treated. PMB does not permit the transfer of agents between 
institutions (unless prior approval from PMB is obtained – see general information) The 
CTEP-assigned protocol number must be used for ordering all CTEP-supplied 
investigational agents.  The responsible investigator at each participating institution must 
be registered with CTEP, DCTD through an annual submission of FDA Form 1572 
(Statement of Investigator), Curriculum Vitae, Supplemental Investigator Data Form 
(IDF), and Financial Disclosure Form (FDF).  If there are several participating 
investigators at one institution, CTEP-supplied investigational agents for the study 
should be ordered under the name of one lead investigator at that institution.
Active CTEP-registered investigators and investigator-designated shipping designees 
and ordering designees can submit agent requests through the PMB Online Agent Order 
Processing (OAOP) application (https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx).
Access to OAOP requires the establishment of a CTEP Identity and Access 
Management (IAM) account (https://eapps-ctep.nci.nih.gov/iam/) and the maintenance of 
an “active” account status and a “current” password.
NCI Supplied Agent(s) – General Information
Questions about drug orders, transfers, returns, or accountability should be 
addressed to the PMB by calling 240-276-6575 Monday through Friday between 
8:30 AM and 4:30 PM Eastern Time or email PMBAfterHours@mail.nih.gov
anytime.
Drug Returns: All undispensed drug supplies should be returned to the PMB. When it is 
necessary to return study drug (e.g., sealed bottles remaining when PMB sends a stock 
recovery letter), investigators should return the study drug to the PMB using the NCI 
Return Agent Form available on the NCI home page (http://ctep.cancer.gov).
Drug Accountability: The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, disposition, and return of 
agent received from the PMB using the NCI Investigational Agent Accountability Record 
Form for Oral Agents available on the NCI home page (http://ctep.cancer.gov). Maintain 
separate NCI Investigational Agent Accountability Records for each agent, strength, 
formulation and ordering investigator.
Investigator Brochure Availability: The current versions of the IBs for PMB-supplied 
agents will be accessible to site investigators and research staff through the PMB Online 
Agent Order Processing (OAOP) application.  Access to OAOP requires the 
establishment of a CTEP Identity and Access Management (IAM) account and the 
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maintenance of an “active” account status and a “current” password.  Questions about IB 
access may be directed to the PMB IB coordinator at IBCoordinator@mail.nih.gov.
5.1
VS-6063 (defactinib hydrochloride) (NSC #781450)
5.1.1
Other Names 
Defactinib, PF-04554878
5.1.2
Classification 
Focal adhesion kinase (FAK) inhibitor
5.1.3
Mode of Action 
VS-6063 is an ATP-competitive inhibitor of focal adhesion kinase 
(FAK) and proline-rich tyrosine kinase 2 (Pyk2).  FAK and Pyk2 are 
members of the same family of nonreceptor protein tyrosine kinases 
sharing significant sequence homology and are implicated as 
important integrating molecules in signal transduction cascades.
5.1.4
Storage and Stability 
Storage:
Store VS-6063 tablets at controlled room temperature 
(15-25°C/59-77°F).
Stability:
Shelf-life stability studies of VS-6063 tablets are ongoing.
5.1.5
Dose Specifics 
400 mg will be taken every 12 hours immediately following a meal 
with a full glass of water (approximately 8 ounces).
5.1.6
How Supplied
VS-6063 tablets are supplied by Verastem, Inc. and distributed by the 
Pharmaceutical Management Branch, CTEP/DCTD/NCI.  VS-6063 is 
supplied as 200 mg immediate release tablets (white to off-white, oval 
shaped) packaged in 64-count high density polyethylene (HDPE) 
bottles.  The tablets contain a blend of drug substance, 
microcrystalline cellulose, lactose monohydrate, sodium starch 
glycolate, and magnesium stearate.
The pharmaceutical collaborator does not have stability data to 
support repackaging VS-6063 tablets in any container other than what 
is provided.
The active ingredient used for the VS-6063 clinical supplies is the 
hydrochloride salt.
5.1.7
Route of Administration 
Oral.
5.1.8
Incompatibilities 
VS-6063 is metabolized by CYP2C9 and 3A4.  Avoid coadministration 
of strong CYP2C9 and 3A4 inhibitors/inducers.  VS-6063 is a weak 
inhibitor of CYP2C9 and 3A4, a substrate and a weak inhibitor of P-
gp, and an inhibitor of OATP1B1, 1B3, and UGT1A1 in vitro. 
Concomitant administration of substrates for CYP2C9, 3A4, P-gp,
OATP1B1, 1B3, and UGT1A1 should be used with caution.
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VS-6063 may have the potential to increase warfarin exposure due to 
a potential drug-drug interaction affecting warfarin’s metabolism.  An 
increased level of caution is recommended. If subjects can safely stop 
taking warfarin, they should do so. If subjects require anti-coagulation, 
an alternative to warfarin should be considered. Subjects who require 
anti-coagulation but cannot discontinue warfarin should be monitored 
closely and have their INRs checked more frequently.
NOTE:
Warfarin may not be started while enrolled in the EAY131 
study.
5.1.9
Side Effects 
See Section 3.3 for side effects.
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6.
Translational Studies
Please refer to the MATCH Master Protocol for information on the Translational Studies. 
7.
References
1.
Siesser PM, Hanks SK. The signaling and biological implications of FAK 
overexpression in cancer. Clinical cancer research : an official journal of the 
American Association for Cancer Research. 2006;12(11 Pt 1):3233-3237.
2.
Poulikakos PI, Xiao GH, Gallagher R, et al. Re-expression of the tumor suppressor 
NF2/merlin inhibits invasiveness in mesothelioma cells and negatively regulates 
FAK. Oncogene. 2006;25(44):5960-5968.

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Molecular Analysis for Therapy Choice (MATCH)
MATCH Treatment Subprotocol U: VS-6063 (defactinib) in Patients with Tumors with NF2 
Loss
Appendix I
Patient Pill Calendar
Pill Calendar Directions
1.
Take your scheduled dose by mouth twice daily at the same time each morning and 
evening approximately 12 hours between doses.
2.
If you forget, the missed tablets should not be taken later.
3.
Please bring the empty bottle or any leftover tablets and your pill calendar to your 
next clinic visit.
4.
Swallow tablets whole (do not crush, dissolve, or chew tablets).
5.
Take VS-6063 (defactinib) immediately following a meal with a full glass of water 
(approximately 8 ounces).
6.
Store tablets at room temperature.
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Patient Pill Calendar
This is a calendar on which you are to record the time and number of tablets you take 
each day.  You should take your scheduled dose of each tablet. Note the times and the 
number of tablets that you take each day. If you develop any side effects, please 
record them and anything you would like to tell the doctor in the space provided.  Bring 
any unused tablets and your completed pill calendar to your doctor’s visits.
VS-6063 (defactinib)
DAY 
Date
Time tablets
taken
Number of tablets
taken
Use the space below to make 
notes about things you would like 
to tell the doctor (including 
unusual symptoms you 
experience, other medicine you 
have taken and anything else you 
think would be of interest.)
Month
Day
Year
AM
PM
AM
PM
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Patient Signature: __________________________________ Date: _____________

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Molecular Analysis for Therapy Choice (MATCH)
MATCH Treatment Subprotocol U: VS-6063 (defactinib) in Patients with Tumors with NF2 
Loss
Appendix II
Information on Possible Drug Interactions
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements
The patient ____________________________ is enrolled on a clinical trial using the 
experimental study drug VS-6063 (defactinib).  This clinical trial is sponsored by the National 
Cancer Institute.  This form is addressed to the patient, but includes important information for 
others who care for this patient.
These are the things that you as a prescriber need to know:
VS-6063 (defactinib) interacts with certain specific enzymes in the liver and transport proteins 
that help move drugs in and out of cells.
x
The enzymes in question are CYP 3A4, 2C9, and UGT1A1. VS-6063 (defactinib) is 
metabolized by CYP 3A4 and 2C9 and may be affected by other drugs that inhibit or induce 
these enzymes.  VS-6063 (defactinib) is an inhibitor of CYP 3A4, 2C9, and UGT1A1 and 
may affect metabolism of other drugs that are substrates for these enzymes.
x
The proteins in question are P-gp, OATP1B1, and OATP1B3. VS-6063 (defactinib) is a 
substrate of P-gp and may be affected by other drugs that inhibit or induce P-gp.  VS-6063
(defactinib) is an inhibitor of P-gp, OATP1B1, and OATP1B3, and may affect transport of 
other drugs in and out of cells.
To the patient: Take this paper with you to your medical appointments and keep the 
attached information card in your wallet.
VS-6063 (defactinib) may interact with other drugs which can cause side effects.  For this 
reason, it is very important to tell your study doctors of any medicines you are taking before you 
enroll onto this clinical trial.  It is also very important to tell your doctors if you stop taking any 
regular medicines, or if you start taking a new medicine while you take part in this study.  When 
you talk about your current medications with your doctors, include medicine you buy without a 
prescription (over-the-counter remedy), or herbal supplements such as St. John’s Wort.  It is 
helpful to bring your medication bottles or an updated medication list with you.
Many health care providers can write prescriptions.  You must tell all of your health care 
providers (doctors, physician assistants, nurse practitioners, or pharmacists) you are taking part 
in a clinical trial.
These are the things that you and they need to know:
VS-6063 (defactinib) must be used very carefully with other medicines that need certain liver 
enzymes or transport proteins to be effective or to be cleared from your system. Before 
you enroll onto the clinical trial, your study doctor will work with your regular health care 
providers to review any medicines and herbal supplements that are considered “strong 
inducers/inhibitors of CYP 3A4 and 2C9 or substrates of CYP 3A4, 2C9, UGT1A1, P-gp,
OATP1B1, and OATP1B3.”
Rev. 5/16
Rev. 12/16

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Version Date: July 10, 2019
NCI Update Date: August 12, 2015
31
x
Please be very careful!  Over-the-counter drugs (including herbal supplements) may contain 
ingredients that could interact with your study drug.  Speak to your doctors or pharmacist to 
determine if there could be any side effects. 
x
Your regular health care provider should check a frequently updated medical reference or 
call your study doctor before prescribing any new medicine or discontinuing any medicine.  
Your study doctor’s name is
_____________________________________ 
and he or she can be contacted at 
_____________________________________.
STUDY DRUG INFORMATION WALLET CARD  
You are enrolled on a clinical trial using the 
experimental study drug VS-6063 (defactinib). This
clinical trial is sponsored by the NCI. VS-6063 
(defactinib) may interact with drugs that are 
processed by your liver, or use certain transport 
proteins in your body. Because of this, it is very 
important to:
¾ Tell your doctors if you stop taking any medicines or if 
you start taking any new medicines.
¾ Tell all of your health care providers (doctors, 
physician assistants, nurse practitioners, or 
pharmacists) that you are taking part in a clinical trial.
¾ Check with your doctor or pharmacist whenever you 
need to use an over-the-counter medicine or herbal 
supplement.
VS-6063 (defactinib) interacts with CYP 3A4, 2C9, 
UGT1A1, P-gp, OATP1B1, and OATP1B3, and must be
used very carefully with other medicines that interact with 
these enzymes.
¾ Before you enroll onto the clinical trial, your study 
doctor will work with your regular health care providers 
to review any medicines and herbal supplements that 
are considered “strong inducers/inhibitors of CYP 
3A4 and 2C9 or substrates of CYP 3A4, 2C9, 
UGT1A1, P-gp, OATP1B1, and OATP1B3”
¾ Before prescribing new medicines, your regular 
prescribers should go to a frequently-updated medical 
reference for a list of drugs to avoid, or contact your 
study doctor.  
¾ Your study doctor’s name is
_____________________________ and can be 
contacted at _________________________________.

ECOG-ACRIN
EAY131-U
Cancer Research Group
Version Date: July 10, 2019
NCI Update Date: August 12, 2015
32
Molecular Analysis for Therapy Choice (MATCH)
MATCH Treatment Subprotocol U: VS-6063 (defactinib) in Patients with Tumors with NF2 
Loss
Appendix III
Actionable Mutations for Sub-Protocol EAY131-U
NF2 is a tumor suppressor gene. Inactivating deleterious mutations could occur 
anywhere in the coding regions. Instead of listing all possible deleterious mutations, we 
have implemented a function in MATCHBOX that can identify any point mutations 
creating stop codons that will lead to premature truncations or any insertions/deletions 
causing frameshifts, which are predicted to result in a non-functional or absent protein. 
Those mutations will be considered to be actionable mutations with level of evidence 3. 
Variants, including missense mutations, were not included for eligibility if there was a 
lack of adequate evidence that such variants resulted in loss of function in NF2 gene.
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ECOG-ACRIN
EAY131-U
Cancer Research Group
Version Date: July 10, 2019
NCI Update Date: August 12, 2015
33
Molecular Analysis for Therapy Choice (MATCH)
MATCH Treatment Subprotocol U: VS-6063 (defactinib) in Patients with Tumors with NF2 
Loss
Appendix IV
CYP3A4 Inducers and Inhibitors
Because the lists of these agents are constantly changing, it is important to regularly 
consult a frequently-updated list such as Facts and Comparisons or Lexicomp; medical 
reference texts such as the Physicians’ Desk Reference may also provide this 
information. The Principal Investigator should be alerted if the subject is taking any agent 
on these lists.
List of CYP3A4 Inducing Agents:
Carbamazepine
Phenytoin
Dexamethasone
Primidone
Ethosuximide
Progesterone
Glucocorticoids
Rifabutin
Griseofulvin
Rifampin
Modafinil
Rifapentine
Naficillin
Rofecoxib
Nelfinavir
St. John’s Wort
Nevirapine
Sulfadimidine
Oxcarbazepine
Sulfinpyrazone
Phenobarbitol
Tipranavir
Phenylbutazone
Troglitazone
List of CYP3A4 Inhibitors:
Amiodarone
Mifepristone
Cimetidine
Nefazodone
Ciprofloxacin
Nelfinavir
Clarithromycin
Norfloxacin
Delavirdine
Norfluoxetine
Diethyl-dithiocarbamate
Ritonavir
Diltiazem
Roxithromycin
Erythromycin
Saquinavir
Fluconazole
Troleandomycin
Fluvoxamine
Voriconazole
Gestodene
Warfarin
Grapefruit or Grapefruit juice
Amprenavir
Indanvir
Atazanavir
Itraconazole
Miconazole
Ketoconazole
Telithromycin
Mibefradil
Verapamil
Rev.2/16