Clinical trial NCT04720417
Conditions: Metastatic Uveal Melanoma
Sponsor: Thomas Jefferson University
Start date: 2021-01-26; Completion date: 2024-04-30
Enrollment: 13 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies the effect of combining defactinib and VS-6766 in treating patients with uveal melanoma that has spread to other places in the body (metastatic). The way cells communicate with one another (different cell signaling pathways) are overactive in uveal melanoma tumor cells. Giving defactinib together with VS-6766 may block pathways that are important for the growth of uveal melanoma cells, and may result in shrinkage or stabilization of the cancer and prolonged time to disease progression and survival.

Detailed description:
PRIMARY OBJECTIVE:

I. To investigate the potential efficacy of the combination of defactinib hydrochloride (defactinib \[VS-6063\]) and Raf/MEK serine/threonine kinase inhibitor RO5126766 (VS-6766) in patients with metastatic uveal melanoma.

SECONDARY OBJECTIVES:

I. To assess the effectiveness of defactinib in combination with VS-6766 in patients with metastatic uveal melanoma (MUM).

II. To assess the safety and toxicity profile of the combination of defactinib and VS6766.

EXPLORATORY OBJECTIVES:

I. To study the pharmacodynamic profile of defactinib in combination with VS-6766 in pre-treatment, on-treatment, and post-treatment tumor biopsies.

II. To investigate mechanisms of resistance to the combination of defactinib and VS-6766.

III. To investigate the potential efficacy of circulating cell free deoxyribonucleic acid (DNA) for prediction/monitoring.

OUTLINE:

Patients receive defactinib orally (PO) twice daily (BID) and VS-6766 PO twice a week (BIW) (Monday and Thursday or Tuesday and Friday) for 3 weeks in every cycle. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo tumor biopsy at baseline, after cycle 1 or 2, and post-treatment.

After completion of study treatment, patients are followed every 3 months until death or up to 2 years after the last patient is enrolled.

Arms: arm 1: Patients receive defactinib PO BID and VS-6766 PO BIW (Monday and Thursday or Tuesday and Friday) for 3 weeks in every cycle. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Defactinib Hydrochloride intervention 2: Raf/MEK Inhibitor VS-6766 intervention 3: Biopsy
Intervention descriptions: intervention 1: Given PO intervention 2: Given PO intervention 3: Undergo tumor biopsy

Protocol documents:
Prot_SAP_000.pdf: 
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         THOMAS JEFFERSON UNIVERSITY 
Sidney Kimmel Cancer Center 
 
A Phase II trial of Defactinib (VS-6063) combined with VS-6766 (CH5126766) in 
patients with metastatic uveal melanoma  
Principal Investigator: 
Rino S. Seedor, MD 
Department of Medical Oncology 
215-955-8874 
 
Co-Investigator(s): 
Takami Sato, MD, PhD 
Department of Medical Oncology 
215-955-1195 
 
Marlana Orloff, MD 
Department of Medical Oncology 
215-955-8874 
 
Erin Sharpe-Mills, MSN, CRNP 
Department of Medical Oncology 
215-955-8874 
 
Andrew Aplin, PhD 
Sidney Kimmel Cancer Center 
Thomas Jefferson University 
 
Maddi Wechsler, CRNP 
Department of Medical Oncology 
215-955-8874 
 
 
J. Silvio Gutkind, PhD 
University of California, San Diego – Moores Cancer Center 
3855 Health Sciences Dr. 
La Jolla, CA 92037 
858-534-5980 
 
Statistician: 
Inna Chervoneva, PhD 
Department of Pharmacology & Experimental Therapeutics 
215-955-4083 
Funding Sponsor: 
Verastem Oncology, Inc. 
117 Kendrick Street, Suite 500 
Needham, MA 02494 
781-292-4200 
IND/IDE Holder: 
Takami Sato, MD, PhD 
IND/IDE Number: 
153970 
Study Product: 
VS-6063 (Defactinib) and VS-6766 
Protocol IDs: 
JeffTrial # 16166 
IRB Control # 20P.1113 


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Version Number: 
Version Date: 
1.0 
06/12/2020 
1.1 
07/18/2020 
1.2 
09/16/2020 
1.3 
10/12/2020 
1.4 
12/11/2020 
2.0 
08/07/2021 
2.1 
03/07/2022 
3.0 
06/21/2022 
*Protocol history appears in Appendix IV 
 
CONFIDENTIAL 
This document is confidential and the property of THOMAS JEFFERSON UNIVERSITY. No part 
of it may be transmitted, reproduced, published, or used by other persons without prior written 
authorization from the study sponsor. 
 
 


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Table of Contents 
Signature Page .........................................................................................................................10 
Statement of Compliance ..........................................................................................................10 
List of Abbreviations ..................................................................................................................11 
Study Summary ........................................................................................................................15 
1 
Introduction .........................................................................................................................18 
1.1 
Background Information ..............................................................................................18 
Figure 1 .................................................................................................................................20 
1.2 
Clinical Studies ...........................................................................................................20 
1.3 
Potential Risks ............................................................................................................21 
1.3.1 Potential Risks.........................................................................................................21 
2 
Study Objectives .................................................................................................................29 
2.1 
Objectives ...................................................................................................................29 
2.1.1 Primary ....................................................................................................................29 
2.1.2 Secondary ...............................................................................................................29 
2.1.3 Exploratory ..............................................................................................................29 
2.2 
Endpoints/Outcome Measures ....................................................................................29 
2.2.1 Primary ....................................................................................................................29 
2.2.2 Secondary ...............................................................................................................29 
2.2.3 Exploratory ..............................................................................................................30 
3 
Study Design ......................................................................................................................30 
3.1 
Characteristics ............................................................................................................30 
3.2 
Number of Participants ...............................................................................................30 
3.3 
Duration of Therapy ....................................................................................................31 
3.4 
Duration of Follow Up .................................................................................................31 


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3.5 
Treatment Assignment Procedures .............................................................................31 
3.6 
Study Timeline ............................................................................................................32 
3.6.1 Primary Completion .................................................................................................32 
3.6.2 Study Completion ....................................................................................................32 
4 
Study Enrollment and Withdrawal .......................................................................................32 
4.1 
Eligibility Criteria .........................................................................................................32 
4.1.1 Inclusion Criteria ......................................................................................................32 
4.1.2 Exclusion Criteria ....................................................................................................33 
4.2 
Gender/Minority/Pediatric Inclusion for Research........................................................36 
4.3 
Strategies for Recruitment and Retention ...................................................................36 
4.4 
Participant Withdrawal ................................................................................................36 
4.4.1 Reasons for Withdrawal ..........................................................................................36 
4.4.2 Handling of Participant Withdrawals and Participant Discontinuation of Study 
Intervention .........................................................................................................................37 
4.5 
Premature Termination or Suspension of Study ..........................................................37 
5 
Study Intervention ...............................................................................................................38 
5.1 
Study Product .............................................................................................................38 
5.2 
Defactinib (VS-6063) ...................................................................................................38 
5.2.1 Acquisition ...............................................................................................................38 
5.2.2 Formulation, Packaging, and Labeling .....................................................................38 
5.2.3 Product Storage and Stability ..................................................................................38 
5.2.4 Mechanism of action of VS-6063 .............................................................................39 
Figure 2. ................................................................................................................................39 
5.2.5 Non-clinical anti-tumor activity .................................................................................40 
5.2.6 Toxicology ...............................................................................................................40 
5.2.7 Clinical experience ..................................................................................................40 
5.2.8 Pharmacokinetics ....................................................................................................41 


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5.2.9 Pharmacodynamics .................................................................................................42 
5.2.10 
Efficacy ................................................................................................................42 
5.3 
VS-6766 (CH5126766) ...............................................................................................43 
5.3.1 Acquisition ...............................................................................................................43 
5.3.2 Formulation, Packaging, and Labeling .....................................................................43 
5.3.3 Product Storage and Stability ..................................................................................43 
5.3.4 Mechanism of action of VS-6766 .............................................................................43 
5.3.5 Non-clinical anti-tumor activity .................................................................................44 
5.3.6 Toxicology ...............................................................................................................45 
5.3.7 Clinical experience ..................................................................................................45 
5.3.8 Pharmacokinetics ....................................................................................................48 
5.3.9 Pharmacodynamics .................................................................................................48 
5.3.10 
Efficacy ................................................................................................................49 
5.4 
Rationale for the proposed trial and dosing regimen ...................................................50 
5.5 
Dosage, Preparation, and Administration ....................................................................50 
5.6 
Dose Modifications and Dosing Delays .......................................................................51 
Table 1: Dose reductions ....................................................................................................52 
5.7 
Study Product Accountability ......................................................................................53 
5.8 
Assessing Participant Compliance with Study Product Administration ........................53 
5.9 
Concomitant Medications/Treatments .........................................................................53 
5.10 
Dietary Restrictions .....................................................................................................55 
6 
Study Schedule ..................................................................................................................55 
6.1 
Pretreatment Period/Screening ...................................................................................55 
6.1.1 Obtaining written informed consent .........................................................................55 
6.1.2 Evaluations within four weeks (28 days) ..................................................................55 
6.1.3 Evaluations within two weeks (14 days) ..................................................................56 


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6.2 
Evaluations during the trial ..........................................................................................57 
6.3 
Evaluations at ‘off-study’ visit ......................................................................................58 
6.4 
Follow-up ....................................................................................................................59 
6.5 
Withdrawal Visit/Discontinuation of Therapy ...............................................................59 
6.6 
Laboratory Procedures/Evaluations ............................................................................60 
6.6.1 Clinical Laboratory Evaluations ...............................................................................60 
6.6.2 Special Assays or Procedures .................................................................................61 
7 
Evaluation of Efficacy .........................................................................................................62 
7.1 
Measurement of Effects ..............................................................................................63 
7.1.1 Measurable and Non-Measurable Disease ..............................................................63 
7.1.2 Baseline documentation of “Target” and “Non-Target” Lesions ................................63 
7.2 
Timing of tumor assessments .....................................................................................64 
7.2.1 Baseline evaluations ...............................................................................................64 
7.2.2 Evaluations during and at ‘off-study’ ........................................................................64 
7.3 
Evaluation of overall response of metastasis ..............................................................65 
7.4 
Response Criteria for metastases ...............................................................................65 
Table 2. The definition of response of metastases ....................................................................66 
Table 3. Evaluation of Target and Non-Target Lesions .............................................................66 
7.4.1 Recording of response in eCRF ..............................................................................67 
7.5 
Evaluation of progression free survival (PFS) .............................................................67 
7.6 
Evaluation of overall survival (OS) ..............................................................................67 
8 
Evaluation of Safety ............................................................................................................67 
8.1 
Specification of Safety Parameters .............................................................................67 
8.1.1 Unanticipated Problems ..........................................................................................67 
8.1.2 Adverse Events .......................................................................................................67 
8.1.3 Serious Adverse Events ..........................................................................................68 


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8.2 
Safety Assessment and Follow-Up .............................................................................68 
8.3 
Recording Adverse Events ..........................................................................................68 
8.3.1 Relationship to Study Intervention ...........................................................................68 
8.3.2 Expectedness ..........................................................................................................69 
8.3.3 Severity of Event .....................................................................................................69 
8.3.4 Intervention .............................................................................................................69 
8.4 
Safety Reporting .........................................................................................................69 
8.4.1 Reporting to IRB ......................................................................................................70 
8.4.2 Reporting to SKCC DSMC ......................................................................................71 
8.4.3 Reporting of serious adverse events to Verastem Oncology....................................72 
8.4.4 Reporting to FDA .....................................................................................................73 
8.4.5 Sponsor reporting responsibilities ............................................................................73 
8.4.6 Recording of AE and SAEs in eCRFs ......................................................................74 
8.4.7 Reporting of Pregnancy ...........................................................................................74 
8.5 
Halting Rules ..............................................................................................................76 
9 
Study Oversight ..................................................................................................................77 
10 
Clinical Site Monitoring and Auditing ..............................................................................78 
11 Statistical Considerations .....................................................................................................78 
10.1 
Study Hypotheses .......................................................................................................78 
10.2 
Analysis Plans ............................................................................................................78 
10.3 
Interim Analyses and Stopping Rules..........................................................................80 
10.3.1 
Efficacy Review ...................................................................................................80 
10.4 
Defining the end of trial ...............................................................................................80 
10.5 
Sample Size Considerations .......................................................................................80 
10.5.1 
Replacement Policy .............................................................................................81 
10.5.2 
Accrual Estimates ................................................................................................81 


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10.6 
Data Analysis ..............................................................................................................81 
10.7 
Evaluation of Safety ....................................................................................................82 
10.8 
Pharmacodynamics ....................................................................................................82 
11 
Source Documents and Access to Source Data/Documents ..........................................82 
12 
Quality Control and Quality Assurance ...........................................................................83 
13 
Ethics/Protection of Human Participants .........................................................................84 
13.1 
Ethical Standard .........................................................................................................84 
13.2 
Institutional Review Board ...........................................................................................84 
13.3 
Informed Consent Process ..........................................................................................84 
13.4 
Exclusion of Women, Minorities, and Children (Special Populations) ..........................85 
13.5 
Participant Confidentiality............................................................................................85 
13.6 
Future Use of Stored Specimens and Other Identifiable Data .....................................86 
14 
Data Handling and Record Keeping ...............................................................................86 
14.1 
Data Management Responsibilities .............................................................................86 
14.2 
Data Capture Methods ................................................................................................86 
14.3 
Types of Data .............................................................................................................87 
14.4 
Study Records Retention ............................................................................................87 
14.5 
Protocol Deviations .....................................................................................................87 
15 
Study Finances ...............................................................................................................88 
15.1 
Funding Source ..........................................................................................................88 
15.2 
Conflict of Interest .......................................................................................................88 
15.3 
Participant Stipends or Payments ...............................................................................88 
16 
Publication and Data Sharing Policy ...............................................................................88 
17 
Literature References .....................................................................................................90 
Appendices ...............................................................................................................................94 
APPENDIX A: SCHEDULE OF EVENTS ..................................................................................95 


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APPENDIX B: MEASUREMENT OF DISEASE (42, 43) ............................................................97 
APPENDIX C: RECOMMENDATIONS RELATED TO CONTRACEPTION AND PREGNANCY 
TESTING IN CLINICAL TRIALS (45) ........................................................................................98 
APPENDIX D: PROTOCOL HISTORY ......................................................................................99 
 


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Signature Page 
The signature below constitutes the approval of this protocol and the attachments, and 
provides the necessary assurances that this trial will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable US federal 
regulations and ICH guidelines. 
Principal Investigator: 
Signed: 
 
Date:  
Name: 
Rino Seedor, MD 
Title:  
Assistant Professor of Medical Oncology 
 
Statement of Compliance 
This study will be conducted in accordance with the International Conference on Harmonisation 
guidelines for Good Clinical Practice (ICH E6), the Code of Federal Regulations on the Protection 
of Human Subjects (45 CFR Part 46), and Thomas Jefferson University research policies. 
 
 
 


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List of Abbreviations 
AE 
Adverse Event/Adverse Experience 
Alk phos 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
BOR 
Best overall response 
BP 
Blood pressure 
0C 
Degrees Celsius 
CDM 
Clinical Data Manager 
CFR 
Code of Federal Regulations 
CI 
Chief Investigator 
CIOMS 
Council for International Organizations of Medical Sciences 
CK 
Creatine kinase 
Ceff 
Efficacious free concentration 
Cmax 
Maximum observed plasma concentration 
Css,ave 
Average steady-stage concentration 
CNS 
Central nervous system 
CONSORT 
Consolidated Standards of Reporting Trials 
CPK 
Creatine phosphokinase 
CR 
Complete response 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CRMO 
Clinical Research Management Office 
CRO 
Clinical Research Organization 
CSFs 
Colony stimulating factors 
CSM 
Clinical Study Manager 
CT 
Computerized tomography 
CTA 
Clinical trial authorization 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
Circulating free tumor DNA 
CTFG 
Clinical Trial Facilitation Group 
CTM 
Clinical Trial Manager 
Day 
Calendar Day 
DCR 
Disease control rate 


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DDU 
Drug Development Unit 
DLT 
Dose limiting toxicity 
DSMC 
Data and Safety Monitoring Committee 
DSMP 
Data and Safety Monitoring Plan 
DVT 
Deep vein thrombosis 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
FAK 
Focal adhesion kinase 
FDA 
Food and Drug Administration 
FDG 
Fluorodeoxyglucose 
FFPE 
Formalin fixed and embedded in paraffin 
FIH 
First in Human 
FWA 
Federalwide Assurance 
GCP 
Good Clinical Practice 
g/dL 
Gram(s) per deciliter 
GGT 
Gamma-glutamyltranspeptide 
GWAS 
Genome-Wide Association Studies 
Hb 
Hemoglobin 
HCG 
Human chorionic gonadotropin 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
HR 
Hazard ratio 
IB 
Investigator’s Brochure 
IC-50 
50% inhibitory concentration 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IDE 
Investigational Device Exemption 
IMP 
Investigational medicinal product 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
IST 
Investigator-sponsored trials 
ITF 
Investigator trial file 
LVEF 
Left ventricular ejection fraction 
LGSOC 
Low-grade serous ovarian cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 


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mg/m2 
Milligram per square meter 
MOP 
Manual of Procedures 
MRI 
Magnetic resonance imaging 
MT/TF 
Monday Thursday/ Tuesday Friday 
MTD 
Maximum tolerated dose 
MUM 
Metastatic uveal melanoma 
N 
Number (typically refers to participants) 
NA 
Not applicable 
NCI 
National Cancer Institute 
NE 
Not evaluable 
NIH 
National Institutes of Health 
NSCLC 
Non-small cell lung cancer 
NYHA 
New York Heart Association 
OCR 
Office for Civil Rights 
OHRP 
Office for Human Research Protections 
OPRR 
Office for Protection from Research Risks 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cells 
PD 
Pharmacodynamic 
PDX 
Patient Derived Xenograft 
PD-1 
Programmed cell death 1  
PE 
Pulmonary embolism 
PET 
Positron emission tomography 
PFS 
Progression-free survival 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
PR 
Partial response 
PRC 
Protocol Review Committee 
PV 
Pharmacovigilance 
QA 
Quality Assurance 
QC 
Quality Control 
QP 
Qualified person 
Qtc 
Corrected QT interval 
REC 
Research Ethics Committee 


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RECIST 
Response Evaluation Criteria in Solid Tumours 
RVO 
Retinal vein occlusion 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SD 
Stable disease 
SDS 
Safety Data Sheet (formerly MSDS; Material Safety Data Sheet) 
SDV 
Source data verification 
SKCC 
Sidney Kimmel Cancer Center 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected unexpected serious adverse (drug) reaction 
T1/2 
Terminal elimination half-life 
Tmax 
Time to reach Cmax 
TEAE 
Treatment-emergent adverse effects 
TJU 
Thomas Jefferson University 
UAP 
Unanticipated Problem 
ULN 
Upper limit of normal 
UM 
Uveal melanoma 
USM 
Urgent safety measure 
WBC 
White blood cell 
WHO 
World Health Organization 
 
 


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Study Summary 
Title: 
A Phase II trial of Defactinib (VS-6063) combined with VS-6766 
(CH5126766) in patients with metastatic uveal melanoma 
Précis: 
This is a prospective, single arm, phase II clinical trial of the 
combination of the FAK inhibitor, Defactinib (VS-6063), and the dual 
RAF/MEK inhibitor, VS-6766 (CH5126766) in patients with 
metastatic uveal melanoma. The efficacy of this combination 
treatment will be assessed with the Simon’s two stage design. The 
choice of design is guided by a desire to stop the trial early if the 
actual stabilization rate (CR + PR + SD) is 20% or less. The 
recommended doses of the two medications were previously 
determined in a Phase I study of the combination of Defactinib (VS-
6063) and VS-6766 (CH5126766) in patients with advanced solid 
tumours (IST-VS-6063-003, protocol CCR4642, FRAME).  
Objectives: 
 
Primary:  
To investigate the potential efficacy of the combination of Defactinib 
(VS-6063) and VS-6766 in patients with metastatic uveal melanoma. 
 
Secondary: 
(1) To assess the survival benefit of Defactinib in combination with 
VS-6766 in patients with MUM. 
(2) To assess the safety and toxicity profile of Defactinib in 
combination with VS-6766.  
 
Exploratory: 
(1) To study the pharmacodynamic profile of Defactinib in 
combination with VS-6766 in pre-treatment, on-treatment, and post-
treatment tumor biopsies. 
(2) To investigate mechanisms of resistance to the combination of 
Defactinib and VS-6766. 
(3) To investigate the potential efficacy of circulating cell free DNA 
for prediction/monitoring. 
Population: 
Male and female patients with metastases from uveal melanoma; 18 
years or older. Sample size will be 18 subjects. 
Phase: 
Phase II 
Number of Sites: 
Thomas Jefferson University Hospital 
Description of 
Intervention: 
Patients will be treated with a combination of Defactinib (FAK 
inhibitor) with VS-6766 (dual RAF/MEK inhibitor), given in an 
intermittent schedule. The dose of Defactinib (VS-6063) will be 
200mg twice daily. The dose of VS-6766 (CH5126766) will be 3.2mg 


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once a day. Defactinib (VS-6063) will be administered orally twice a 
day within 30 minutes after a meal. VS-6766 will be administered 
orally twice a week on Monday/Thursday or Tuesday/Friday at least 
one hour prior or two hours after a meal. Dose modification will be 
considered based on toxicity.   
A cycle length is 4 weeks (28 days). Combination dosing (Defactinib 
and VS-6766) will commence on Cycle 1 Day 1 for 3 weeks followed 
by one week without either drug in week 4 (i.e. 3 weeks on, 1 week 
off). If this schedule is not tolerated, alternative schedules may be 
explored following discussion with Verastem Oncology. 
Study Duration: 
Estimated time from when the study opens to enrollment until 
completion of data analyses is 42 months. 
Participant 
Participation 
Duration: 
Patients may receive treatment until maximum clinical benefit is 
obtained, the development of intolerable side effects, or progression 
of disease is confirmed. Post-treatment, patients will be followed for 
survival until their death or up to 2 years after the last patient is 
enrolled. 
Estimated Time to 
Complete 
Enrollment: 
It is expected that the trial recruitment duration will be 6 to 18 
months with an expected accrual rate of approximately 1-3 patients 
per month at Thomas Jefferson University Hospital. A total of up to 
18 patients will be entered into this trial, depending on the disease 
control rate in the first stage of the study. 


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Schematic of Study Design: 
 
 Screening 
(within 28 days 
of first dose)  
 
 
Enrollment visit 
(within 14 days 
of first dose)  
 
 
 
 
Visit 1 
(Cycle 1 Day 1) 
 
 
 
 
Visit 2 
(Cycle 2 Day 1) 
 
 
 
 
 
Visit 3+ 
(Day 1 of  
each cycle) 
 
 
 
 
 
 
 
 
 
 
 
 
Visit Study Exit 
Time Point 
 
 
 
 
 
Obtain informed consent, perform baseline assessments - medical history, pre-
treatment tumor biopsy, radiological disease assessments, echocardiogram or 
MUGA, and ophthalmological examination. 
Perform physical exam- clinical disease measurements, vital signs, ECG, 
baseline laboratory tests, baseline blood samples for PD and ctDNA analysis, 
and pregnancy test.  
Continuation of study drugs.  
Perform follow-up assessments of outcome measures and safety evaluation, 
physical exam, vitals, labs, pregnancy test, toxicity assessment. 
*Blood samples for PD cycle on C3D1 
**Ophthalmological examination on C5D1 and every 3 cycles thereafter. 
***Disease assessment every 2 cycles. 
****ctDNA analysis every 2 cycles (up to 6 cycles). 
Perform pre-treatment assessments - physical exam, vitals, ECG,  
laboratory tests (weekly), pregnancy test, toxicity assessment 
*Ophthalmological examination at end of Cycle 2 before Visit 3. 
**On-treatment tumor biopsy after Cycle 1 or 2.  
Perform final Assessments - physical 
exam, vitals, labs, ECG, pregnancy 
test, ophthalmological examination, 
post-treatment tumor biopsy, blood 
sample for PD and ctDNA analysis, 
disease assessment, AE evaluation. 
Perform pre-treatment assessments - physical exam, vitals,  
laboratory tests (weekly), pregnancy test.  
Administer initial study drugs. 
*Ophthalmological examination at end of Cycle 1 before Visit 2.  


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1 Introduction 
1.1 
Background Information 
Uveal melanoma (UM) is the most common intraocular malignant tumor in adults.  Primary 
UMs are effectively treated by plaque radiotherapy or enucleation; however, up to 50% 
of UM patients who are treated for their primary tumors ultimately succumb to advanced 
disease (1, 2). The liver is the organ of metastasis in ~90% of advanced-stage disease 
(3, 4). Standard chemotherapies rarely induce clinical responses in patients with macro-
metastasis (5-7) and 1-year survival of metastatic UM (MUM) patients is <30% (8, 9). UM 
tumors have a low mutational burden (10, 11), which is thought to contribute to their low 
immunogenicity and poor responses to immunotherapy. Objective response rates appear 
low in retrospective studies, ranging from 5% with ipilimumab, 3.6% with anti-
programmed cell death 1 (PD-1) antibodies, and 10-21% with combination ipilimumab 
and nivolumab (12-17). Currently, there is no Food and Drug Administration (FDA) 
approved treatment for MUM. There is an urgent unmet need for effective therapeutic 
strategies for advanced-stage UM.  
 
Activating mutations (typically Q209) in genes encoding alpha subunits of the 
heterotrimeric G proteins, GNAQ and GNA11, are found in 80-90% of UM (18-21). Mutant 
GNAQ and GNA11 signal to several pathways including MEK-ERK1/2 which are required 
for tumor cell growth (19, 20, 22, 23). Unfortunately, inhibition of the MEK/ERK pathway 
has failed to provide clinical benefits in metastatic uveal melanoma (MUM) patients. In a 
phase II trial (NCT01143402), the MEK inhibitor, selumetinib, exhibited a 15% partial 
response rate and improved median progression-free survival (PFS) compared to 
standard chemotherapy (temozolomide/ dacarbazine) (15.9 versus 7.0 weeks, 
respectively); however, overall survival improvement did not reach statistical significance, 
possibly due to the cross-over design of the trial (24). The SUMIT phase III trial (25) 
analyzing selumetinib in combination with dacarbazine was terminated early since it 
showed a poor response rate and only a 1 month improvement of median PFS, compared 
to dacarbazine alone. This suggests that, although MEK/MAPK networks activated by 
PLC-β may contribute to UM initiation, they may not be critical for the maintenance of 
tumorigenic potential in UM.  
 
Using a synthetic biology approach and a genome-wide RNAi screen, Dr. Gutkind's group 
at UCSD have shown that Gαq activates a highly conserved Rho-GEF, TRIO, and the 
consequent stimulation of Rho-regulated pathways leading to the activation of YAP, 
independently of PLC-β, the best known target of Gαq (26). Using a novel computational 
biology approach to identify synthetic lethal gene interactions, his group further 
discovered that the tyrosine kinase FAK provides a direct link between Gαq and tyrosine 
phosphorylation networks controlling YAP and promotes UM growth (27).  
 


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FAK is a cytosolic protein kinase which has multiple effects on a cancer cell and its 
environment. It is associated with drug resistance as it can be activated in cancer cells 
when it is exposed to other signal tyrosine kinase inhibitors. FAK can also be activated 
by cellular stress and receptor tyrosine kinase inhibitors and signal through critical nodes 
in signal transduction pathway such as MEK (28). It has been shown that targeting FAK 
kinase activity has the potential to modulate intra- tumoral Treg levels establishing an 
immunosuppressive tumor microenvironment. These findings suggest that FAK may have 
a significant impact on tumor stroma, restoring anti-tumor immunity (29). 
 
Interestingly, UM represents the human cancer harboring the highest level of FAK 
overexpression (27). Furthermore, PTK2 expression (the gene that encodes for FAK) has 
been significantly correlated with reduced overall survival in UM patients, aligning with its 
potential biological role in UM (27). Dr. Gutkind’s group has previously confirmed that a) 
FAK knock down (KD) or CRISPR/Cas9 genome editing reduces UM cell proliferation and 
tumorigenesis, b) treatment FAK inhibitors had limited effects in SKCM harboring BRAF 
oncogenes, but inhibited FAK (and YAP), and reduced cell proliferation and tumor growth 
in vivo in UM (28), thereby establishing FAK as a druggable target in UM.  
 
Building on this, laboratories of Drs. Gutkind, Aplin, and Sato have directed their efforts 
on identifying combinatorial precision therapies which may be used for the treatment of 
uveal melanoma. They have found that the combination of FAK and MEK inhibition 
synergistically inhibits uveal melanoma growth (Fig. 1A) and promotes apoptosis in vitro, 
and reduces xenograft tumor volume in vivo (Fig. 1B).  
 
Together, the robust preliminary data generated by our team and, the urgent need for 
therapeutic options for patients with MUM provide a promising opportunity to use this 
combination in MUM patients. The strong basic science, translational, and clinical 
expertise of our team put us in an excellent position to conduct bi-directional bench to 
clinic and clinic to bench translational research.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Figure 1 
 
 
 
1.2 
Clinical Studies 
The combination of Defactinib (VS-6063) and VS-6766 (CH5126766) has previously been 
evaluated in patients with advanced solid tumours (IST-VS-6063-003, protocol CCR4642, 
FRAME). Preliminary efficacy results are available for a small number of subjects with 
low-grade serous ovarian cancer (LGSOC, KRAS wild-type or mutant) and non-small cell 
lung cancer (NSCLC) with KRAS mutations treated with a combination of VS-6766 and 
Defactinib. The response rates in subjects with KRAS-mutated LGSOC were 67% (4 of 6 
subjects with PR) and 50% (4 of 8 subjects with PR) of all subjects with LGSOC (KRAS 
wild-type or mutant). Five of the 8 subjects had prior MEK inhibitor therapy, including 3 
responders. Of the 10 subjects with NSCLC, 1 subject with KRAS (G12V)-mutated cancer 
achieved PR; 3/10 subjects received treatment for ≥24 weeks. The results of the 
combination treatment are promising.  
Together, the robust preliminary data generated by our team and the urgent need for 
therapeutic options for patients with MUM provide a promising opportunity to use this 
combination in metastatic uveal melanoma patients to improve outcomes.   
 
 
Figure 1: Combination of FAK and MEK inhibitors in uveal melanoma.  
A: Synergistic effects of combination treatment with FAK and MEK inhibitors on 92.1 uveal melanoma 
cell line. The CI value indicates synergism (CI < 1), additive effect (CI = 1), or antagonism (CI > 1) 
induced by the drug combination. Combination of FAK inhibitor (VS4718) and various MEK inhibitors 
including RO512766 showed synergistic effects on uveal melanoma cells.  
B: Growth suppression of metastatic uveal melanoma (UM001) established in the liver of NSG mice. 
MEK inhibitor (Trametinib) in combination with FAK inhibitor (VS4718) completely suppressed the 
growth of metastatic uveal melanoma cells in the liver (red line).   
Tumor Growth in Each Group  
A.  
B. 


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1.3 
Potential Risks  
The clinical data for both Defactinib (VS-6063) and VS-6766 (CH5126766) can be found 
in the Investigator Brochures. The safety and tolerability of the combination of the two 
drugs was shown in the ongoing investigator-sponsored basket study of Defactinib with 
VS-6766 (IST-VS-6063-003, protocol CCR4642, FRAME). 
1.3.1 
Potential Risks 
1.3.1.1 Toxicity seen in Defactinib (VS-6063) Clinical Studies 
A summary of treatment-emergent adverse effects (TEAEs) reported among patients with 
advanced cancer treated with Defactinib can be found in the IB. Overall, 277 (75.5%) of 
367 patients with cancer treated with Defactinib experienced at least 1 TEAE that was 
considered by the Investigator to be at least possibly related to Defactinib. Overall, GI 
disorders were the most common type of treatment-related TEAEs reported to date (171 
patients; 46.6%), with nausea being the most common individual study drug-related TEAE 
(85 patients; 23.2%) and diarrhea (76 patients; 20.7%) and vomiting (50 patients; 13.6%) 
being among the most common. Other common study drug-related TEAEs included 
fatigue (78 patients; 21.3%), hyperbilirubinemia (48 patients; 13.1%)/blood bilirubin 
increased (43 patients; 11.7%), and decreased appetite (37 patients; 10.1%). 
 
Overall, 85 (23.2%) of 367 patients with cancer treated with Defactinib experienced at 
least 1 SAE. The most common types of SAEs were respiratory, thoracic, and mediastinal 
disorders (20 patients; 5.4%); GI disorders (19 patients; 5.2%); and infections and 
infestations (15 patients; 4.1%). The most commonly reported serious adverse events by 
preferred terms were malignant neoplasm progression (16 patients; 4.4%), vomiting (7 
patients; 1.9%), dyspnea (6 patients; 1.6%), and nausea and pneumonia (each 5 patients; 
1.4%). All other SAEs occurred in ≤3 patients. 
 
Overall, 19 (5.2%) of 367 patients experienced at least 1 serious adverse reaction (SAR) 
(i.e., an SAE that was considered by the Investigator to be at least possibly related to 
Defactinib. GI disorders were the most common type of SAR, occurring in 6 (1.6%) 
patients. The only individual SARs occurring in >1 patient included nausea and vomiting 
(each 3 patients; 0.8%) and dehydration (2 patients; 0.5%). 
 
In addition, in 3 non-Verastem-sponsored clinical trials, 46 SAEs have been reported in 
a total of 21 (38.8%) of 54 patients. The most commonly reported SAEs are abdominal 
pain (7 patients; 13.0%), disease progression (2 patients; 3.7%) and hyponatremia (2 
patients; 3.7%). Abdominal pain and disease progression were also reported as SAEs in 
Verastem-sponsored trials. Hyponatremia however was only reported as an SAE in non-
Verastem-sponsored clinical trials. Of the SAEs reported in the 3 studies, SAEs 


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considered related by the investigator included single reports (1 patient; 1.9%) of 
abdominal pain, arthralgia, asthenia, back pain, dehydration, nausea, and syncope. 
 
Gastrointestinal Effects 
Nausea with or without vomiting and diarrhea are commonly reported with Defactinib. In 
the VS-6063-202 study in patients with malignant pleural mesothelioma, nausea and 
diarrhea were reported more commonly in patients on Defactinib than in patients who 
received placebo, whereas the incidence of vomiting was relatively similar. These events 
are generally mild or moderate (Grade 1 or 2) in intensity and non-serious, although 
serious cases have been reported. Prophylactic medications may be used as needed if 
nausea is found to occur with administration of Defactinib and cannot be managed with 
small amounts of food. Diarrhea should be managed as described in the clinical study 
protocol. 
 
Increased Bilirubin 
Increased bilirubin has been observed with Defactinib. These increases are generally 
asymptomatic and not associated with increases in AST or ALT. Increased bilirubin often 
resolves spontaneously, even with continued drug treatment. 
 
Non-serious adverse events reported from monotherapy studies VS-6063-102, VS-6063-
201, VS-6063-202, VS-6063-203, B0761001 (N=313) that are determined by the sponsor 
to be expected with the use of VS-6063 include hyperbilirubinemia (N=38; 12.1%) and 
blood bilirubin increase (N=32; 10.2%) with a maximum CTCAE Grade 3. 
 
Drug Interactions 
In vitro studies have shown that Defactinib and metabolites inhibits CYP2C9 and/or 
CYP3A4 in human liver microsomes. Extrapolation to expected human exposure 
indicates the potential for inhibition or induction of CYP enzymes is low. However, as the 
clinical significance of these potential interactions has not been formally assessed, it is 
recommended that compounds that are substrates for CYP2C9 and CYP3A4 are used 
with caution in concomitant administration with Defactinib may increase their exposure. 
Defactinib inhibited efflux transporter P-gp (IC=16 μM) and influx transporters OATP 1B1 
(IC50= 0.4 μM) and OATP1B3 (IC50=8.5 μM) in vitro. Defactinib and metabolites inhibited 
UGT1A1 in vitro. 
 
Additionally, Defactinib has been shown to be metabolized by CYP2C9 and CYP3A4, 
concomitant use of strong inhibitors and inducers of CYP3A4 or CYP2C9 should be 
avoided if possible or used with caution. 
 
 


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Warfarin 
Defactinib may have the potential to increase warfarin exposure due to a potential drug-
drug interaction affecting warfarin’s metabolism. Based on a review of information from 
all VS-6063 clinical studies, an increased level of caution is recommended. If patients can 
safely stop taking warfarin, they should do so. If patients require anti-coagulation, an 
alternative to warfarin should be considered. Patients who require anti-coagulation but 
cannot discontinue warfarin should be monitored closely and have their INRs checked 
more frequently whilst on Defactinib. For patients requiring the start of anti-coagulation 
therapy during the course of any Defactinib study, alternatives to warfarin are 
recommended. 
 
Pregnancy and Fertility 
Fertility and teratology studies with Defactinib have not been conducted. Safety for 
women of childbearing capacity cannot be implied from the existing data. It is required for 
clinical studies that men and women of childbearing potential agree to use adequate 
contraception (double barrier birth control) for the duration of study therapy and for 3 
months after the last dose of Defactinib. 
 
Additional Precautions 
As with any investigational agent, there is also the potential risk of toxicities observed in 
preclinical studies. 
 
With the exception of some hepatobiliary and testicular toxicities, the toxicities observed 
in the preclinical studies may reasonably be expected to reverse following drug 
discontinuation. Corresponding slight to marked increases in ALT, AST, ALP, total 
bilirubin, and GGT were generally seen in affected animals, although individual animal 
parameters were highly variable. Elevated liver enzymes generally preceded the 
observation of histopathological findings, although a rigorous time course of enzymes and 
histological changes was not investigated. These parameters will be routinely monitored. 
 
Defactinib has not been tested for carcinogenic activity in a lifetime rodent bioassay. The 
risk associated with the finding of in vitro aneuploidy with Defactinib in an advanced 
cancer population is unknown. 
 
1.3.1.2 Toxicity seen in VS-6766 (CH5126766) Clinical Studies 
Final safety data are available for two Phase 1 clinical studies (30, 31). The overall 
frequency of VS-6766 (CH5126766) treatment-emergent adverse events (TEAEs) is 
based on the data from 52 subjects in Phase 1 study NO21805, with comparative TEAE 
data provided by Phase 1 study JO22631 in 12 Japanese subjects.  
 


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The most commonly reported TEAEs (≥25%) were dermatitis acneiform and rash (67%), 
diarrhea (65%), blood creatinine phosphokinase increase (58%), asthenia (46%), 
peripheral edema (40%), nausea (38%), blurred vision (37%), constipation (33%), 
hypoalbuminemia (33%), vomiting (29%), aspartate aminotransferase (AST) increase 
(27%), stomatitis (27%) and pyrexia (25%). In general, the available TEAE data from the 
other studies are consistent with this safety profile. 
 
The identified risks for VS-6766 treatment are skin toxicity, eye toxicity, creatinine 
phosphokinase elevation, gastrointestinal tract toxicities, and edema. The potential risks 
are effects on cartilage, genotoxicity, hematological toxicity, drug-drug interactions, liver 
function abnormalities, renal toxicity, and tissue mineralization.  
 
There were 103 SAEs reported in the total of 131 subjects in monotherapy studies 
NO31895 (CSR final data), JO22631 (CSR final data), MED18-052 (29 Aug 2019 data 
cut-off) and ISTCCR3808 monotherapy cohorts (April 1, 2020 data cut-off). There were 
43 SAEs judged to be at least possibly treatment related, with most frequent (≥2 events) 
being rash (8 events), CPK elevation (5 events), increased alkaline phosphatase (2 
events) and diarrhea (2 events). The remaining single events were abnormal hepatic 
function, acute pigment epithelial detachment, abdominal pain, ALT increase, anemia, 
AST increase, auditory hallucination, blurred vision, bronchial infection, capillary leak 
syndrome, confusional state, dyspnea, febrile neutropenia, gamma-glutamyltransferase 
increase, left ventricular dysfunction, myopathy, nausea, pulmonary embolism, pyrexia, 
retinal detachment, troponin increase, urosepsis, venous embolism, visual hallucinations, 
visual impairment and vomiting. 
 
The AE and SAE profile of VS-6766 is generally consistent with the AEs reported for other 
MEK/BRAF inhibitors. 
 
 
IDENTIFIED RISKS 
Skin Toxicity 
Skin disorders have been one of the most frequently reported study treatment-related 
adverse events observed in Study NO21895. Eighty-two treatment-related adverse 
events were observed in 41 out of 52 subjects in the “skin and subcutaneous tissue 
disorders” System Organ Class. Thirty-five (35) events of dermatitis acneiform and rash 
were observed, of which 13 events were Grade 3. In Study JO22631, all 12 subjects 
experienced AEs reported as treatment-related rash. The most common event was 
dermatitis acneiform (10 subjects). One subject experienced Grade 3 rash. In Study 
CCR3808, 40 events of acneiform and/or maculopapular skin rash were reported, of 
which 10 events were Grade 3. 


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Rash-related toxicity and the intensity of such reactions were reversible after drug 
decrease and/or drug interruption, and were associated with adequate medical treatment 
including corticosteroids (topical and systemic) and antibiotics (topical and systemic). 
 
Recommended guidelines for rash management are as follows: 
• 
Grade 1: No change in study drug. Any of the following: minocycline 
(recommended dose: 200 mg twice daily [loading dose] followed by 100 mg 
oral twice daily x 7 to 10 days), topical tetracycline, topical clindamycin, topical 
silver sulfadiazine, oral diphenhydramine, or oral prednisone (short course) at 
discretion of the Investigator. 
• 
Grade 2: No change in study drug. Manage as described above for Grade 1 
rash. 
• 
Grade 3 (or intolerable Grade 2): Dose reduce or interrupt. Manage as 
described above for Grade 1 rash. Dose can be re-escalated when rash is 
Grade ≤2. 
• 
Grade 4: Discontinue subject from study or treat with a reduced dose (previous 
dose level or intermediate dose after approval of Sponsor) according to clinical 
judgment. Manage as described above for Grade 1 rash. 
 
Treatment options for rash could also follow recent treatment strategies that have been 
proposed in published guidelines for effective management of EGFR inhibitor-associated 
cutaneous toxicities (32). Where possible drug related skin toxicity will be further 
characterized by photography, paired biopsies (affected and unaffected skin) and in the 
case of ≥ Grade 3 rash a predose PK blood sample. 
 
Subjects should be advised to avoid sun exposure, and to use sunscreen (sun protection 
factor [SPF] 30 or higher) containing zinc or titanium oxide rather than synthetic sun 
blocks, wear protective clothing and apply lip balm with sunscreen. Subjects should use 
soap-free face cleansers (such as no-rinse cleansing gel twice a day). It is recommended 
to use an antimicrobial soap, however, to effectively clean areas like the armpits and 
genitals, which are prone to infection, subjects should use a mild soap for showering. 
Subjects should use an alcohol-free, oil-free moisturizing cream twice daily. Gloves 
should be worn to protect the subjects’ hands when household cleaning is performed. If 
subjects experience skin toxicity, they should inform the Investigator and discuss 
treatment of the skin. 
 
Meanwhile, investigations of intermittent regimens have been implemented in an attempt 
to decrease the incidence and intensity of skin disorders observed in Study NO21895 


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while retaining the plasma exposure at levels expected to have a potential for therapeutic 
benefit. 
 
Eye Toxicity 
Eye disorders, including blurred vision and retinal disorders, have been observed in Study 
NO21895. Fifty-eight adverse events in 36 out of 52 subjects in the “eye disorders” 
System Organ Class. Blurred vision was observed in 19 events, 3 of which were Grade 
3. In Study JO22631, blurred vision occurred in 4 out of 12 subjects, of which all of them 
were Grade 1 or 2. In Study CCR3808, 20 events of visual abnormalities such as blurred 
vision were reported, of which one subject experienced Grade 3 blurred vision with Grade 
3 acute pigment epithelial detachment. 
 
Complete ophthalmologic examinations should be performed and interpreted by a 
qualified ophthalmologist, including visual acuity test, corneal examination, intraocular 
pressure 
measurements 
by 
tonometry, 
slit-lamp 
ophthalmoscopy, 
indirect 
ophthalmoscopy, spectral domain optical coherence tomography (OCT), digital fundus 
photography and, if indicated, angiography. Interruption and/or reduction of dosing is 
recommended for management of eye toxicity. Any abnormality observed by an 
ophthalmologic examination as well as symptoms should be carefully monitored until 
improved. Guidelines from a specialized ophthalmologist can be provided if requested by 
the Investigator. 
 
Creatine Phosphokinase Elevation 
In Study NO21895, there were 30 events of blood CPK elevation reported (29 treatment-
related events) including 6 Grade 3 events and 1 Grade 4event. In Study JO22631, blood 
creatine phosphokinase increased in 10 out of 12 subjects, of which all of them were 
Grade 1 or 2. In study CCR3808, CPK elevation was observed in 29 out of 44 subjects 
including 4 subjects with Grade 3 events and one subject with a Grade 4 event.  
 
In the event of Grade 3 CPK elevation, Investigators should measure myoglobinuria using 
dipstick or accurate urine analysis and consider additional diagnostic evaluation (CPK-
MB, CPK electrophoresis, troponin) to help determine the etiology of the CPK abnormality 
and to guide treatment. Investigators should check for any cardiac symptoms and conduct 
a muscle examination. Information regarding muscle symptoms, exercise, concomitant 
medications, and alcohol consumption should be recorded. 
 
Regardless of the grade of the CPK elevation, CPK should be monitored until levels return 
to normal and at least weekly and/or bimonthly as per the protocol. 
 
 


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Gastrointestinal Tract Toxicities 
Gastrointestinal toxicities were observed in Study NO21895. A total of 145 adverse 
events occurred in 45 out of 52 subjects in the “gastrointestinal disorders” System Organ 
Class. The most commonly reported AEs was diarrhea (34 events). There were no ≥ 
Grade 3 AEs of gastrointestinal disorders. In Study JO22631, gastrointestinal AEs, which 
at least 4 out of 12 subjects experienced, were diarrhea (11), stomatitis (9), nausea (4), 
constipation (4) and decreased appetite (4). There were no ≥ Grade 3 AEs of 
gastrointestinal disorders. 
 
Recommended guidelines for diarrhea are as follows: 
• 
Grade 1: No change in study drug. Consider treatment with loperamide (4 mg 
at first onset, followed by 2 mg every 2-4 hours until diarrhea free for 12 hours). 
• 
Grade 2: No change in study drug. Manage as described for Grade 1. 
• 
Grade 3: Decrease dose or interrupt dosing. Manage as described for Grade 
1. Dose can be re-escalated when diarrhea is Grade ≤ 1. 
• 
Grade 4: Discontinue subject from study or treat with a reduced dose (previous 
dose level or intermediate dose after approval of Sponsor) according to clinical 
judgment. Manage as described for Grade 1. 
 
Interruption and/or reduction of dosing as well as supportive treatment will improve 
gastrointestinal toxicity in the clinical studies. If gastrointestinal bleeding is suspected, 
interruption of dosing and a standard work-up of the gastrointestinal tract is required. 
 
Edema 
In Study NO21895, 21 events of peripheral edema were observed, 1 of which was Grade 
3. In Study JO22631, edema occurred in 5 out of 12 subjects, of which all were Grade 1 
or 2. 
 
 
POTENTIAL RISKS 
Effects on the Bone and Cartilage 
Relevance of bone and cartilage findings, which were only observed in nonclinical 
species, is considered low in adult subjects in clinical studies. In rats, bone and cartilage 
thickening was observed at higher doses, with bone changes partially or completely 
resolving during the recovery period. A single monkey showed osteoclast activation and 
decreased osteoblasts at a dose above the repeat dose MTD. There were no effects on 
bone in monkeys at any dose. Suspicion of bone and cartilage changes should lead to 
evaluation. 
 
 


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Genotoxicity 
No genotoxic potential was observed in any of the tests (Ames test, chromosome 
aberration test, or in vivo micronucleus test) conducted with VS-6766. 
 
Hematological Toxicity 
Hematological toxicity is unlikely and is assessed in clinical studies. Dose interruption 
and/or dose reduction for management of hematological toxicities is recommended. 
 
Drug-drug interactions 
No drug interaction studies have been conducted with VS-6766. In vitro testing 
demonstrated a low potential for drug-drug interactions mediated by CYP inhibition at 
pharmacologically relevant concentrations; however, a weak potential for CYP3A4 
induction was noted in vitro. 
 
VS-6766 exposure may be affected by CYP3A4 inhibitors or inducers since VS-6766 is 
mainly metabolized by CYP3A4 enzymes. As such, concomitant administration of 
CYP3A4 inhibitors and inducers is not recommended. 
 
Liver Function Abnormalities 
In Study NO21895, aspartate aminotransferase increase, alanine aminotransferase 
increase, and blood lactate dehydrogenase increase were reported in 14 events (3 
treatment-related), 11 events (2 treatment-related), and 9 events (no treatment-related), 
respectively. Among them, Grade 3 events were observed (5, 2, 4 events, respectively). 
In Study JO22631, aspartate aminotransferase increase was observed in 9 out of 12 
subjects, blood ALP increase was observed in 5 subjects and ALT increase was observed 
in 4 subjects. Treatment-related ≥ Grade 3 AEs occurred in one subject each as AST 
increase, ALT increase and gamma-glutamyl transferase increase. Only the AST 
increase was determined as Grade 4, and the other seven events were determined as 
Grade 3. 
 
Liver related laboratory abnormalities, including AST, ALT, and ALP, can be observed in 
the standard monitoring of blood chemistries in the clinical studies. If any clinically 
significant increase in liver enzyme level occurs, the dosing should be suspended. 
 
Renal Toxicity 
In Study NO21895, only one treatment-related adverse event in one subject was 
observed in the “renal and urinary disorders” System Organ Class, which was proteinuria. 
Abnormalities of kidney function, including creatinine and blood urea nitrogen, can be 
observed through standard monitoring of blood chemistries in the clinical studies. If any 


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clinically significant increase in creatinine and/or blood urea nitrogen level occur, the 
dosing should be suspended. 
 
Tissue Mineralization 
The relevance of VS-6766 treatment-related tissue mineralization for humans is 
considered low. Suspicion of ectopic mineralization should lead to evaluation, with 
consideration of dosing interruption. 
2 Study Objectives 
2.1 
Objectives 
2.1.1 
Primary 
• To investigate the potential efficacy of the combination of Defactinib (VS-6063) and 
VS-6766 in patients with metastatic uveal melanoma. 
2.1.2 
Secondary 
• To assess the effectiveness of Defactinib in combination with VS-6766 in patients 
with MUM. 
• To assess the safety and toxicity profile of the combination of Defactinib and VS-
6766. 
2.1.3 
Exploratory 
• To study the pharmacodynamic profile of Defactinib in combination with VS-6766 
in pre-treatment, on-treatment, and post-treatment tumor biopsies. 
• To investigate mechanisms of resistance to the combination of Defactinib and 
VS-6766. 
• To investigate the potential efficacy of circulating cell free DNA for 
prediction/monitoring. 
2.2 
Endpoints/Outcome Measures 
2.2.1 
Primary 
• Determination of best overall response (BOR) and disease control rate (DCR) 
(CR+PR+SD) as determined by RECIST criteria version 1.1. 
2.2.2 
Secondary 
• Determination of progression free survival and overall survival. 


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• Determination of causality of each adverse event to Defactinib and VS-6766 and 
grading severity according to the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) Version 5.0. 
2.2.3 
Exploratory 
• Changes in tumor metabolic activity, signaling to the ERK, YAP, FAK, and PI3K-
TOR pathways, changes in UM cell proliferation (Ki67) and apoptosis induction 
(caspase activation), and changes in tumor microenvironment. 
• Detection of biomarkers of resistance.   
• Correlation of circulating free DNA with cancer remission and predicting cancer 
relapse. 
3 Study Design 
3.1 
Characteristics 
This is an investigator-initiated, Phase II trial evaluating the combination of a FAK inhibitor 
(Defactinib, VS-6063) with a RAF/MEK inhibitor (VS-6766, CH5126766) for the treatment 
of patients with metastatic uveal melanoma.  
 
No medication is approved for MUM by the US FDA and potential clinical benefit could 
be obtained if MUM patients achieve stable disease (SD); therefore, we will consider 
Disease Control Rate (DCR) (CR+PR+SD) of 50% as a meaningful endpoint for this early 
phase clinical study. This is considered to be an appropriate goal since the Overall 
Response Rates (ORR) (CR+PR) and Disease Control Rate (DCR) (CR+PR+SD) of 
combination treatments using the FDA approved medications ipilimumab and nivolumab 
are reported to be 11.8-16.7% and 29.4-64%, respectively (15). 
 
The efficacy of this combination treatment will be assessed using the Simon’s two stage 
design [Optimal Design]. The trial is carried out in two stages. In stage I, a total number 
of 8 patients are accrued. If there are 2 or fewer overall responses (CR+PR+SD) among 
these 8 patients, further enrollment of patients may be stopped with the conclusion that 
the DCR cannot be 50% or greater. Otherwise, an additional 10 patients will be accrued 
in stage II, resulting in a total sample size of 18. If there are 7 or more responses among 
these 18 patients, we reject the null hypothesis and claim that the treatment is promising. 
3.2 
Number of Participants 
A total of up to 18 patients will be entered into this trial, depending on the disease control 
rate in the first stage of the study. 


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3.3 
Duration of Therapy 
Treatment should continue for up to 2 years unless (a) the patient asks to be withdrawn, 
(b) there is evidence of disease progression or (c) the patient is experiencing 
unacceptable toxicity or for any of the reasons listed in Section 11.4. 
In the absence of treatment delays due to adverse event(s), treatment may continue until 
one of the following criteria applies: 
• 
Disease progression, 
• 
Intercurrent illness that prevents further administration of treatment, 
• 
Unacceptable adverse event(s), 
• 
Patient decides to withdraw from the study, or 
• 
General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
 
If patients have mild progression (20-30% increase in the sum of the longest diameters 
from the baseline), and if the Principal Investigator concludes that patients have had 
clinical benefit from the study medications, the study treatment will be allowed to continue 
for 2 more cycles as long as patients tolerate the study medications without grade 3 or 
higher toxicity.  If further progression is confirmed with follow-up imaging studies, patients 
will be removed from the study. Patients who are treated past mild progression must meet 
the following criteria: 
• 
Absence of symptoms and signs indicating clinically significant progression of 
disease. 
• 
No decline in ECOG or Karnofsky performance status. 
• 
Absence of symptomatic rapid disease progression requiring urgent medical 
intervention (e.g., symptomatic pleural effusion, spinal cord compression). 
 
If patients obtain significant benefit from the study treatment (CR or PR), treatment 
continuation beyond 2 years will be discussed with Verastem Oncology, Inc. 
3.4 
Duration of Follow Up 
Post-treatment, patients will be followed for survival until their death or up to 2 years after 
the last patient is enrolled. 
3.5 
Treatment Assignment Procedures 
All patients will be given the combination of a FAK inhibitor (Defactinib, VS-6063) with a 
RAF/MEK inhibitor (VS-6766, CH5126766). There is no randomization procedure or 
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3.6 
Study Timeline 
3.6.1 
Primary Completion 
Estimated time from when the study opens to enrollment until completion of enrollment is 
6 to 18 months with an expected accrual rate of approximately 1 to 3 patients per month 
at Thomas Jefferson University Hospital. Patients may receive treatment until maximum 
clinical benefit is obtained, the development of intolerable side effects, or progression of 
disease is confirmed. Post-treatment, patients will be followed for survival until their death 
or up to 2 years after the last patient is enrolled.  
3.6.2 
Study Completion 
Estimated time from when the study opens to enrollment until completion of data analyses 
is 42 months. 
4 Study Enrollment and Withdrawal 
4.1 
Eligibility Criteria 
4.1.1 
Inclusion Criteria 
Individuals must meet all of the following inclusion criteria in order to be eligible to 
participate in the study: 
1. 
Histologically confirmed metastatic uveal melanoma.  
2. 
Predicted life expectancy of at least 12 weeks. 
3. 
4. 
 
5. 
ECOG performance status of 0 or 1.  
Measurable disease according to RECIST 1.1 based on spiral CT or MRI scan, 
all radiology studies must be performed within 28 days prior to registration. 
Corrected QT interval (QTc) < 470 ms (as calculated by the Fridericia 
correction formula, averaged over 3 ECGs). 
6. 
Hematological and biochemical indices within the ranges shown below. These 
measurements must be performed within two weeks (Day -14 to Day 1) before 
the patient goes on the trial. 
Laboratory Test 
Value required 
Hemoglobin (Hb) 
≥ 9.0 g/dL 
Absolute neutrophil count (ANC) 
≥ 1.5 x 109/L 
Platelet count 
≥ 100 x 109/L 
Serum bilirubin 
≤ 1.5 x upper limit of normal (ULN) 
Albumin 
≥ 3.0 mg/dL 
Creatine phosphokinase (CPK) 
≤ 2.5 x ULN 


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Alanine aminotransferase (ALT) 
and/or aspartate aminotransferase 
(AST) 
≤ 2.5 x ULN unless raised due to tumour 
in which case up to 5 x ULN is 
permissible 
Calculated creatinine clearance 
≥ 45 mL/min by the Cockcroft-Gault 
formula 
INR 
≤ 1.5 in absence of anticoagulation or 
therapeutic levels in presence of 
anticoagulation 
PTT 
≤ 1.5 x ULN in absence of anticoagulation 
or therapeutic levels in presence of 
anticoagulation 
 
7. 
Patients with adequate cardiac function (left ventricular ejection fraction ≥ 50%) 
by echocardiography or MUGA scan. 
8.  
No active retinopathy or retinal vein occlusion confirmed by full ophthalmological 
exam in the eye unaffected by uveal melanoma. 
9.  
Adequate recovery from toxicities related to prior treatments to at least Grade 1 
by CTCAE Version 5.0. Exceptions include alopecia and peripheral neuropathy 
grade ≤ 2. Subjects with other toxicities that are stable on supportive therapy 
may be allowed to participate with prior approval by the Sponsor. 
10. 
Men and women aged 18 years or over. 
11.  
Females with reproductive potential and their male partners agree to use highly 
effective method of contraceptive (per Clinical Trial Facilitation Group [CFTG] 
recommendations in Appendix C during the trial and for 3 months following the 
last dose of study drug. 
12. 
Written (signed and dated) informed consent and be capable of cooperating 
with treatment and follow-up. 
13. 
Absence of any psychological, familial, sociological or geographical condition 
potentially hampering compliance with the study protocol and follow-up 
schedule. 
 
4.1.2 
Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation in 
this study: 
1. 
Radiotherapy (except for palliative reasons), endocrine therapy, biological 
therapy, immunotherapy or chemotherapy during the previous four weeks (six 
weeks for nitrosoureas, Mitomycin-C) before treatment. 


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2. 
Ongoing toxic manifestations of previous treatments. Exceptions to this are 
alopecia or certain Grade 1 toxicities, which in the opinion of the Investigator 
and the DDU should not exclude the patient. 
3. 
Known untreated or active central nervous system (CNS) metastases 
(progressing or requiring corticosteroids for symptomatic control). Patients 
with a history of treated CNS metastases are eligible, provided they meet all 
of the following criteria: 
• 
Evaluable or measurable disease outside the CNS is present. 
• 
Radiographic demonstration of improvement upon the completion of 
CNS-directed therapy and no evidence of interim progression between 
the completion of CNS- directed therapy and the baseline disease 
assessment for at least 28 days. 
4. 
Gilbert syndrome diagnosed with elevated indirect (unconjugated) bilirubin 
( >1.2 mg/dl) at least two occasions with normal direct bilirubin in the absence 
of hemolysis or structural liver damage. 
5.  
Ability to become pregnant (or already pregnant or lactating). However, those 
female patients who have a negative serum or urine pregnancy test before 
enrollment and agree to use two medically approved forms of contraception 
(oral, injected or implanted hormonal contraception and condom, have an 
intra-uterine device and condom, diaphragm with spermicidal gel and 
condom) from time of consent, during the trial and for six months afterwards 
are considered eligible. 
6. 
Male patients with partners of child-bearing potential (unless they agree to 
take measures not to father children by using one form of medically approved 
contraception [condom plus spermicide] during the trial and for six months 
afterwards). Men with pregnant or lactating partners should be advised to use 
barrier method contraception (for example, condom plus spermicidal gel) to 
prevent exposure to the fetus or neonate. 
7. 
Major surgery within 4 weeks prior to entry to the study (excluding placement 
of vascular access), or minor surgery within 2 weeks of entry into the study 
and from which the patient has not yet recovered.  
8.  
Treatment with warfarin. Patients on warfarin for DVT/PE can be converted to 
low-molecular-weight heparin (LMWH). 
9. 
Acute or chronic pancreatitis. 
10. 
At high medical risk because of non-malignant systemic disease including 
active uncontrolled infection. 
11. 
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immunodeficiency virus (HIV). 
 
12.  
Patients with the inability to swallow oral medications or impaired 
gastrointestinal absorption due to gastrectomy or active inflammatory bowel 
disease. 
13. 
History of abdominal fistula, gastro-intestinal perforation, or diverticulitis.  
14.  
Patients with history of symptomatic cholelithiasis or cholecystitis within six 
months before enrollment. 
15. 
Concurrent ocular disorders in the eye unaffected by uveal melanoma: 
a) Patients with history of retinal vein occlusion (RVO), predisposing factors 
for RVO, including uncontrolled hypertension, uncontrolled diabetes 
b) Patients with history of retinal pathology or evidence of visible retinal 
pathology that is considered a risk factor for RVO, intraocular pressure > 
21 mm Hg as measured by tonometry, or other significant ocular pathology, 
such as anatomical abnormalities that increase the risk for RVO. 
c) Patients with a history of corneal erosion (instability of corneal epithelium), 
corneal degeneration, active or recurrent keratitis, and other forms of 
serious ocular surface inflammatory conditions. 
16. 
Concurrent congestive heart failure, prior history of class III/ IV cardiac disease 
(New York Heart Association [NYHA]), myocardial infarction within the last 6 
months, unstable arrhythmias, unstable angina or severe obstructive 
pulmonary disease. 
17. 
Patients exposed to strong CYP3A4 and strong CYP2C9 inhibitors within 7 
days prior to the first dose. Because the lists of these agents are constantly 
changing, it is important to regularly consult a frequently-updated list such as 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference texts 
such as the Physicians’ Desk Reference may also provide this information. 
18.  
Is a participant or plans to participate in another interventional clinical trial, 
whilst taking part in this Phase II study of VS-6766 in combination with VS-
6063. Participation in an observational trial would be acceptable. 
19.  
Patients with a history of hypersensitivity to any of the inactive ingredients 
(hydroxypropylmethylcellulose, mannitol, magnesium stearate) of the 
investigational product. 
20.  
Prior corticosteroids as anti-cancer therapy within a minimum of 14 days of 
first receipt of study drugs. 
21. 
Any other condition which in the Investigator’s opinion would not make the 
patient a good candidate for the clinical trial. 
 
 


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4.2 
Gender/Minority/Pediatric Inclusion for Research  
Our study will include both women and minorities but no children. Recruitment of patients 
will be non-biased, but there are epidemiological differences in the incidence of MUM 
which may be reflected in the final enrollment numbers.  
 
In population-based epidemiological studies, the age-adjusted incidence of uveal 
melanoma is higher in males compared with females. However, gender differences in 
large cohort clinical studies with no age adjustments have not been found (33). We expect 
about half of our patients to be female (9 of 18 patients).  
 
The relative risk calculation of uveal melanoma in various racial groups (Black, Asian and 
Pacific Islander, Hispanic, and non-Hispanic White) in 1352 patients using 1992 to 2000 
SEER program data revealed the ratios of Black:Asian:Hispanic:non-Hispanic White at 
1 : 1.2 : 5 : 19 (33). Therefore, we expect less than 5 patients to be of minority.   
4.3 
Strategies for Recruitment and Retention 
Thomas Jefferson University and Wills Eye Hospital are national referral centers for uveal 
melanoma. We have been seeing approximately 500 new uveal melanoma patients 
annually, in which 50-100 patients are metastatic; therefore, accrual of 18 uveal 
melanoma patients with metastasis within 18 months is feasible. This study will be 
registered on Clinicaltrials.gov; therefore, referral from other cancer institutes is expected.  
Furthermore, we will notify melanoma patient-supporting organizations such as MRF, 
OMF, and Cure-in-Sight once we open this study at Thomas Jefferson University 
Hospital. 
4.4 
Participant Withdrawal 
4.4.1 
Reasons for Withdrawal 
Participants are free to withdraw from participation in the study at any time upon request. 
The following are justifiable reasons for the Investigator to withdraw a patient from trial. 
• 
Unacceptable toxicity (AE/SAE) 
• 
Withdrawal of consent 
• 
Serious violation of the trial protocol (including persistent patient attendance 
failure and persistent non-compliance) 
• 
Sponsor’s decision to terminate the trial 
• 
Withdrawal by the Investigator for clinical reasons not related to the study 
medications 


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• 
Evidence of disease progression. If patients have mild progression (20-30% 
increase in the sum of the longest diameters from the baseline) and meet 
criteria listed in section 3.3, and if Investigators conclude that patients have had 
clinical benefit from the study medications, the study treatment will be allowed 
to continue for 2 more cycles as long as patients tolerate the study medications 
without grade 3 or higher toxicity.  If further progression is confirmed with follow-
up imaging studies, patients will be removed from the study.  
• 
Symptomatic deterioration 
• 
Pregnancy 
 
Patients that are discontinued from the study will be followed for their survival. 
4.4.2 
Handling of Participant Withdrawals and Participant Discontinuation of 
Study Intervention 
The Investigator must make every reasonable effort to keep each patient on trial for the 
whole duration of the trial (i.e. until 28 days after last combination therapy administration). 
However, if the Investigator removes a patient from the trial or if the patient declines 
further participation, final ‘off-study’ assessments should be performed before any 
therapeutic intervention. All the results of the evaluations and observations, together with 
a description of the reasons for withdrawal from the trial, must be recorded in the medical 
records and in the eCRF. 
 
Patients who are removed from the trial due to adverse events (clinical or laboratory) will 
be treated and followed according to accepted medical practice until adverse events 
become grade 1 or less, or chronic. All pertinent information concerning the outcome of 
such treatment must be recorded in the eCRF and on the serious adverse event (SAE) 
report form where necessary. 
 
Patients who do not complete one cycle of dosing with VS-6766 and Defactinib (VS-6063) 
for reasons other than toxicity will be replaced. 
4.5 
Premature Termination or Suspension of Study 
This study may be suspended or prematurely terminated if there is sufficient reasonable 
cause. Written notification, documenting the reason for study suspension or termination, 
will be provided by the suspending or terminating party to Verastem Oncology and the 
Food and Drug Administration (FDA). If the study is prematurely terminated or 
suspended, the principal investigator will promptly inform the IRB and will provide the 
reason(s) for the termination or suspension.  
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• Determination of unexpected, significant, or unacceptable risk to participants. 
• Insufficient adherence to protocol requirements. 
• Data that is not sufficiently complete and/or evaluable.  
• Determination of futility. 
5 Study Intervention 
5.1 
Study Product  
This is an investigator-initiated, Phase II trial evaluating the combination of a FAK inhibitor 
(Defactinib, VS-6063) with a RAF/MEK inhibitor (VS-6766, CH5126766) for the treatment 
of patients with metastatic uveal melanoma. Both VS-6063 and VS-6766 are 
investigational medicinal products of Verastem Oncology. 
5.2 
Defactinib (VS-6063) 
Defactinib, or VS-6063, is a small molecule, orally available potent adenosine-5'-
triphosphate (ATP)-competitive, reversible inhibitor of focal adhesion kinase (FAK) and 
proline-rich tyrosine kinase-2 (Pyk2). 
5.2.1 
Acquisition 
Defactinib (VS-6063) will be supplied by Verastem Oncology. 
5.2.2 
Formulation, Packaging, and Labeling 
Defactinib (VS-6063) 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, 
formulation components include microcrystalline cellulose, lactose monohydrate, sodium 
starch glycolate, and magnesium stearate. VS-6063 tablets are packaged in 120 cc 
(HDPE) bottles, using an induction seal closure and a white polypropylene child-resistant 
cap. Packaging and labelling will be prepared to meet all regulatory requirements. 
5.2.3 
Product Storage and Stability 
All supplies must be stored in a secure, limited access storage area. 
 
Defactinib is stable when stored in the defined container closure (HDPE bottles). The 
labelled storage condition for the drug product is “Store between 15 and 25°C (59 and 
77°F).” Bottles are labelled with pill strength and other information as per local regulatory 
requirements. 
 
Dispensing and storage instructions for Defactinib will be provided in the Pharmacy 
Manual. 


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5.2.4 
Mechanism of action of VS-6063 
FAK and Pyk2 are members of the same family of non-receptor protein tyrosine kinases 
sharing significant sequence homology and are implicated as important integrating 
molecules in signal transduction cascades (Figure 2) (34). High expression of the protein 
tyrosine kinase FAK has been frequently demonstrated to be associated with invasive 
and metastatic malignancies, implicating FAK in malignant progression of multiple 
epithelial tumors (35). The role of Pyk2 in tumorigenesis is not as well established. 
However, recently Pyk2 upregulation was identified as a critical mechanism of feedback 
following inhibition of FAK function in endothelial cells implicating the dual inhibition of 
both FAK and Pyk2 as a potential strategy for targeting tumor angiogenesis (36). A 
comprehensive evaluation of selectivity against a large panel of other kinases in enzyme 
assays demonstrated that VS-6063 was highly selective for FAK and Pyk2 kinases 
strongly suggesting that its predominant pharmacologic activity is mediated by inhibition 
of FAK and Pyk2 kinases. 
Figure 2. 
 
 
 
 
Defactinib (VS-6063) has demonstrated antitumor efficacy in multiple human tumor 
xenograft models in mice including glioma, ovarian, colon, and pancreatic carcinoma 
[Biochemical Pharmacology, 73: 597-609, 2007] 


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models. In these studies, oral administration of VS-6063 resulted in significant growth 
inhibition of established tumors at well tolerated dose levels. 
5.2.5 
Non-clinical anti-tumor activity 
Oral administration of Defactinib (VS-6063) demonstrated antitumor efficacy in multiple 
human tumor xenograft models in mice including glioma, ovarian, colon, pancreatic, 
breast and mesothelioma models. 
 
For additional information concerning VS-6063, refer to the Investigator Brochure. 
5.2.6 
Toxicology 
A detailed review of nonclinical toxicology, PK and pharmacodynamic findings for 
Defactinib (VS-6063) are provided in the Investigator’s Brochure. Based on the nonclinical 
studies conducted with VS-6063, the liver and gallbladder, gastrointestinal tract, 
hematopoietic system, testes/epididymis, and cardiovascular system have been identified 
as potential targets. With the exception of hepatobiliary and testicular toxicities, the 
toxicities observed in the nonclinical studies for each of the 2 compounds may reasonably 
be expected to reverse following drug discontinuation. Appropriate monitoring in humans 
includes serial liver function testing, routine blood biochemical and hematological 
parameters, urinalyses, vital signs, and electrocardiograms (ECGs). 
5.2.7 
Clinical experience 
Defactinib (VS-6063) has been evaluated in eleven clinical studies to date: five clinical 
studies of single-agent treatment with VS-6063 in subjects with non-hematologic 
malignancies, three combination studies with VS-6063 in subjects with non-hematologic 
malignancies and three clinical studies in healthy volunteers. 
 
To date, a total of 408 patients have received VS 6063 in Verastem-sponsored clinical 
trials. Forty-one of these patients received VS- 6063 in healthy volunteer studies (VS-
6063-103, VS-6063-105, VS-6063-106), and the remaining 367 patients received VS-
6063 for advanced cancer. These include 194 patients who have received VS-6063 in an 
open-label study (studies B0761001, VS-6063-101, VS-6063-102, VS-6063-104, VS-
6063-107, VS-6063-201, and VS-6063-203) and 173 patients who received VS-6063 in 
one randomized blinded placebo-controlled phase 2 study (study VS-6063-202). Of these 
367 patients with cancer, 313 received VS-6063 as monotherapy and 54 received VS-
6063 in combination, 22 in combination with paclitaxel, 11 in combination with avelumab 
and 21 in combination with the Verastem investigational agent VS- 5584. In addition, 171 
patients received placebo in a VS-6063 clinical study (Study VS-6063-202). 
 
Additionally, three Investigator-sponsored trials (IST) have been initiated with Defactinib 
and have enrolled a total of 54 patients: IST-VS-6063-001 (Protocol 201510157, IND 


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128,094), a Phase 1 study of VS-6063 in combination with pembrolizumab and 
gemcitabine in patients with advanced cancer (sponsored by Washington University 
School of Medicine). For this study patient recruitment is currently ongoing. A total of 20 
patients have been enrolled and received VS-6063.  
 
IST-VS-6063-002 (Protocol FAK-PD12015, EudraCT 2015-003928-31), a Phase 1/2A 
study of VS-6063 in combination with pembrolizumab in patients with NSCLC, 
mesothelioma and pancreatic cancer (sponsored by Cancer Research UK). This study is 
being conducted in the UK and a total of 4 patients have been enrolled and received VS-
6063. IST-VS-6063-004 (IND 126,200), a Phase 2 study of single-agent VS-6063 in 
patients with tumors with NF2 loss (sponsored by National Cancer Institute). A total of 30 
patients have been enrolled and received VS-6063. 
 
Clinical studies conducted to date indicate that VS-6063 has a safety (AE and laboratory) 
profile that is clinically manageable at the doses administered. Based on the review of the 
cumulative data the potential risks identified in association with VS-6063 justify the 
continued investigation of VS-6063 in subjects with advanced cancer. 
5.2.8 
Pharmacokinetics 
Absorption of Defactinib (VS-6063) in rats and dogs was low to moderate. Defactinib 
showed high plasma protein binding with average unbound fractions similar for mice, 
dogs, and humans with less binding for rats. Hepatic metabolism was predicted to be the 
major clearance pathway for Defactinib in humans. Based on in vitro and in vivo 
evaluations, systemic blood clearance is 3.1 mL/min/kg, volume of distribution at steady 
state is 1.7 L/kg, elimination half-life is 4.4 hours, and oral bioavailability for Defactinib in 
humans is projected to be 19%. Assuming complete dissolution, a dosing regimen of 163 
mg BID is anticipated to achieve a targeted Css,ave of 133 ng/mL total (13.3 ng/mL free 
or 26 nM) to produce the intended pharmacologic effects. Twice a day dosing is expected 
to result in plasma concentrations above Ceff of 133 ng/mL for >15 hours. 
 
In the phase 1 First-in-Human (FIH, B0761001) study, under fasted conditions, single and 
multiple (Day 15) oral doses of Defactinib were rapidly absorbed and maximum serum 
concentrations were generally achieved 1 to 2 hours post dose. Cmax and AUC generally 
increased with increasing dose across the entire dose range, however, interpatient 
variability was high (>60%). Mean terminal elimination half-life was approximately 9 hours 
across the dose groups, but individual values showed high variability. Administration with 
food appeared to delay time to maximal concentration, and there was a trend towards 
increased exposure, but due to interpatient variability and the small number of patients, 
this data was inconclusive. Based on the phase 1 PK data for 425 mg BID fasted, the 
C12 for fasted patients at 400 mg BID (recommended Phase 2 dose) has been estimated 
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In follow-up studies in healthy males, with tablet formulation at 200 mg (VS-6063-103) 
and 400 mg (VS-6063-105), exposures increased by approximately 2 to 3-fold following 
single dose administration of Defactinib in the fed state compared to the fasted state. 
5.2.9 
Pharmacodynamics 
Due to the limited number of patients in each of the dosing cohorts in Study B0761001, 
no conclusions could be drawn regarding the pharmacodynamics effect of Defactinib (VS-
6063) on any of the collected biomarkers in that study. Ongoing clinical studies are 
continuing to investigate the pharmacodynamics of Defactinib by testing several 
biomarkers. Pharmacodynamic data from ongoing studies are not yet available. 
5.2.10 Efficacy 
The clinical data in subjects with KRAS mutant non-small cell lung cancer (Study VS-
6063-201) has recently been published. Fifty-five patients with KRAS mutant NSCLC 
were enrolled across 9 US sites between September 2013 and June 2016 (37). The 
patients were enrolled to one of the four molecularly defined cohorts. The mean age was 
62 years; 51% were female. The median number of prior lines of therapy was 4 (range 1-
8). Fifteen (28%) patients met the 12-week PFS endpoint, with one patient achieving a 
PR. Median PFS was 45 days. All enrolled patients terminated treatment before the study 
ended. Clinical efficacy did not correlate with secondary mutation status across this KRAS 
mutant population. Adverse events considered at least possibly related to VS-6063 were 
experienced by forty-four patients (80%). The majority of these were grade 1 or 2. Fifteen 
patients (27%) experienced at least possibly related grade 3-5 events, including 1 grade 
5 respiratory failure event. Underlying disease was a confounding factor in many patients. 
The most commonly reported treatment emergent adverse events of any grade were 
fatigue (35%), nausea (22%), diarrhea (20%), vomiting (18%), and increased bilirubin 
(16%). 
 
Study VS-6063-202 was terminated due to futility, following a Data Safety Monitoring 
Board (DSMB) recommendation from a pre-planned interim analysis. The study was not 
stopped due to any safety concerns with the study drug. The results of the analysis 
demonstrated that Defactinib was generally well-tolerated, but that there was not a 
sufficient level of efficacy in this patient setting (maintenance setting in malignant pleural 
mesothelioma patients with stable disease after ≥4 cycles of pemetrexed/platinum 
chemotherapy) to warrant continuation of the study. 
 
In Study B0761001 which evaluated the safety and efficacy of multiple doses of Defactinib 
in patients with an advanced non hematologic malignancy who were unresponsive to 
currently available therapies or for whom no standard therapy existed, no patient (N=46) 
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disease was achieved in 16 of 37 patients (43%) treated at doses ≥ 100 mg BID. Stable 
disease was not achieved at doses < 100 mg BID (N=9). Of note, 8 patients enrolled in 
this study had ovarian cancer. Of these patients, 4 patients achieved stable disease (3 
for ≥6 months) and the duration of stable disease with Defactinib was equal to or 
exceeded that reported with prior therapy. 
 
For further information on clinical studies with VS-6063 please refer to the Investigator 
Brochure. 
 
5.3 
VS-6766 (CH5126766) 
VS-6766 (CH5126776) is a dual RAF/MEK inhibitor which inhibits BRAF, CRAF and MEK. 
It has undergone a phase I trial and expectedly, the dose limiting toxicities have been 
chronic skin toxicity and acute eye toxicity (30). The drug has shown proof of mechanism 
inhibition of downstream biomarkers such as p-ERK in normal tissue and in tumor. 
5.3.1 
Acquisition 
VS-6766 will be supplied by Verastem Oncology. 
5.3.2 
Formulation, Packaging, and Labeling 
A complete certificate of analysis and a Qualified Person (QP) certification must be 
provided with each batch of study medications and be retained in the Investigator Trial 
File (ITF)/Pharmacy File. 
 
All study drug will be packaged and labelled in accordance with local regulations and 
Good Manufacturing Practice, stating that the drug is for clinical trial use only and should 
be kept out of the reach and sight of children. VS-6766 will be labeled, QP released and 
distributed by Verastem. 
 
VS-6766 will only be dispatched to sites after receipt of confirmation that the regulatory 
checklist is complete.  
 
VS-6766 will be supplied as hydroxypropyl methyl cellulose (HPMC; hypromellose) 
capsules for oral administration at a dosage strength of 0.8 mg. The capsule fill consists 
of VS-6766 and the inactive ingredients mannitol and magnesium stearate. 
5.3.3 
Product Storage and Stability 
All supplies must be stored in a secure, limited access storage area. VS-6766 must be 
stored at 2-8 C protected from light and moisture. 
5.3.4 
Mechanism of action of VS-6766 


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VS-6766 is a highly selective, dual RAF and MEK inhibitor. VS-6766 inhibited RAF family 
enzymes and MEK1 with a 50% inhibitory concentration (IC50) of 0.056 μM (RAF-1), 
0.019 μM (BRAF), 0.0082 μM (BRAF V600E), and 0.16 μM (MEK1). VS-6766 does not 
inhibit other serine/threonine and tyrosine kinases in enzyme assays against 32 kinases 
(The Institute of Cancer Research) and in the ATP competitive binding assay against 253 
kinases (Ambit Biosciences). VS-6766 is the first example of a tandem MAPK signaling 
pathway inhibitor and provides a new strategy for cancer therapy. 
5.3.5 
Non-clinical anti-tumor activity 
In in vitro cell-based assays, VS-6766 inhibited the phosphorylation of both MEK1/2 and 
ERK1/2, the direct substrates of RAF and MEK1/2, respectively, in a dose-dependent 
manner. The effects of VS-6766 on cell growth from the blocking of the RAF/MEK kinase 
were evaluated in various cancer cell lines, with wild-type and mutated KRAS and BRAF. 
A broad spectrum of anti-proliferation activity was observed; in particular in melanoma, 
non-small cell lung cancer (NSCLC), pancreatic cancer and colorectal cancer cells. For 
additional information, please refer to the Investigator’s Brochure. 
 
In vivo anti-tumor activities of VS-6766 were evaluated in xenograft models. VS-6766 
demonstrated a potent and wide spectrum of anti-tumor activities in diverse human tumor 
xenograft models, including NSCLC, pancreatic, colorectal, melanoma, acute myelocytic 
leukemia, and hepatocellular carcinoma. Preferential efficacy was observed both in BRAF 
and RAS mutated tumors. Especially, KRAS and BRAF mutated tumors exhibited better 
responsiveness to VS-6766 with complete tumor regressions observed. 
 
In a 4-week repeated-dose toxicity study of VS-6766 in rats, skin lesion and tissue 
mineralization effects on the epithelium and findings in the gastrointestinal tract, the 
lymphohematopoietic system, the bone, and the liver were observed. Two male rats died 
during the dosing or withdrawal period. The cause of death was attributed to hemorrhage 
in the stomach due to vascular rupture related to vessel mineralization. 
 
From the results of safety pharmacology studies, no critical effects on the central nervous, 
the respiratory, and the cardiovascular systems were observed in rats or monkeys, and 
an in vitro study revealed that the effect on hERG currents was not concerning. There 
was no genotoxicity in any of the in vitro and in vivo tests. 
 
VS-6766 markedly suppressed the activation of the MAPK pathway in peripheral blood 
mononuclear cells (PBMC) as evidenced by the significant inhibition of the PMA-induced 
phosphorylation of both MEK and ERK. Clear correlation of pharmacokinetics (PK) and 
pharmacodynamics (PD) was observed. 
 


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VS-6766 is mainly metabolized by CYP3A4. Excretion of VS-6766 and its metabolites 
into urine and feces was almost completed within 48 h post-dose, suggesting both renal 
and biliary elimination. In rat urine, mainly the demethylated derivative and three unknown 
metabolites were observed; the parent compound was only a minor component. 
 
VS-6766 showed low potential for drug-drug interactions mediated by CYP inhibition at 
pharmacologically relevant concentrations. Exposure of VS-6766 may be affected by 
CYP3A4 inhibitors or inducers. In vitro, VS-6766 had no marked potential for induction of 
CYP1A2 activity and had weak potential for induction of CYP3A4 activity. It may affect 
the efficacy of co-administered compounds. 
5.3.6 
Toxicology 
Observed adverse effects following repeated administration were reversible, and they 
were considered to pose a reasonable safety risk/benefit profile for human subjects 
receiving a repeated oral administration in a well-controlled clinical setting. Based on the 
non-clinical safety data available, no major concerns were identified and data supported 
the Phase I clinical study to investigate the pharmacokinetics, pharmacodynamics, safety, 
and tolerability of VS-6766 in consenting cancer patients. 
5.3.7 
Clinical experience 
To date, an estimated 198 subjects have been exposed to VS-6766, as monotherapy 
(n=131) or in combination with other agents (n=67), in 5 clinical studies in subjects with 
advanced solid tumors or multiple myeloma. These studies included 2 terminated dose-
escalation Phase 1 studies (n=64 subjects) and 3 ongoing Phase 1 Investigator-
sponsored trials (IST) (n=134 subjects).  
 
The First in Human (FIH) Phase 1 trial was conducted in the Drug Development Unit 
(DDU) at The Royal Marsden Hospital (NO21895)(30). Expectedly, the dose limiting 
toxicities were chronic skin toxicity and acute eye toxicity (30). Fifty-two patients received 
VS-6766 at doses of 0.1–2.7 mg (QD), 2.7–4.0 mg (4-days-on, 3-days-off schedule (4/3)) 
or 2.7–5.0 mg (7-days-on, 7-days-off schedule (7/7)). The most common dose limiting 
toxicities (DLTs) were elevated creatine phosphokinase (CPK) n=3 and blurred vision, 
n=3. MTDs for each of the dosing schedules were 2.25 mg (QD), 4.0 mg (4/3) and 2.7 
mg (7/7). The most frequent adverse events (AEs) were rash-related (94.2%) and 
gastrointestinal disorders, predominantly diarrhea and stomatitis (79%). Cmax was 
reached 1–2 hours after dosing, with a mean terminal half-life of ~60 hours. Target 
inhibition was demonstrated in both normal skin and tumor tissue. Tumor shrinkage was 
observed in 42.2% of patients evaluable for response, including three partial responses 
(two confirmed and one unconfirmed). Efficacy findings were also supported by 
fluorodeoxyglucose positron emission tomography (FDG-PET) imaging data, which 
showed a reduction of FDG uptake in 71% of patients between baseline and Day 15. 


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VS-6766 PK parameters were linear and time-independent with a substantially longer 
half-life than has been reported for other specific MEK inhibitors (38-40). Plasma 
concentrations and exposure increased dose-proportionally and all doses of VS-6766 
achieved plasma concentrations known to be effective in preclinical models (41). VS-
6766 had a favorable PK/PD profile and encouraging preliminary anti-tumor activity in this 
population of heavily pre- treated patients, achieving tumor shrinkage in >40% of patients 
across all dose levels. Based on observed DLTs, MTDs, safety, PK/PD assessments, 
efficacy and the long-term expected tolerability a dose regimen of 2.7 mg (4/3) was 
proposed for further investigation in Phase II trials (RP2D). 
 
Study JO22631 was a Phase 1 dose escalation study in 12 Japanese subjects with 
advanced solid tumors (31). Doses of 0.8, 1.2, 1.8, and 2.25 mg once daily were tested. 
Three patients were enrolled in each dose cohort for a total of 12 patients. In the dose 
range tested, there was no evidence of a DLT and the MTD was not identified. As 2.25 
mg/day was had already been defined as the MTD of the QD dosing regimen in study 
NO21895, a decision was made by the sponsor to terminate the study without 
administering doses higher than 2.25 mg/day. No partial responses were observed in this 
study, but four of 12 subjects achieved stable disease. 
 
In study JO22631 a total of 10 SAEs occurred in 6/12 subjects, these being 1 subject in 
each of the 0.8 mg/day and the 1.2 mg/day cohorts, and 2 subjects in each of the 1.8 
mg/day and the 2.25 mg/day cohorts (CSR final data). Except for Contrast media allergy 
(1subject in the 1.2 mg/day cohort), a causal relationship to VS-6766 could not be ruled 
out in all SAEs, and these included embolism venous (1 subject in the 0.8 mg/day cohort), 
rash and pyrexia (1 subject in the 1.8 mg/day cohort), AST increase, ALT increase and 
gamma-glutamyltransferase increase (1 subject in the 1.8 mg/day cohort), rash (1 subject 
in the 2.25 mg/day cohort), and visual impairment and auditory hallucination (1 subject in 
the 2.25 mg/day cohort).  
 
IST-MED18-052 is a Phase 1 dose confirmation/expansion IST evaluating VS-6766 
single agent in ~31 subjects with advanced NSCLC with KRAS mutation and prior 
treatment with PD-1/PD-L1 inhibitor. The dose confirmation phase (3+3 design) is 
assessing the safety and tolerability of 4mg twice weekly VS-6766 dosing, with one 
possible dose reduction, to select a dose for expansion. The dose expansion phase will 
treat 25 subjects and assess efficacy (ORR per RECIST version 1.1). Approximately 31 
subjects will be enrolled. Ten subjects had been treated as of August 29, 2019. There 
were a total of 13 SAEs, with 10 at least possibly related to VS-6766 (4 mg BIW) (August 
29, 2019 data cut-off). The treatment-related SAEs were Grade 3 rash, Grade 3 
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phosphatase increase, Grade 2 alkaline phosphatase increase, Grade 2 nausea, Grade 
2 diarrhea, Grade 3 bilirubin increase, Grade 3 anemia, and Grade 2 vomiting. The study 
was opened in August 2018 and is ongoing.  
 
IST-CCR3803 is a Phase 1 dose escalation/expansion IST evaluating VS-6766 single 
agent in ~88 subjects with advanced tumors or multiple myeloma (~54 subjects), and VS-
6766 combined with everolimus, a mTORC1 inhibitor, in subjects with advanced solid 
tumors (~24 subjects). On evaluating two different dosing schedules (twice-weekly and 
thrice-weekly), the study showed that VS-6766 was more tolerable when administered at 
an intermittent twice weekly dosing schedule. One subject experienced a DLT in the 4.0 
mg thrice-weekly cohort (Grade 3 ophthalmological toxicity – acute pigment epithelial 
detachment). Two subjects experienced a DLT in the 3.2 mg thrice-weekly cohort; one 
subject had grade 3 CPK elevation, for which they were hospitalized, and Grade 3 skin 
rash (face, upper trunk, back, abdomen and both arms); the second subject had Grade 3 
skin rash (face, chest and trunk). No subjects experienced a DLT in the 4.0mg, twice 
weekly cohort. The MTD/RP2D was determined to be 4 mg twice weekly. Approximately 
54 subjects will be enrolled in the monotherapy cohorts. A total of 22 subjects have been 
treated in the dose escalation cohorts and 35 subjects in the single-agent dose (4mg 
twice weekly) expansion cohorts as of April 1, 2020. Approximately 34 subjects will be 
enrolled in the combination cohorts and as of April 1,2020 14 subjects have been treated 
but no results are currently available. The study was initiated in May 2013 and is ongoing. 
 
Finally, IST-VS-6063-003 (protocol CCR4642, FRAME) is a Phase 1 dose 
escalation/expansion IST evaluating the combination of VS-6766 and Defactinib, a 
FAK/PYK2 inhibitor, in ~80 subjects with advanced solid tumors, including KRAS-mutant 
NSCLC, low-grade serous ovarian cancer (KRAS wild-type or mutant) and RAS-mutant 
colorectal cancer.  
 
Dose escalation was conducted using the following four regimens: 
• 
Cohort 1: 3.2 mg VS-6766 twice weekly + 200 mg Defactinib BID, 3 of 4 weeks 
• 
Cohort 2a: 4 mg VS-6766 twice weekly + 200 mg Defactinib BID, 3 of 4 weeks 
• 
Cohort 2b: 3.2 mg VS-6766 twice weekly + 400 mg Defactinib BID, 3 of 4 weeks 
• 
Cohort 3: 4 mg VS-6766 twice weekly + 400 mg Defactinib BID, 3 of 4 weeks 
 
No subjects experienced a DLT in Cohort 1 or Cohort 2a. There was a DLT of Grade 2 
rash in 2 of 3 subjects in Cohort 2b. Cohort 3 was not conducted due to the DLTs in 
Cohort 2b. Due to chronic Grade 2 toxicities in subjects on treatment > 6 months in Cohort 
2a, the Cohort 1 dose of 3.2 mg twice weekly VS-6766 + 200 mg BID Defactinib for 3 of 
4 weeks was selected as the RP2D for dose expansion. 
 


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Preliminary data from 52 subjects as of 18 Mar 2020 indicated that the most common 
TRAEs were rash (90%), CPK elevation (56%), hyperbilirubinemia (42%), AST elevation 
(38%), fatigue (31%), glossitis/oral mucositis/mouth ulcers (31%), ALT elevation (29%), 
diarrhea (29%), visual disturbance (29%), nausea (25%) and peripheral edema (21%), 
most of which were Grades 1 or 2 and reversible. Hyperbilirubinemia is an identified risk 
for Defactinib and was a frequent AE associated with VS-6766 monotherapy. Grade ≥3 
TEAEs reported in more than 1 subject were CPK elevation (5/52, 10%), rash (4/52, 8%), 
anemia (3/52, 6%) and Glossitis/Oral Mucositis/Mouth Ulcers (2/52, 4%).  
 
There were 51 SAEs reported as of 18 Mar 2020, with 4 judged by the Investigator as at 
least possibly related to study treatment. G2 diarrhea, G3 facial cellulitis and G3 rash 
were judged by the Investigator to be at least possibly related to only VS-6766, and both 
treatments possibly related to G2 pneumonitis. 
 
Dose interruptions or modifications were due primarily to rash and CPK elevation. There 
was 1 AE of bilirubinemia leading to discontinuation. There have been no deaths reported. 
 
Dose expansion is ongoing in cohorts of subjects with KRAS-mutant NSCLC, low-grade 
serous ovarian cancer (KRAS wild-type or mutant), RAS-mutant colorectal cancer, and 
advanced solid tumors accessible to biopsy. Approximately 80 subjects will be enrolled. 
A total of 12 subjects were treated in dose-escalation cohorts and 41 subjects treated in 
dose-expansion cohorts as of March 18, 2020. The study was initiated in December 2017 
and is ongoing. 
5.3.8 
Pharmacokinetics 
Clinical PK data were obtained for daily continuous dosing (studies NO21895 and 
JO22631) (30, 31), intermittent (4 days on/3 off and 7 days on/7 off) schedules (study 
NO2189) and twice weekly and thrice weekly dosing regiments (IST CCR3808). VS-6766 
exhibited consistent dose-proportional plasma concentration profiles and steady state 
accumulations supportive of long-term daily dosing in subjects. In study NO21895 and 
JO22631, maximum plasma concentration (Cmax) occurred 1 to 2 hours after dosing with 
a mean terminal half-life of approximately 55-60 hours. Apparent systemic clearance was 
6 mL/min. Plasma exposure of VS-6766 increased approximately dose-proportionally. 
Steady state was reached by Day 15 and drug accumulations of between 2- and 7-fold 
were observed. PK parameters were consistent with that predicted by pre-clinical models 
(39). 
5.3.9 
Pharmacodynamics 
The Pharmacodynamic effect of VS-6766 was assessed in studies NO21895 and 
JO22631 by pERK and pMEK suppression in peripheral blood mononuclear cells 
(PBMCs) and tumor biopsies (NO21895 only) (30, 31). The inhibition of pERK and pMEK 


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in PBMCs increased proportionally with VS-6766 dose. In NO21895, 6 of 11 subjects with 
paired tumor biopsies showed a reduction in pERK expression in tumor cells by 20% or 
more, of which 2 showed a reduction of more than 90% between baseline and day 15. In 
study IST-CCR3808, matched baseline and post-treatment biopsies from three subjects 
were obtained and reduction in pMEK (average decrease in cytoplasmic H-score: 66.7%) 
and pERK expression (average decrease in cytoplasmic H-score: 82.0%) occurred in all 
three subjects post treatment suggesting therapeutic effects on RAF and MEK activity. 
5.3.10 Efficacy 
VS-6766 has shown preliminary clinical benefit as monotherapy in various advanced solid 
tumor malignancies (including RAS/RAF melanoma, KRAS NSCLC, and RAS/RAF 
gynecological malignancies). While studies were not statistically powered to formally 
assess efficacy, preliminary signs of antitumor effects were observed in several advanced 
cancers, including tumors with RAS/RAF mutations. In NO21895, tumor shrinkage was 
observed in 40% (18/45) of subjects including minor response (≥10% shrinkage) in 20% 
(9/45) of subjects; 7 of 9 minor responses were in subjects with melanoma (30). There 
were partial responses (PR) per RECIST version 1.1 in 6.7% (3/45) of subjects with 
melanoma. Two of these subjects with PR had tumors with BRAF(V600E) mutation and 
one with an NRAS(Q61K) mutation. In study JO22631 five out of 12 subjects achieved 
stable diseases, including a melanoma subject maximum of 25 % regression (31). 
 
In the KRAS-mutant NSCLC expansion cohort (n=10) in IST-CCR3808, 5 subjects had a 
tumor reduction of ≥10%, and 3 achieved PR (≥30% reduction). The 3 subjects with PR 
and 1 with stable disease (SD) had progression-free survival (PFS) >24 weeks, with PFS 
in 1 subject of >50 weeks and in another subject of >100 weeks. In 5 subjects with 
RAS/RAF-mutant gynecological cancers (3 ovarian, 2 endometrial), 3 of 5 subjects (2 
ovarian, 1 endometrial) achieved a PR5,6. Two of the ovarian subjects with PR had PFS 
>24 weeks, with PFS in 1 subject >45 weeks. 
 
In IST-VS-6063-003 preliminary efficacy results are available for a small number of 
subjects with LGSOC (KRAS wild-type or mutant) and NSCLC with KRAS mutations 
treated with a combination of VS-6766 and Defactinib (VS-6063). The response rates in 
subjects with KRAS-mutated LGSOC were 67% (4 of 6 subjects with PR) and 50% (4 of 
8 subjects with PR) of all subjects with LGSOC (KRAS wild-type or mutant). Five of the 8 
subjects had prior MEK inhibitor therapy, including 3 responders. Of the 10 subjects with 
NSCLC, 1 subject with KRAS(G12V)- mutated cancer achieved PR; 3/10 subjects 
received treatment for ≥24 weeks. 
 
For additional information concerning VS-6766, refer to the Investigator Brochure. 
 


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5.4 
Rationale for the proposed trial and dosing regimen 
There is evidence that focal adhesion kinase (FAK) activation can drive the emergence 
of resistance after inhibition of the RAS-RAF-MEK pathway. In this trial, we propose the 
combination of Defactinib (FAK inhibitor, VS-6063) with VS-6766 (dual RAF/MEK 
inhibitor), given in an intermittent schedule. Our group has previously found that the 
combination of FAK and MEK inhibition (specifically VS-6766 with Defactinib) 
synergistically inhibits uveal melanoma growth and promotes apoptosis in vitro, and 
reduces xenograft tumor volume in vivo.  
 
From previous phase I and II trials, both VS-6063 and VS-6766 are safe and tolerable. 
The regimen for Defactinib is based on the findings of the Phase I FIH study and 
supporting nonclinical data. In the FIH study, subjects received doses of 12.5 to 750 mg 
twice daily for 21 days. Exposure did not increase significantly above 425 mg twice daily; 
therefore, the maximum tolerated dose (MTD) was not established and the observed half-
life was 9 hours supporting the twice daily dosing schedule. The Phase I trial for VS-6766 
evaluated 3 schedules and determined the RP2D as 4mg 2 days per week (Mondays and 
Thursdays) with high efficacy and lower toxicity compared to more dose intense 
schedules.  
 
The safety and tolerability of the combination of the two drugs was shown in the ongoing 
investigator-sponsored basket study of VS-6766 with Defactinib (IST-VS-6063-003, 
protocol CCR4642, FRAME) conducted by Dr. Banerji in UK. The dosing regimen for 
Defactinib (VS-6063) is 200mg twice daily administered continuously for 21 days followed 
by 7 days break, in 28 day cycles. The dosing regimen for VS-6766 is 3.2mg 2 days per 
week (Mondays and Thursdays), given 3 of 4 weeks, in 28 day cycles.  
 
Together, the robust preliminary data generated by our team and the urgent need for 
therapeutic options for patients with MUM provide a promising opportunity to use this 
combination in MUM patients. The strong basic science, translational, and clinical 
expertise of our team puts us in an excellent position to conduct bi-directional bench to 
clinic and clinic to bench translational research.   
5.5 
Dosage, Preparation, and Administration  
The dose of VS-6766 will be 3.2mg once a day. VS-6766 will be administered orally once 
a day on 2 days per week (Mondays and Thursdays or Tuesdays and Fridays) for 3 out 
of 4 weeks. VS-6766 should be taken 1 hour before or 2 hours after a meal. The dose of 
Defactinib (VS-6063) will be 200mg twice daily. Defactinib will be administered orally 
twice a day for 3 out of 4 weeks. Defactinib should be taken within 30 minutes after a 
meal. One cycle consists of 28 days and neither drug should be taken in the last week of 
any cycle.  


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A sufficient supply of study drugs (one cycle worth) will be dispensed to the subject by 
the Investigational Pharmacy for the subject to take on an outpatient basis between visits. 
5.6 
Dose Modifications and Dosing Delays 
If a patient experiences a clinically significant study drug-related (definite, probable, or 
possible) Grade 3 or greater toxicity that is not attributable to the disease or disease-
related processes under investigation, dosing will be interrupted and supportive therapy 
administered as required. One or both study medications may be reduced, depending on 
the causality of the toxicity. If patients experience Grade 4 clinical toxicity or Grade 3 
ophthalmological toxicity, the patient will be removed from the study. 
 
The expected toxicity of each drug can be found in section 1.3.1 which can be used to 
guide investigators in attributing causality to the study drug(s) and dose modification.   
 
The examples of expected toxicities are listed below: 
VS-6766 
Skin: dermatitis, acneiform rash 
GI: diarrhea, constipation, vomiting, stomatitis 
General: peripheral edema, pyrexia, asthenia 
Eye: blurred vision, retinal disorders 
Laboratory abnormalities: 
• Blood creatinine phosphokinase increase 
• Liver function abnormalities: hypoalbuminemia, AST/ALT increase, ALP increase 
 
Defactinib (VS-6063) 
GI: diarrhea, vomiting, abdominal pain 
General: fatigue, decreased appetite 
Laboratory abnormalities: 
• Hyperbilirubinemia  
• Low sodium level 
 
Once the drug-related toxicity resolves or reverts to Grade 1, the study treatment is 
allowed to restart. If the drug-related toxicity resolves or reverts to Grade ≤ 1 within 14 
days of onset of treatment with the combination of VS-6766 and Defactinib, both may be 
restarted at the same dose. This is with the exception of elevated CK or rash; these 
toxicities should resolve or revert to Grade ≤ 2 within 14 days of onset to restart treatment 
with the combination of VS-6766 and Defactinib at the same dose. If it is necessary to 
interrupt the dose again the patient should be treated at a reduced dose level. If it takes 
more than 14 days until the study-related toxicity resolves or reverts to Grade 1, the 
dose(s) of study medication will be reduced according to Table 2. If the study-related 


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toxicity does not resolve or revert to Grade 1 within 28 days, the patient will be removed 
from the study. 
 
Patients can have more than one dose reduction (see Table 1 below). If a patient cannot 
tolerate the first reduced dose or in the event a toxicity cannot be clearly associated with 
one study drug, both drugs will be dose reduced (2nd dose reduction).   
 
If despite appropriate dose reductions and/or delays, the patient experiences 
unacceptable toxicities specifically attributed to either VS-6766 or Defactinib then 
consideration will be given to continuing a patient on single agent treatment at the 
discretion of the Principal Investigator. 
 
In the event of multiple toxicities, dose modification should be based on the worst toxicity 
observed. Patients are to be instructed to notify Investigators at the first occurrence of 
any adverse sign or symptom. 
 
Once the dose has been reduced it may not be re-escalated. 
 
If a dose interruption is required within a cycle, the clock does not stop and cycles and 
visit dates continue until the end of the cycle. If a dose is delayed between cycles, the 
patient will have unscheduled visits until treatment is restarted at the next cycle. Patients 
may have their cycle delayed by up to two weeks, but if the dose is held more than 2 
cycles the patient will be discontinued from the study. 
 
Adverse events assessed by the Investigator as exclusively related to underlying disease, 
medical condition or concomitant treatment will not be taken into consideration for 
treatment interruption and dose reduction.  
 
Table 1: Dose reductions 
 
 
VS-6766 
Defactinib (VS-6063) 
Starting Dose 
3.2mg once daily MT/TF 
for 3 out of 4 weeks 
200mg twice daily continuous dosing 
for 3 out of 4 weeks 
1st Dose Reduction 
for Defactinib 
3.2mg once daily MT/TF 
for 3 out of 4 weeks 
200mg once daily continuous dosing for 
2 out of 4 weeks  


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1st Dose Reduction 
for VS-6766 
2.4mg once daily MT/TF 
for 2 out of 4 weeks 
200mg twice daily continuous dosing for 
3 out of 4 weeks 
2nd Dose Reduction 2.4mg once daily MT/TF 
for 2 out of 4 weeks 
200mg once daily continuous 
dosing for 2 out of 4 weeks 
 
In cases not involving drug related toxicity, study medications may be interrupted for a 
maximum of 28 days including the scheduled week off. 
5.7 
Study Product Accountability 
Accurate records of all study medication shipments, tablets/capsules dispensed, and all 
tablets/capsules returned must be maintained. Study medications supplies are to be used 
only in accordance with this protocol and under the supervision of the Investigator. 
 
The Investigator delegates responsibility for study medication management to the 
Investigational Pharmacy. The Investigational Pharmacy undertakes not to destroy any 
unused study medications unless directed to by Verastem Oncology. Any unused study 
medications must be destroyed according to hospital procedures and properly accounted 
for using the Study Medication Destruction Form and also on the Study Medication 
Accountability Record. During the course of the trial the Investigational Pharmacy will 
check the numbers of capsules of VS-6766/tablets of Defactinib shipped to the center, 
the number used and the number destroyed or returned. The Investigational Pharmacy 
will give an account of any discrepancy. 
5.8 
Assessing Participant Compliance with Study Product Administration 
Patients will maintain pill diaries to record compliance to the dosing schedule. At the 
time of each study visit, patients will bring the pill diaries and the bottle of study 
medications for pill counts. Study physicians and coordinators will also assess 
participant compliance during their visit. If non-compliance is identified, it will be 
recorded in the Case report form (CRF) and continuation of study treatment will be 
discussed with the patients.  
5.9 
Concomitant Medications/Treatments 
Concomitant medication may be given as medically indicated. Details (including doses, 
frequency, route and start and stop dates) of the concomitant medication given must be 
recorded in the patient’s medical records and the case report form (CRF). The Principal 


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Investigator should be alerted if the patient is taking any agent known to affect or with the 
potential to affect selected CYP450 isoenzymes. 
 
The patient must not receive other anti-cancer therapy or investigational drugs while on 
the trial. 
 
Radiotherapy may be given concomitantly for the control of pain; however, the irradiated 
lesions will not be evaluable for response, unless they are clearly progressing at the time 
of initiating systemic therapy. 
 
In in vitro studies, Defactinib (VS-6063) has been shown to be metabolized by CYP2C9 
and CYP3A4. In vitro studies have shown that VS-6063 inhibits CYP2C9 and CYP3A4 in 
human liver microsomes. Extrapolation to expected human exposure indicates the 
potential for inhibition or induction of CYP enzymes is low. VS-6766 is metabolized mainly 
by CYP3A4. 
 
Therefore, it is recommended that: 
• 
Concomitant use of strong inhibitors of CYP3A4 or CYP2C9 are prohibited. 
Concomitant use of moderate or weak inhibitors of CYP3A4 or CYP2C9 
should be avoided if possible or used with caution. 
• 
Concomitant use of strong inducers of CYP3A4 or CYP2C9 should be 
avoided if possible or used with caution. Concomitant use of moderate or 
weak inducers of CYP3A4 or CYP2C9 should be used with caution. 
• 
Compounds that are substrates for CYP3A4 or CYP2C9 should be used with 
caution. 
 
Because the list of these agents are constantly changing, it is important to regularly 
consult a frequently-updated list such as 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference texts such as the 
Physicians’ Desk Reference may also provide this information. 
 
If subjects require anticoagulation an alternative to warfarin should be used. Patients who 
require anticoagulation but cannot discontinue warfarin are excluded from this study. For 
subjects requiring the start of anti-coagulation therapy during the course of any VS-6063 
trial, alternatives to warfarin should be used. 
 
Routine use of colony stimulating factors (CSFs) is not permitted during this study; 
furthermore, patients should not receive prophylactic growth factors. 
Use of erythropoietin is allowed. 
Use of stimulators of thrombopoiesis is not allowed. 


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Supportive or other palliative measures are permitted, with any exceptions as noted. 
5.10 Dietary Restrictions 
There are no dietary restrictions that participants must adhere to during this trial.  
6 Study Schedule  
The full schedule of events can be found in Appendix A.  
In cases where a patient has investigations at a different hospital, for example weekly 
blood samples, then it is the Investigator’s responsibility to ensure he/she receives and 
reviews the results. The results must be recorded on the electronic case report form 
(eCRF) and the reports from the other hospitals must be available for source data 
verification. Laboratory reference ranges, including effective dates, and evidence of 
laboratory accreditation must be obtained from all laboratories used. 
6.1 
Pretreatment Period/Screening 
Details of all evaluations/investigations for enrolled patients, including relevant dates, 
required by the protocol must be recorded in the medical records so that the eCRF can 
be checked against the source data. 
6.1.1 
Obtaining written informed consent  
Written informed consent must be obtained from the patient before any protocol-specific 
procedures are carried out and within four weeks before the patient’s first dose of the 
study medications (VS-6766 and Defactinib). Informed consent process detailed in 
section 14.3.  
 
6.1.2 
Evaluations within four weeks (28 days) 
The following must be performed/obtained within the four weeks before the patient 
receives the first dose. 
 Written informed consent (as detailed in Section 6.1.1); 
 Demographic details; 
 Medical history including prior diagnosis, prior treatment, concomitant diseases 
and concomitant treatment; 
 Tumor biopsy: the first biopsy should be taken at baseline within 28 days prior to 
first dose (mandatory) (see Section 6.6.2.1);  
 Coagulation: PT, aPTT and INR required to confirm eligibility. Should also be 
tested prior to each biopsy as per institutional standard practice (at minimum within 
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 Echocardiogram or MUGA scan to ensure adequate cardiac function (left 
ventricular ejection fraction ≥ 50%); 
 Radiological disease assessments: Computerized Tomography (CT) scan of the 
chest and pelvis; and Magnetic Resonance Imaging (MRI) scan of the abdomen. 
Radiological measurements must be performed within four weeks of the patient’s 
first dose; 
 Complete ophthalmologic examinations should be performed and interpreted by a 
qualified ophthalmologist, including visual acuity test, corneal examination, 
intraocular pressure measurements by tonometry, slit-lamp ophthalmoscopy, 
indirect ophthalmoscopy, spectral domain optical coherence tomography (OCT), 
digital fundus photography and, if indicated, angiography. 
 
Note that all adverse events (AEs) must be monitored and recorded in the eCRF from the 
time the patient consents to any protocol-specific procedure (see Section 8 for further 
details). 
6.1.3 
Evaluations within two weeks (14 days) 
The following must be performed within the two weeks before the patient receives the 
first dose: 
 Clinical disease measurements: If applicable (i.e. patients with clinically 
assessable disease); 
 Complete physical examination: Cardiovascular, respiratory, abdominal, 
central and peripheral nervous system, dermatological and any other system 
which might be relevant to the patient’s medical history; 
 Vital signs: Height, weight, ECOG performance status, temperature, blood 
pressure (BP) and pulse rate; 
 Electrocardiogram (ECG): Resting 12-lead ECG, conducted in triplicate 
taken up to 5 minutes apart, with manual calculation of QT interval (QTcF); 
 Laboratory tests (blood/urine samples) to confirm eligibility: 
o Hematology – hemoglobin (Hb), white blood cells (WBC) with 
differential count (neutrophils and lymphocytes), platelets, and D-dimer 
assay; 
o Biochemistry – sodium, potassium, adjusted calcium, phosphate, urea, 
creatinine, total protein, albumin, bilirubin, alkaline phosphatase (alk 
phos), 
alanine 
aminotransferase 
(ALT) 
and 
aspartate 
aminotransferase (AST), gamma- glutamyltranspeptide (GGT) and 
creatine phosphokinase (CPK); 
o Urinalysis – pH, specific gravity, glucose, protein and blood. 
 Serum or urine human chorionic gonadotropin (HCG) test to rule out 
pregnancy at trial entry; results must be obtained and reviewed before the first 


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dose of the study medications are administered, if applicable (i.e. women of 
child bearing potential). See Section 8.4.7 for further details; 
 Collection of blood sample for PD analysis: to be collected within 28 days 
before first dose (see Section 6.6.2.1); 
 Blood sample for circulating free DNA (ctDNA) analysis (as detailed in Section 
6.6.2.2). 
 
6.2 
Evaluations during the trial 
Patients will be followed up weekly during Cycles 1 and 2, then seen on Day 1 of each 
cycle thereafter. 
* There will be visit windows of +/- 2 days in Cycle 1, or on Day 1 of any cycle. The 
cycle length must always remain 28 +/- 2 days.   
 Physical examination: Physical examination will be performed on the first 
day of each cycle before VS-6766 and Defactinib administration; 
 Vitals: ECOG performance status, temperature, pulse rate and BP must be 
repeated at each visit, before the administration of VS-6766 and Defactinib. 
Bodyweight should be taken on Day 1 of every cycle; 
 Adverse events and concomitant treatments: At each visit, before VS-6766 
and Defactinib administration, an assessment of any AE experienced since 
the previous visit must be made by the Investigator or Clinical Research 
Coordinator. The start and stop dates of the AE together with the relationship 
of the event to treatment with VS-6766 and Defactinib (causality assessment) 
must be recorded in the medical records. All AE severity must be graded 
according to NCI CTCAE Version 5.0. Seriousness of the AE, actions taken 
regarding each study drug, and outcome should also be collected. Any 
concomitant treatment must also be recorded in the medical records and in 
the eCRF. (See Section 8 for further details regarding AE reporting 
requirements); 
 Laboratory tests: 
Hematology and biochemistry: must be repeated weekly during cycles 1 and 
2 and every 4 weeks (i.e. prior to dosing on Day 1 of each cycle) thereafter. 
Hematology and Biochemistry may be performed the day prior to dosing. If on 
a day of dosing, hematology, biochemistry and urinalysis should be before 
VS-6766 and VS-6063 administration. 
o Hematology: detailed in Section 6.1.3; 
o Biochemistry: detailed in Section 6.1.3; 
o Urinalysis: repeated pre-dose on Day 1 of each cycle, as detailed in 
Section 6.1.3. 
 Electrocardiogram (ECG): resting 12-lead ECG, conducted in triplicate taken 


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up to 5 minutes apart, with manual calculation of QT interval (QTcF); to be 
performed on Cycle 2 Day 1, and within 28 days after the last dose of the 
study drugs and as clinically indicated.  
 Serum or urine human chorionic gonadotropin (HCG) test to rule out 
pregnancy; to be performed every 4 weeks if applicable (i.e. women of child 
bearing potential). See Section 8.4.7 for further details. 
 Ophthalmological examination: This will be repeated at the end of Cycle 1 
(between Cycle 1 Day 22 and pre-dose Cycle 2 Day 1), at the end of Cycle 2 
(between Cycle 2 Day 22 and pre-dose Cycle 3 Day 1), at the end of Cycle 4 
(between Cycle 4 Day 22 and pre-dose on Cycle 5 Day 1) and every 3 cycles 
thereafter and within 28 days after the last dose of the study drugs. The result 
must be available prior to dosing. Interruption and/or reduction of dosing is 
recommended for management of eye toxicity. Any abnormality observed by 
an ophthalmologic examination as well as symptoms should be carefully 
monitored until improved. Guidelines from a specialized ophthalmologist can 
be provided if requested by the Investigator. Further ophthalmological 
examinations may be performed in addition to these if clinically indicated. All 
ophthalmological examinations must be performed and interpreted by a 
qualified ophthalmologist. Examination detailed in Section 6.1.2;  
 Assessment of disease: This must be repeated every 2 cycle(s)/8 weeks of 
continuous treatment, i.e. between C2D22-C3D1, C4D22-C5D1, C6D22-
C7D1 etc. (Refer to Section 7). For patients who continue on treatment after 
six cycles the frequency may be reduced; 
 Tumor biopsy: Tumor biopsies will be collected from patients (mandatory) if 
clinically feasible. The second biopsy should be taken 2-6 hours after VS-
6766 is taken, on day 1-21 of cycle 2 or 3 (see Section 6.6.2.1); 
 Collection of blood sample for PD analysis: to be collected on C3D1 prior 
to taking the combination dosing of VS-6766 and Defactinib (pre-Cycle 3, see 
Section 6.6.2.1); 
 Blood sample for circulating free DNA analysis: will be taken at the end of 
every 2 cycles for up to 6 cycles as per Section 6.6.2.2, i.e. C3D1 & C5D1. 
6.3 
Evaluations at ‘off-study’ visit 
Evaluations at the ‘off-study’ visit must be performed within 28 days after the last 
dose of VS-6766 and Defactinib. The following investigations must be done: 
 Physical examination including ECOG performance status, temperature, 
pulse rate, BP and bodyweight; 
 Hematology tests: detailed in Section 6.1.3; 
 Biochemistry tests: detailed in Section 6.1.3; 
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 Serum or urine human chorionic gonadotropin (HCG) test if applicable (i.e. 
women of child bearing potential). 
 ECG: detailed in Section 6.1.2; 
 Ophthalmological exam: detailed in Section 6.1.2; 
 Tumor biopsy (third biopsy sample): detailed in Section 6.6.2.1; 
 Blood sample for PD analysis: detailed in Section 6.6.2.1; 
 Blood sample for circulating free DNA analysis: detailed in Section 6.6.2.2; 
 Assessment of tumor disease, unless assessment has been performed within 
the previous four weeks (28 days); 
 Assessment of AEs (also see Section 8); and 
 Assessment of concomitant treatments. 
 
6.4 
Follow-up 
Post-treatment, patients will be followed for survival until their death or up to 5 years 
after the last patient is enrolled. All AEs regardless of causality that are still present 
28 days after the last administration of VS-6766 and/or Defactinib will be followed 
monthly until resolution (grade 1 or less) or stabilization. Adverse event evaluation 
and abnormal laboratory values will be monitored during the monthly follow up visits. 
Survival information will be collected via telephone or clinical record review. The date 
and cause of death will be recorded; the cause of death will be categorized as either 
cancer-related or cancer-unrelated. Patients will be considered “lost to follow-up” 
after 3 unsuccessful contact attempts by telephone (attempts occurring within 2 
years). 
 
6.5 
Withdrawal Visit/Discontinuation of Therapy 
The Investigator must make every reasonable effort to keep each patient on trial for the 
whole duration of the trial (i.e. until 28 days after last combination therapy administration). 
However, if the Investigator removes a patient from the trial or if the patient declines 
further participation, final ‘off-study’ assessments should be performed before any 
therapeutic intervention. All the results of the evaluations and observations, together with 
a description of the reasons for withdrawal from the trial, must be recorded in the medical 
records and in the eCRF. 
 
Patients who are removed from the trial due to adverse events (clinical or laboratory) will 
be treated and followed according to accepted medical practice. All pertinent information 
concerning the outcome of such treatment must be recorded in the eCRF and on the 
serious adverse event (SAE) report form where necessary. 
 
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• 
Unacceptable toxicity (AE/SAE) 
• 
Withdrawal of consent 
• 
Serious violation of the trial protocol (including persistent patient attendance 
failure and persistent non-compliance) 
• 
Sponsor’s decision to terminate the trial 
• 
Withdrawal by the Investigator for clinical reasons not related to the study 
medications 
• 
Evidence of disease progression.  If patients have mild progression (20-30% 
increase in the sum of the longest diameters from the baseline), and meet criteria 
listed in section 3.3, and if Investigators conclude that patients have had clinical 
benefit from the study medications, the study treatment will be allowed to continue 
for 2 more cycles as long as patients tolerate the study medications without grade 3 
or higher toxicity.  If further progression is confirmed with follow-up imaging studies, 
patients will be removed from the study.  
• 
Symptomatic deterioration 
• 
Pregnancy 
 
Patients that are discontinued from the study are still evaluable as defined in section 3.3. 
6.6 
Laboratory Procedures/Evaluations 
6.6.1 
Clinical Laboratory Evaluations 
Laboratory tests (blood/urine samples) performed in our trial include: 
 Hematology – hemoglobin (Hb), white blood cells (WBC) with differential count 
(neutrophils and lymphocytes), platelets, PT/INR, PTT, and D-dimer assay; 
o PT/INR and PTT required for inclusion criteria and subsequently prior 
to each biopsy as per institutional standard practice (at minimum within 
7 days prior to biopsy). 
 Biochemistry – sodium, potassium, adjusted calcium, phosphate, urea, 
creatinine, total protein, albumin, bilirubin, alkaline phosphatase (alk phos), 
alanine aminotransferase (ALT) and aspartate aminotransferase (AST), 
gamma- glutamyltranspeptide (GGT) and creatine phosphokinase (CPK); 
 Urinalysis – pH, specific gravity, glucose, protein and blood. 
 Serum or urine human chorionic gonadotropin (HCG) test 
 


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6.6.2 
Special Assays or Procedures  
6.6.2.1 Pharmacodynamic assays 
Tumor Biopsies  
Patients will be consented for collection of three mandatory pre- and post-treatment tumor 
biopsies. These should be collected at the following time points as long as clinically 
feasible: 
• 
Baseline (within 28 days before first dose); 
• 
On-treatment (after Cycle 1 or Cycle 2); 
• 
Post-treatment (within 28 days after last dose). 
 
As the fasting requirements of VS-6766 and Defactinib (VS-6063) differ, the drugs cannot 
be taken at the same time. Therefore, the second biopsy following combination dosing 
should be scheduled from the time of VS-6766 dose. The second biopsy should be 
scheduled for 2-6 hours after a dose of VS-6766 is taken in Cycle 2 or 3. The third biopsy 
should also if possible be taken 2-6 hours after a dose of VS-6766 is taken, before the 
patient stops drug.  
 
Samples of tumor will undergo analysis for possible changes in tumor metabolic activity, 
signaling to the ERK, YAP, FAK, and PI3K-TOR pathways, changes in UM cell 
proliferation (Ki67) and apoptosis induction (caspase activation), and changes in tumor 
microenvironment. The resistance mechanism of this combination treatment will also be 
investigated. The specific type and number of biomarkers from the tumor samples will be 
decided during the course of the study and documented in the study records. 
 
Core needle tumor biopsies will be taken according to local procedures. Within 28 days 
of the first dose, tumor biopsies will be divided into 3 samples, one to be immediately 
snap frozen in liquid nitrogen or a dry ice bath for PD analysis, one to be formalin fixed 
and embedded in paraffin (FFPE) as per local procedures for PD biomarker analysis, and 
one to establish PDX models. If clinically feasible, additional 1 core biopsy specimen will 
be obtained during the first biopsy for NGS analysis on oncogenic mutations and 
amplifications. 
 
For the second biopsy (on-treatment), if the biopsy will be performed after cycle 1 the 
tumor biopsies will be divided into two samples, one to be immediately snap frozen in 
liquid nitrogen or a dry ice bath for PD analysis and one to be formalin fixed and 
embedded in paraffin (FFPE) as per local procedures for PD biomarker analysis. If the 
biopsy will be performed after cycle 2 the tumor biopsies will be divided into three 
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analysis, one to be formalin fixed and embedded in paraffin (FFPE) as per local 
procedures for PD biomarker analysis, and one to establish PDX models. 
 
Where there is limited tissue to biopsy, priority should be given to securing a FFPE sample 
over a snap frozen sample. 
 
Tumor biopsies will be analyzed at the laboratories of Dr. Takami Sato and Dr. Andrew 
Aplin (Thomas Jefferson University/Sidney Kimmel Cancer Center – 1015 Walnut St. 
Philadelphia, PA 19107), Dr. Gutkind (University of California-San Diego Moores Cancer 
Center – 3855 Health Sciences Dr. La Jolla, CA 92037), and other external laboratories 
that utilize techniques required for our study. Please refer to the Study Laboratory 
Standard Operating Procedures for handling, storage and shipment of samples. 
 
Blood Samples 
PD blood samples (30ml) will be collected: 
• 
Baseline (within 14 days before first dose); 
• 
Pre-Cycle 3 (on C3D1 prior to combination dosing of VS-6766 and Defactinib); 
• 
Progression (within 28 days after last dose). 
PD blood samples will be analyzed at the aforementioned laboratories (Drs. Sato & Aplin, 
Dr. Gutkind, external laboratory). Please refer to the Study Laboratory Standard 
Operating Procedures for handling, storage and shipment of samples. 
 
6.6.2.2 Predictive biomarker assays 
Analysis of circulating free DNA 
Circulating free tumor DNA in plasma will be sequenced for genetic mutations according 
to agreed SOPs and validated methods. 
 
20ml of plasma will be collected for all patients at baseline (within 14 days of first dose), 
at the end of every 2 cycles for up to 6 cycles and at progression. This is for the purpose 
of studying circulating free DNA and correlating it to response. 
 
Samples will be analyzed at the aforementioned laboratories (Drs. Sato & Aplin, Dr. 
Gutkind, external laboratory). Please refer to the Study Laboratory Standard Operating 
Procedures for handling, storage and shipment of samples. 
7 Evaluation of Efficacy 


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Disease must be measured according to the RECIST criteria (version 1.1) given in 
Appendix B. These criteria are based on the revised guidelines by Eisenhauer et al. (42, 
43). 
7.1 
Measurement of Effects 
7.1.1 
Measurable and Non-Measurable Disease 
Measurable Disease 
Measurable disease is defined by the presence of at least one measurable lesion as 
defined below and adapted from the RECIST criteria version 1.1 (Appendix B).  All 
measurements must be recorded in metric notation.  
 
The longest diameter (LD) of the largest lesion should be ≥ 10 mm by CT or MRI in order 
to become eligible for the study as previously mentioned.   
 
Since some melanoma metastases contain melanin pigment and since successfully 
treated liver metastases may develop significant necrosis/hemorrhage, evaluation of 
radiological response after embolization treatments is generally difficult. Therefore, we 
will obtain an MRI of the liver, preferably with gadoxetate disodium (Eovist) contrast 
study for the precise evaluation of radiological responses in liver metastasis. If MRI is not 
available, triphasic CT of the abdomen will be obtained. However, the same modality will 
be used for measurement of the liver metastases and assessment of treatment response. 
The hepatobiliary phase images of MRI with gadoxetate disodium (Eovist) contrast is 
preferred for tumor response assessment due to its superiority in measurement of tumor 
size.  
 
Non-measurable disease 
All other lesions including small lesions (<10 mm on spiral CT scans or MRI) are 
considered “non-measurable”.  The following lesions are also considered as “non-
measurable”: Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusion, 
abdominal masses that are not confirmed and followed by imaging techniques, tumors 
treated by radiation, ablation or surgical resection.     
 
7.1.2 
Baseline documentation of “Target” and “Non-Target” Lesions 
Target Lesions (Indicator Lesions) 
The target lesions are defined as measurable lesions that will be used for evaluation of 
response. For this protocol, target lesions require serial measurement of a longest 
diameter and should be ≥10 mm by triphasic CT or MRI at the time of study entry. 


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Previously irradiated lesions can be taken into account as measurable disease when they 
are clearly progressing at the time of initiating systemic therapy. 
 
Lymph nodes that have a short axis of <10mm are considered non-pathological and 
should not be recorded or followed. Pathological lymph nodes with <15mm but >10mm 
short axis are considered non measurable. Pathological lymph nodes with 15mm short 
axis are considered measurable and can be selected as target lesions, however lymph 
nodes should not be selected as target lesions when other suitable target lesions are 
available. 
 
Target lesions (up to a maximum number of 2 lesions per organs) must be identified and 
measured at baseline prior to the initiation of treatment. Target lesions must be selected 
on the basis of their size (LD) and suitability for repetitive measurements. 
 
Non-Target Lesions 
All other lesions (or sites of melanoma) must be identified as “non-target” and their 
location and characteristics must be recorded at baseline. During follow-up evaluations, 
these lesions must be followed as “present” or “absent”.  
 
7.2 
Timing of tumor assessments 
7.2.1 
Baseline evaluations 
These must include radiological measurements and as indicated chest, abdominal and 
pelvic computerized tomography (CT) scan, magnetic resonance imaging (MRI) and/or 
clinical measurements as appropriate. All areas of disease present must be documented 
(even if specific lesions are not going to be followed for response). Any non-measurable 
lesions must be stated as being present. For clinical measurements, documentation by 
color photography including a ruler to estimate the size of the lesion is strongly 
recommended, as this aids external independent review of responses (see Appendix B 
for RECIST 1.1 criteria). 
7.2.2 
Evaluations during and at ‘off-study’ 
Tumor assessments must be repeated every 2 cycle(s)/8 weeks if continuous treatment 
or more frequently, when clinically indicated. All lesions measured at baseline must be 
measured at every subsequent disease assessment, and recorded clearly on the scan 
reports. All non-measurable lesions noted at baseline must be noted on the scan report 
as present or absent. 
 
All patients, who are removed from the trial for reasons other than progressive disease, 
must be re-evaluated at the time of treatment discontinuation, unless a tumor assessment 
was performed within the previous four weeks. 


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It is the responsibility of the Principal Investigator to ensure that the radiologists are aware 
of the requirement to follow-up and measure every target lesion mentioned at baseline 
and comment on the non-target lesions in accordance with RECIST 1.1 criteria. 
7.3 
Evaluation of overall response of metastasis 
The investigators must identify target indicator lesions and measure them within 4 weeks 
prior to the first treatment as baseline. The investigators will then measure the same target 
lesions after each treatment cycle.  
 
New lesions will be defined as: A lesion equal or greater than 10 mm in longest 
diameter or a lymph node equal or greater than 15 mm in short axis is considered 
to be a new lesion if the lesion is not previously detected or less than 0.5 cm in 
baseline imaging. 
The sum of the baseline LDs will be compared to the sum of LDs after treatment.   
 
7.4 
Response Criteria for metastases 
The response of metastases will be evaluated by MRI or CT using the criteria adapted 
from the international criteria proposed by the Response Evaluation Criteria in Solid 
Tumors (RECIST) Committee. The same imaging modality must be used for the serial 
measurements of tumor diameter.  The definition of response of metastases is shown in 
Table 2. Evaluation of target and non-target lesions to determine response of metastases 
is shown in Table 3.  The best response during study treatment will be used for efficacy 
analysis.  
 
To be assigned a status of complete response (CR) or partial response (PR), changes in 
tumor measurements must be confirmed by repeat measurements performed no less 
than four weeks after the response criteria are met. To be assigned a status of stable 
disease (SD), follow-up measurements must have met the SD criteria at least once and 
at least six weeks after the initial dose of the investigational medicinal product VS-6766 
and Defactinib (VS-6063) is given. 
 
Tumor response should be classified as “not evaluable” (NE), only when it is not possible 
to classify it under another response category, for example, when baseline and/or follow-
up assessment is not performed or not performed appropriately.   
 
 
 
 


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Table 2. The definition of response of metastases 
Complete Response 
(CR) 
Disappearance of all target and non-target lesions  
Partial Response (PR) 
>30% decrease in the sum of the longest diameters (“sum 
LD”) relative to baseline sum LD with at least stable non-target 
lesions 
Stable Disease (SD) 
Absence of change which would qualify as response or 
progression 
Progression (PD) 
>20% increase in the sum LD in target lesions or unequivocal 
progression of non-target lesions 
Appearance of one or more new lesions >10 mm 
 
Table 3. Evaluation of Target and Non-Target Lesions 
 
 
 
 
 
 
 
 
 
 
Target 
Lesions 
Non-Target 
Lesions 
New Lesions  
Overall 
Response 
CR 
CR 
No 
CR 
CR 
SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 


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7.4.1 
Recording of response in eCRF 
The applicable overall response category for each visit that includes disease assessment 
must be recorded in the eCRF, even though the criteria for determination of a complete 
response (CR) or partial response (PR) by the protocol must be confirmed after two 
consecutive observations, no less than four weeks apart. 
7.5 
Evaluation of progression free survival (PFS) 
PFS is measured from the start of the first study treatment to confirmation of progression 
of disease by either imaging tests or death of patient, whichever comes first. Patients 
without progression of metastasis at the last follow-up visit will be censored.  
7.6 
Evaluation of overall survival (OS) 
Overall survival (OS) is measured from the first treatment to patient death. Date and 
cause of death will be recorded. The cause of death will be categorized as either cancer-
related or cancer-unrelated. Patients who are alive at the last follow-up visit will be 
censored. 
 
8 Evaluation of Safety 
8.1 
Specification of Safety Parameters 
8.1.1 
Unanticipated Problems 
Unanticipated problems (UAPs) include, in general, any incident, experience, or outcome 
that meets the following criteria: 
• 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 participant population being studied; 
UAPs are considered to pose risk to participants or others when they suggest that the 
research places participants or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized. 
8.1.2 
Adverse Events 
An adverse event is any untoward or unfavorable medical occurrence in a human 
participant, including any abnormal sign (for example, abnormal physical exam or 
laboratory finding), symptom, or disease, temporally associated with the participant’s 


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participation in the research, whether or not considered related to the participant’s 
participation in the research. 
8.1.3 
Serious Adverse Events 
A serious adverse event (SAE) is one that meets one or more of the following criteria: 
• Results in death 
• Is life-threatening (places the participant at immediate risk of death from the 
event as it occurred) 
• Is disabling or incapacitating 
• Results in inpatient hospitalization or prolongation of existing hospitalization 
• Results in a persistent or significant disability or incapacity 
• Results in a congenital anomaly or birth defect  
An important medical event that may not result in death, be life threatening, or 
require hospitalization may be considered an SAE when, based upon appropriate 
medical judgment, the event may jeopardize the participant or may require 
intervention to prevent one of the outcomes listed in this definition.   
8.2 
Safety Assessment and Follow-Up 
For eligible patients, serious adverse event (SAE) and adverse event (AE) collection and 
monitoring commences from the time the patient gives their written consent to participate 
in the trial and continues for 28 days after the last administration of VS-6766 and 
Defactinib (VS-6063). 
 
Follow-up of all AEs will be performed regardless of causality until the events resolve, 
stabilize or the patient starts another anti-cancer therapy. 
8.3 
Recording Adverse Events 
The following subsections detail what information must be documented for each adverse 
event occurring during the time period specified in Section 8.2 Safety Assessment and 
Follow-Up.  
8.3.1 
Relationship to Study Intervention 
The relationship to study intervention or study participation must be assessed and 
documented for all adverse events. Evaluation of relatedness must consider etiologies 
such as natural history of the underlying disease, concurrent illness, concomitant 
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The following guidelines are used to assess relationship of an event to study 
intervention: 
1. Related (Possible, Probable, Definite) 
a. The event is known to occur with the study intervention. 
b. There is a temporal relationship between the intervention and event onset. 
c. The event abates when the intervention is discontinued. 
d. The event reappears upon a re-challenge with the intervention. 
2. Not Related (Unlikely, Not Related) 
a. There is no temporal relationship between the intervention and event 
onset. 
b. An alternate etiology has been established. 
 
8.3.2 
Expectedness 
The PI is responsible for determining whether an AE is expected or unexpected. An AE 
will be considered unexpected if the nature, severity, or frequency of the event is not 
consistent with the risk information previously described for the intervention. Risk 
information to assess expectedness can be obtained from preclinical studies, the 
investigator’s brochure, published medical literature, the protocol, or the informed 
consent document. 
8.3.3 
Severity of Event 
Adverse events will be graded for severity according to the Common Terminology Criteria 
for Adverse Events (CTCAE) version 5.0. 
8.3.4 
Intervention 
Any intervention implemented to treat the adverse event must be documented for all 
adverse events. 
8.4 
Safety Reporting  
The sponsor-investigator shall be responsible for all required periodic safety updates to 
the Regulatory Authorities and expedited reporting of all SAEs occurring during the 
performance of the Study, for initial and all subsequent follow-up reports, in accordance 
with local and regional regulations. 
 


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Adverse events (AE) will be reported to the Thomas Jefferson University IRB and the 
Data Safety Monitoring Board (DMSB) via Clinical Research Management Office (CRMO) 
as specified in the TJU Data Safety and Monitoring Plan (Refer to Table). All AEs must 
be graded according to NCI CTCAE Version 5.0 
 
 
 
 
8.4.1 
Reporting to IRB 
8.4.1.1 Unanticipated Problems 
All incidents or events that meet criteria for unanticipated problems (UAPs) as defined in 
Section 8.1.1 Unanticipated Problems require the creation and completion of an 
unanticipated problem report form (OHR-20).  
UAPs that pose risk to participants or others, and that are not AEs, will be submitted to 
the IRB on an OHR-20 form via the eazUP system within 10 working days of the 
investigator becoming aware of the event.  
UAPs that do not pose risk to participants or others will be submitted to the IRB at the 
next continuing review.  
8.4.1.2 Adverse Events  
Grade 1 AEs will be reported to the IRB at continuing review.  
Grade 2 AEs will be reported to the IRB at the time of continuing review.  
8.4.1.3 Serious Adverse Events  
SAEs will be reported to the IRB on OHR-10 forms via the electronic reporting system 
(eSAEy) according to the required time frames described below. 
Grade 3-4 AEs that are unexpected and deemed to be at least possibly related to the 
study will be reported to the IRB within 2 working days of knowledge of the event. 
Grade 3-4 AEs that are deemed unrelated to the study will be reported to the IRB within 
5 working days.  
Grade 5 AEs will be reported to the IRB within one working day of knowledge of the event. 
All SAEs will be submitted to the IRB at continuing review, including those that were 
reported previously. 
8.4.1.4 Events exempt from being reported as SAEs 


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Events specified in this section do not require reporting as SAEs in this trial, unless 
hospitalization is prolonged for any reason and then an SAE form must be completed. 
The events must still be recorded in the appropriate section of the case report form (CRF). 
 
Screening period – SAEs occurring in the period prior to administration of VS-6766 and 
Defactinib (VS- 6063) from the time of informed consent to the day prior to cycle 1 day 1 
of VS-6766 and VS-6063 administration that are not related to the design or conduct of 
the trial are exempt from reporting. 
Elective admissions – Elective admissions to hospital for procedures which were 
planned and documented in the medical records at the time of consent are not SAEs, and 
do not require SAE reporting. Hospitalization for administration of the study medications 
according to the trial protocol is also exempt from being reported as an SAE, unless the 
hospitalization is prolonged by any reason and then an SAE must be reported. 
 
Death due to disease progression – all cases of death during the study period up to 28 
days after the trial should be reported to Verastem. After the 28 day period, cases of 
death due to disease progression do not require reporting unless considered related to 
study medications. 
8.4.1.5 Follow-up of adverse events 
Follow-up will continue until all the necessary safety data for the event has been gathered 
and any AE or SAE regardless of causality has either resolved, returned to baseline or 
stabilized.  
8.4.2 
Reporting to SKCC DSMC 
All AEs and SAEs, safety and toxicity data, and any corrective actions will be submitted 
to the DSMC per the frequency described in the SKCC DSMP. The report to the SKCC 
DSMC will also include any unanticipated problems that in the opinion of the PI should be 
reported to the DSMC. 
For expedited reporting requirements, see table below:   
 
 
 
 
 
 


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DSMC AE/SAE Reporting Requirements 
 
8.4.3 
Reporting of serious adverse events to Verastem Oncology 
All initial and follow-up SAEs and Safety Information including pregnancy reports must be 
reported 
to 
Verastem, 
Inc. 
Safety 
and 
Pharmacovigilance 
in 
English 
at 
drugsafety@verastem.commailto: or via fax at 1-781-465-7936 within 24 hours of 
knowledge of the event concerning the Verastem, Inc. product. 
 
Copies of any correspondence or telephone conversation logs with the applicable 
Regulatory Authorities regarding all SAE(s), irrespective of association with the Study 


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Drug(s), within a reasonable time frame must be provided to Verastem, Inc. Safety and 
Pharmacovigilance. 
 
The Principal Investigator will report such SAEs using an FDA MEDWATCH form and the 
Serious Adverse Event Fax Cover Sheet provided by Verastem Oncology. The event 
term(s) being reported, start and stop dates of the events, outcome of the events, toxicity 
grade for the events, assessment of causality for the events, action taken with the study 
drugs for the event will all be reported. SAEs should be reported as soon as they are 
determined to meet the definition, even if complete information is not yet available.   
a. Follow-Up Information. Institutions will assist Verastem Oncology in investigating 
any SAE and will provide any follow-up information reasonably requested by 
Verastem Oncology. 
b. Regulatory Reporting. Reporting an SAE to Verastem Oncology does not relieve 
Institutions of responsibility for reporting it to the FDA, as required. 
8.4.4 
Reporting to FDA 
SAEs that are related, unexpected, fatal, or life-threatening are reportable through the 
Food and Drug Administration (FDA) MedWatch program by telephone or fax no later 
than 7 calendar days after initial receipt of the information. Further information on the 
timing 
of 
submissions 
are 
as 
directed 
by 
FDA 
guidelines 
(http://www.fda.gov/medwatch/index.html). Serious, unexpected events that suggest 
significant clinical risk will be submitted to within 15 calendar days after initial receipt of 
this information. 
 
Food and Drug Administration: 
Telephone 1-800-FDA-1088 
Fax 1-332-FDA-0178 
http://www.fda.gov/medwatch/report.htm  
 
8.4.5 
Sponsor reporting responsibilities 
1. Adverse events which meet all of the following criteria must be reported to all 
participating institutions for IRB submission within 2 weeks of notification of the 
event.   
a. Unexpected (in terms of nature, severity, or frequency) given 
i. the research procedures that are described in the protocol-related 
documents, such as the IRB-approved research protocol and 
informed consent document; and  
ii. the characteristics of the subject population being studied; 


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b. Possibly related to participation in the research (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 
c. Serious (refer to above definition) or otherwise one that suggests that the 
research places subjects or others at a greater risk of physical or 
psychological harm than was previously known or recognized. 
2. If the adverse event requires modification of the study protocol and informed 
consent Verastem will be informed. If these changes on the protocol are finalized, 
they will be provided to all participating institutions in the form of an amendment 
from the OCR for each site’s IRB of record along with the report of the adverse 
event.   
3. Copies of all related correspondence and reporting documents will be maintained 
in a centralized regulatory file for this study at OCR. 
4. SAEs that are related, unexpected, fatal, or life-threatening are reportable 
through the Food and Drug Administration (FDA) MedWatch program by 
telephone or fax no later than 7 calendar days after initial receipt of the 
information. Further information on the timing of submissions are as directed by 
FDA guidelines (http://www.fda.gov/medwatch/index.html). Serious, unexpected 
events that suggest significant clinical risk will be submitted to within 15 calendar 
days after initial receipt of this information. 
8.4.6 
Recording of AE and SAEs in eCRFs 
All AEs, including SAEs, must be recorded in the eCRF for eligible patients. All 
concomitant medications, including herbal medications and supplements must be 
recorded. Any therapy used to treat the event must be recorded. The eCRF will be 
reconciled with the safety database during and at the end of the trial. Therefore, the sites 
should ensure the data entered on the SAE report form and the data entered into the 
eCRF are consistent. The Safety Review Committee and the Investigator(s) will regularly 
review the safety data from both the safety and the clinical database. 
 
Monthly, the sponsor-investigator site will reconcile a listing of SAEs or Safety Information 
provided by Verastem, Inc. with the site’s records. Discrepancies between the Verastem, 
Inc. and sponsor-investigator site’s records will be investigated by the sponsor-
investigator site. The sponsor-investigator will send an updated AE form, MedWatch or 
CIOMS to Verastem, Inc. or designee to resolve identified discrepancies. 
8.4.7 
Reporting of Pregnancy 
The effects of Defactinib (VS-6063) and VS-6766 on conception, pregnancy, and lactation 
are unknown.  
 


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At Screening, all male and female subjects of reproductive potential (i.e., not surgically 
sterile or female subjects who are not postmenopausal) must be willing to use highly 
effective methods of contraception for the duration of the study intervention and for 3 
months after the last dose of Defactinib and VS-6766. Male subjects must also refrain 
from donating sperm during their participation in the study and for at least 3 months after 
the last dose of Defactinib and VS-6766. Pregnancy testing will be performed throughout 
the study and 28 days after the last dose. 
 
A subject must immediately inform the Investigator if the subject or subject’s partner 
becomes pregnant from the time of consent to 30 days after the last dose of study drug(s). 
Any female subjects receiving study drug(s) who become pregnant must immediately and 
permanently discontinue study drug(s). The Investigator should counsel the subject, 
discussing any risks of continuing the pregnancy and any possible effects on the fetus. 
The pregnant woman should be referred to an obstetrician/gynecologist experienced in 
reproductive toxicity for further evaluation and counseling.  
 
Although pregnancy itself is not regarded as an AE unless there is cause to believe that 
the study intervention may have interfered with the effectiveness of contraceptive 
medication or if the outcome of pregnancy meets SAE criteria (miscarriage or congenital 
anomaly/birth defect, etc.), in which case it should be reported in the same manner and 
timelines as an SAE, the outcome will need to be documented. 
 
Any 
SAEs 
associated 
with 
pregnancy 
(e.g. 
congenital 
abnormalities/birth 
defects/spontaneous miscarriage or any other serious events) must additionally be 
reported. In addition, any infant death or congenital anomaly occurring after 30 days that 
the Investigator suspects is related to the in-utero exposure to the study intervention 
should also be reported as an SAE. Hospitalization for normal delivery of a healthy 
newborn is not an SAE. 
 
Consent to provide follow-up information regarding the outcome of the pregnancy and the 
health of the infant until 30 days old will be requested.  
 
Any pregnancy occurring in a patient or a patient’s partner during treatment with a study 
medication or occurring within six months of last study medication administration must be 
reported to the DSMB and Verastem, Inc. within 24 hours of the Investigator’s knowledge 
of the pregnancy using a Pregnancy Report Form. The Investigator will observe the 
pregnant woman until completion of the pregnancy and must notify Verastem, Inc. of the 
outcome within 24 hours of the Investigator’s knowledge of the pregnancy outcome using 
a Pregnancy Outcome Form. This notification includes pregnancies resulting in live, 
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Highly Effective Methods of Contraception are methods that can achieve a failure rate of 
less than 1% per year when used consistently and correctly are considered as highly 
effective birth control methods. Such methods include: 
• 
combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation1: 
o oral 
o intravaginal 
o transdermal 
• 
progestogen-only hormonal contraception associated with inhibition of 
ovulation1: 
o oral 
o injectable 
o implantable2 
• 
intrauterine device (IUD) 
• 
intrauterine hormone-releasing system2 
• 
bilateral tubal occlusion2 
• 
vasectomized partner2,3 
• 
sexual abstinence4 
 
1Hormonal contraception may be susceptible to interaction with the IMP, which may reduce 
the efficacy of the contraception method. 
2Contraception methods that are considered to have low user dependency. 
3Vasectomized partner is a highly effective birth control method provided that partner is the 
sole sexual partner of the study participant and that the vasectomized partner has received 
medical assessment of the surgical success. 
4Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study 
treatments. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the clinical study and the preferred and usual lifestyle of the patient. 
8.5 
Halting Rules 
Adverse events which meet all of the following criteria must be reported to all 
participating institutions for IRB submission within 2 weeks of notification of the event.   
o Unexpected (in terms of nature, severity, or frequency) given 


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 the research procedures that are described in the protocol-related 
documents, such as the IRB-approved research protocol and 
informed consent document; and  
 the characteristics of the subject population being studied. 
o Possibly related to participation in the research (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 
o Serious (refer to above definition) or otherwise one that suggests that the 
research places subjects or others at a greater risk of physical or 
psychological harm than was previously known or recognized. 
This may prompt temporary suspension of enrollment and/or study interventions until a 
safety review is convened (either routine or ad hoc). The objective of the safety review 
is to decide whether the study (or intervention for an individual or study cohort) should 
continue per protocol, proceed with caution, be further investigated, be discontinued, or 
be modified and then proceed. Suspension of enrollment (for a particular group, a 
particular study site or for the entire study) is a potential outcome of a safety review. 
Subsequent review of serious, unexpected, and related AEs by the Medical Monitor, 
DSMC, IRB, the sponsor(s), or the FDA or relevant local regulatory authorities may also 
result in suspension of further trial interventions/administration of study product at a site. 
The FDA and study sponsor(s) retain the authority to suspend additional enrollment and 
study interventions/administration of study product for the entire study, as applicable. 
 
Urgent safety measures 
The Sponsor or Investigator may take appropriate urgent safety measures (USMs) in 
order to protect the patient of a clinical trial against any immediate hazard to their health 
or safety. This includes procedures taken to protect patients from pandemics or infections 
that pose serious risk to human health. 
 
USMs may be taken without prior authorization from the competent authority. 
 
The Food and Drug Administration (FDA) and the Research Ethics Committee (REC) 
must be notified within three days of such measures being taken. 
9 Study Oversight 
In addition to the PI’s responsibility for oversight, study oversight will be under the 
direction of the SKCC’s Data and Safety Monitoring Committee (DSMC). The SKCC 
DSMC operates in compliance with a Data and Safety Monitoring Plan (DSMP) that is 
approved by the NCI.  


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10 Clinical Site Monitoring and Auditing 
Clinical site monitoring and auditing is conducted to ensure that the rights of human 
participants are protected, that the study is implemented in accordance with the protocol 
and/or other operating procedures, and that the quality and integrity of study data and 
data collection methods are maintained. Monitoring and auditing for this study will be 
performed in accordance with the SKCC’s Data and Safety Monitoring Plan (DSMP) 
developed by the SKCC Data and Safety Monitoring Committee (DSMC). The DSMP 
specifies the frequency of monitoring, monitoring procedures, the level of clinical site 
monitoring activities (e.g., the percentage of participant data to be reviewed), and the 
distribution of monitoring reports. Some monitoring activities may be performed remotely, 
while others will take place at the study site(s). Appropriate staff will conduct monitoring 
activities and provide reports of the findings and associated action items in accordance 
with the details described in the SKCC DSMP. 
   11 Statistical Considerations  
10.1 Study Hypotheses 
The primary objective null hypothesis is that the true response rate is 20%, and the 
alternative hypothesis is that the true response rate is 50%.  
10.2 Analysis Plans 
In order to further characterize the efficacy of the combination of VS-6766 and 
Defactinib (VS-6063) in metastatic uveal melanoma patients, Simon’s Optimal two-
stage design will be used for conducting this clinical trial (44). The best response during 
study treatment in individual patients will be used for efficacy analysis.  
The null hypothesis is that the true response rate is 20%, and the alternative hypothesis 
is that the true response rate is 50%.  The Simon’s Optimal two-stage design was selected 
with a maximum of 18 patients and target alpha level of 0.05 and power 80%. 
 
The cohort escalation design is guided by a desire to stop the trial early if the actual 
stabilization rate is 20% or less. No medication is approved for MUM by the US FDA and 
potential clinical benefit could be obtained if MUM patients achieve stable disease (SD); 
therefore, we will consider overall Disease Control Rate (DCR) (CR+PR+SD) of 50% as 
a meaningful endpoint for this early phase clinical study. This is considered to be an 
appropriate goal since the Overall Response Rates (ORR) (CR+PR) and overall Disease 
Control Rate (DCR) (CR+PR+SD) of combination treatments using the FDA approved 
medications ipilimumab and nivolumab are reported to be 11.8-16.7% and 29.4-64%, 
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We hope that we will have at least 50% overall DCR with reasonable toxicity in this 
expansion cohort. A total of 18 UM patients with systemic metastasis will be enrolled 
based on Simon’s Optimal two-stage design. If overall DCR is less than 20%, we may not 
consider further clinical studies with this combination treatment (Table 4). 
 
The trial is carried out in two stages. In stage I, a total number of 8 patients are accrued. 
If there are 2 or fewer overall responses (CR+PR+SD) among these 8 patients, further 
enrollment of patients may be stopped with the conclusion that the DCR cannot be 50% 
or greater. Otherwise, an additional 10 patients will be accrued in stage II, resulting in a 
total sample size of 18. If there are 7 or more responses among these 18 patients, we 
reject the null hypothesis and claim that the treatment is promising [Optimal Design]. 
 
With this design, we have no more than a 5% chance of concluding effective (>=50% 
stabilization rate) when the success rate is at most 20%. Similarly, we have no more than 
a 20% chance of concluding ineffective (<=20% stabilization rate) when it is effective 
(50% stabilization rate). If the actual response rate is 20% or worse, we have at least a 
0.79 probability that the trial will stop after the first 14 subjects. The overall power of this 
design is 80.0%. 
 
 
Table 4: Cohort Expansion Stages 
Stage 
Look after this number of 
patients 
Stop if number of 
successes is less than or 
equal to 
I 
8 
2 
II 
10 
6 
 
 
The final analysis will be conducted after one of the following conditions is met. 
• The trial is terminated early (for example, due to toxicity or inefficacy as defined 
above). 
• All patients have had the opportunity to receive 1 cycle of treatment and have 
completed their ‘off-study’ visit (i.e. 28 days after the last dose of VS-6766 and/or 
Defactinib). 
 
Once one of the conditions is met, a data cut-off date will be established. All patient visits 
occurring on or before this date will be analyzed and summarized in the final clinical study 
report. Any data collected after this date will be summarized in a supplemental report. 


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10.3 Interim Analyses and Stopping Rules 
10.3.1 Efficacy Review 
As described in section 11.2, the trial is carried out in two stages. In stage I, a total number 
of 8 patients are accrued. If there are 2 or fewer overall responses (CR+PR+SD) among 
these 8 patients, further enrollment of patients may be stopped with the conclusion that 
the DCR cannot be 50% or greater. If this happens, the study results will be shared with 
Verastem Oncology and the future study design will be discussed.  
 
Otherwise, an additional 10 patients will be accrued in stage II, resulting in a total sample 
size of 18.  
10.4 Defining the end of trial 
The ‘end of trial’ is defined as the date when the last patient has completed the ‘off-study’ 
visit or the final follow-up visit (whichever is the latter). 
 
It is the responsibility of the Principal Investigator to inform the Food and Drug 
Administration (FDA) within 90 days of the ‘end of the trial’ that the trial has closed. 
 
The entire trial will be stopped when: 
• 
The drug is considered too toxic to continue treatment before the required number 
of patients being recruited. 
• 
The drug is considered ineffective (actual stabilization rate is 20% or less); see 
section 11.2. 
• 
The stated number of patients to be recruited is reached. 
• 
The stated objectives of the trial are achieved. 
 
Regardless of the reason for termination, all data available for the patient at the time of 
discontinuation of follow-up must be recorded in the eCRF. All reasons for discontinuation 
of treatment must be documented. 
 
In terminating the trial, the Investigators must ensure that adequate consideration is given 
to the protection of the patient’s interest. 
10.5 Sample Size Considerations 
Based on the Simon’s Optimal two-stage design, a total number of 8 patients are accrued 
in stage I. If there are 2 or fewer overall responses (CR+PR+SD) among these 8 patients, 
further enrollment of patients may be stopped with the conclusion that the DCR cannot 
be 50% or greater. Otherwise, an additional 10 patients will be accrued in stage II, 
resulting in a total sample size of 18.  


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Simon’s Optimal two-stage design was selected with a maximum of 18 patients and target 
alpha level of 0.05 and power 80%. With this design, we have no more than a 5% chance 
of concluding effective (>=50% stabilization rate) when the success rate is at most 20%. 
Similarly, we have no more than a 20% chance of concluding ineffective (<=20% 
stabilization rate) when it is effective (50% stabilization rate). If the actual response rate 
is 20% or worse, we have at least a 0.79 probability that the trial will stop after the first 14 
subjects. The overall power of this design is 80.0%. 
10.5.1 Replacement Policy 
Patients who do not complete one cycle of dosing with VS-6766 and Defactinib (VS-6063) 
for reasons other than toxicity will be replaced. 
10.5.2 Accrual Estimates 
It is expected that the trial recruitment duration will be 6 to 18 months with an expected 
accrual rate of approximately 1-3 patients per month at Thomas Jefferson University 
Hospital. A total of up to 18 patients will be entered into this trial, depending on the disease 
control rate in the first stage of the study. 
10.6 Data Analysis 
Data will be presented in a descriptive fashion. Variables will be analyzed to determine 
whether the criteria for the trial conduct are met. This will include a description of patients 
who did not meet all the eligibility criteria, an assessment of protocol violations, study 
medication accountability and other data that study impact on the general conduct of the 
trial. 
 
Baseline characteristics will be summarized for all enrolled patients. Patients who died or 
withdrew before treatment started or did not complete the required safety observations 
will be described and evaluated separately. 
 
Treatment administration will be described for all cycles. Dose administration, dose 
modifications or delays and the duration of therapy will be described. 
 
Documenting anti-tumor activity is the primary objective of this trial. Patients must receive 
at least one cycle of the trial medication and have had at least one post baseline RECIST 
assessment (or have progressed prior to this assessment) to be evaluable for response. 
Best overall response and overall Disease control rate (CR+PR+SD) achieved by each 
patient while on trial and the time to progression will be presented in the data listings.  
 


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Progression free survival (PFS) will be calculated from trial entry until the time of 
documented disease progression or death (whichever occurs first). Overall survival (OS) 
will be calculated from trial entry until the time of documented death. Patients who are 
alive and event free or lost to follow up at the time of analysis will be censored at the time 
the patient was last known to be alive and progression free. A Kaplan Meier graph and 
median PFS will be presented overall and by cohort. 
 
All estimates of rates (e.g. Disease Control Rate and toxicity) will be presented with 
corresponding 95% exact confidence intervals.  For Disease Control Rates, the method 
of Atkinson and Brown will be used to allow for the two-stage design.  
10.7 Evaluation of Safety 
Safety data will be collected from the date of written consent. Safety variables will be 
summarized by descriptive statistics. Laboratory variables will be described using the 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) Version 5.0. 
 
Adverse events (AEs) will be reported for each dose level and presented as tables of 
frequency of AEs by body system and by worse severity grade observed. AE term start 
and end date, severity captured by CTCAE Version 5.0, seriousness, outcome, action 
taken regarding study drugs and relationship to each study drug will also be reported. The 
summary tables will also discuss AEs leading to death and AEs leading to study drug(s) 
discontinuation. Tables should indicate related and unrelated events. Laboratory data will 
be presented by dose level at each observation time. Values outside normal limits will be 
identified and summarized by frequency distribution. 
10.8 Pharmacodynamics 
Tumor biopsies for PD analysis will be collected from patients. Tumor biopsies will be 
collected at baseline (within 28 days before starting treatment), on-treatment (1-24 hours 
after taking the combination (VS-6766 and Defactinib) during Cycle 1 or Cycle 2), and 
upon progression as long as the biopsy of the tumor is feasible. Circulating cell free DNA 
will be collected prior to, before starting Cycle 2, and upon progression.  
The PD data will be presented by listings and summary statistics 
11 Source Documents and Access to Source Data/Documents 
Source data is defined as all information in original records and certified copies of original 
records of clinical findings, observations, or other activities in a clinical trial necessary for 


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the reconstruction and evaluation of the trial. Source data are contained in source 
documents (original records or certified copies). 
 
All data collected in the eCRF must be verifiable by the source data. The electronic data 
capture system for this trial will be Recap.  Therefore, it is the Investigator’s responsibility 
to ensure that both he/she and his/her study team records all relevant data in the medical 
records. The Investigator must allow the SKCC monitor direct access to relevant source 
documentation for verification of data entered into the eCRF, taking into account data 
protection regulations. Entries in the eCRF will be compared with patients’ medical 
records and the verification will be documented on the source data verification (SDV) form 
and the monitoring report. 
 
The patients’ medical records, and other relevant data, may also be reviewed by 
appropriate qualified personnel independent from the study site(s) appointed to audit the 
trial, and by regulatory authorities. Details will remain confidential and patients’ names 
will not be recorded outside the hospital.  
 
Study staff will maintain appropriate medical and research records for this study, in 
compliance with ICH E6, and regulatory and institutional requirements for the protection 
of confidentiality of participant information. Study staff will permit authorized 
representatives of SKCC and regulatory agencies to examine (and when required by 
applicable law, to copy) research records for the purposes of quality assurance reviews, 
audits, and evaluation of the study safety, progress and data validity. 
 
The study data will also be shared with University of San Diego and Verastem Oncology 
for the development of future collaborative activities. In that case, identifiable data on 
individual patients will be completely removed before sharing study data.   
12 Quality Control and Quality Assurance 
Quality Management is the overall process of establishing and ensuring the quality of 
processes, data, and documentation associated with clinical research activities. It 
encompasses both quality control (QC), and quality assurance (QA) activities. All sites 
conducting research under the sponsorship of the SKCC are required to have a plan in 
place for assuring the quality of the research being conducted. 
Data will be evaluated for compliance with the protocol and for accuracy in relation to 
source documents by the KCC medical monitor. The Principal Investigator will ensure that 
the KCC medical monitor or other compliance or quality assurance reviewer is given 
access to all study-related documents and study related facilities (e.g. pharmacy, 
diagnostic laboratory, etc.), and has adequate space to conduct the monitoring visit. 


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All documents including eCRFs, clinic notes, product accountability records, specimen 
tracking logs, will be reviewed by the KCC medical monitor every 3 months or as required 
by the institutional policy.  
Quality assurance issues (correcting procedures that are not in compliance with protocol) 
and quality control issues (correcting errors in data entry) will be addressed by the 
Principal Investigator. The summary of protocol deviation and violation will be included in 
the KCC investigator’s reports to the TJU IRBs as part of its annual progress report.  
Clinical trial staff will be trained in-person on the protocol study design, schedule, and 
data handling by the PI. The PI will track the training of all staff. 
13 Ethics/Protection of Human Participants  
13.1 Ethical Standard 
This study is to be conducted according to US and international standards of Good 
Clinical Practice (FDA Title 21 part 312 and International Conference on Harmonization 
guidelines), applicable government regulations and Institutional research policies and 
procedures. The study will be conducted in accordance with the Declaration of Helsinki 
and with rules and regulations in accord with the U.S. Office of Protection from Research 
Risks (OPRR). 
13.2 Institutional Review Board 
The study will be reviewed and approved by a duly constituted IRB before patients are 
screened for entry. The investigator will ensure that all aspects of the IRB review are 
conducted in accordance with current institutional, local, and national regulations.  
Amendments to the protocol will be subject to the same requirements as the original 
protocol. The Investigator will submit all periodic reports and updates that the IRB may 
require, including any final close out reports. The Investigator will inform the IRB of any 
reportable adverse events as required by local regulations. 
13.3 Informed Consent Process 
Informed consent is a process that is initiated prior to the individual agreeing to 
participate in the study and continues throughout study participation. Extensive 
discussion of risks and possible benefits of study participation will be provided to 
participants and their families, if applicable. A consent form describing in detail the study 
procedures and risks will be given to the participant. Consent forms will be IRB-
approved, and the participant is required to read and review the document or have the 
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study to the participant and answer any questions that may arise. The participant will 
sign the informed consent document prior to any study-related assessments or 
procedures. Participants will be given the opportunity to discuss the study with their 
surrogates or think about it prior to agreeing to participate. They may withdraw consent 
at any time throughout the course of the study. A copy of the signed informed consent 
document will be given to participants for their records. The rights and welfare of the 
participants will be protected by emphasizing to them that the quality of their clinical 
care will not be adversely affected if they decline to participate in this study. The 
consent process will be documented in the clinical or research record.  
 
13.4 Exclusion of Women, Minorities, and Children (Special Populations) 
Males or females younger than 18 years of age will be excluded (children). Individuals 
of any gender or racial/ethnic group may participate.  
13.5 Participant Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  
Those regulations require a signed subject authorization (may be part of Informed 
Consent Form) informing the subject of the following:  
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI. 
 
In documents or reports or on biological samples (i.e. blood, tissue) that may be viewed 
by those other than study staff, patients will be identified only by their initials or a coded 
study number.  No other PHI will be included in these documents or reports.  Study results 
by be published but will contain no personally identifying information about study subjects. 
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of 
subject authorization.  For subjects that have revoked authorization to collect or use PHI, 
attempts should be made to obtain permission to collect at least vital status (i.e. that the 
subject is alive) at the end of their scheduled study period. 


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13.6 Future Use of Stored Specimens and Other Identifiable Data  
Tumor biopsies and PD blood samples will be collected, analyzed, and stored at the 
laboratories of the Investigators listed in the protocol. Please refer to the Study Laboratory 
Standard Operating Procedures for handling, storage and shipment of samples. The 
informed consent will specify whether the patient agrees to the future use of his/her 
specimens. If patients agree, residual biopsy specimen and blood samples will be stored 
at the protocol laboratories after the study is complete and used for unrelated research. 
In that case, patient information will be de-identified on the samples. No genetic testing 
related to inheritable non-cancer disease will be performed on the tumor biopsies or blood 
samples. 
 
14 Data Handling and Record Keeping 
The investigators are responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. All source documents must be completed in a neat, legible 
manner to ensure accurate interpretation of data. The investigators will maintain adequate 
case histories of study participants, including accurate case report forms (CRFs), and 
source documentation. 
14.1 Data Management Responsibilities 
Data collection and accurate documentation are the responsibility of the study staff under 
the supervision of the investigator. All source documents and laboratory reports must be 
reviewed by the study team and data entry staff, who will ensure that they are accurate 
and complete. Unanticipated problems and adverse events must be reviewed by the 
investigator or designee.  
14.2 Data Capture Methods 
Electronic CRFs (eCRFs) will be used to collect the data. These eCRF’s will be in the 
RedCap Electronic Data Capture system. The Investigator is responsible for ensuring the 
accuracy, completeness, clarity and timeliness of the data reported in the eCRFs. 
 
Only the Investigator and those personnel who have signed the Study Team 
Responsibilities Signature Log/Delegation Log have been authorized by the Investigator 
should enter or change data in the eCRFs. All protocol required investigations must be 
reported in the eCRF. The Investigators must retain all source data (contained in original 
reports, traces and images from protocol investigations) for future reference. 
 


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14.3 Types of Data 
Types of data to be collected for this trial will include demographic information, medical 
history, laboratory results (blood and urine), pregnancy test results, tumor biopsy results, 
pharmacodynamic analysis data, physical examination, vital signs, ECG data, 
ophthalmologic examination data, radiological disease assessments (CT and MRI), 
circulating free DNA analysis data, concomitant treatments, and adverse event 
assessments. 
14.4 Study Records Retention 
During the clinical trial and after trial closure the Investigator must maintain adequate and 
accurate records to enable both the conduct of a clinical trial and the quality of the data 
produced to be evaluated and verified. These essential, including source documents 
such as scans, trial related documents and copies of the eCRFs, associated audit trail 
and serious adverse event (SAE) report forms, shall show whether the Investigator has 
complied with the principles and guidelines of Good Clinical Practice (GCP). 
 
All essential documents required to be held by the Investigator must be stored in such a 
way that ensures that they are readily available, upon request, to the Regulatory 
Agencies, for the minimum period of 2 years after completion of the study in accordance 
with the FDA guideline [21CFR 812.140(d), 12 CRF 312.62].    
The medical files of trial subjects shall be retained in accordance with the FDA guideline 
and in accordance with the maximum period of time permitted by the hospital, institution 
or private practice. 
14.5 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical study protocol, Good Clinical 
Practice, or Manual of Procedures requirements. The noncompliance may be on the part 
of the participant, the investigator, or study staff. As a result of deviations, corrective 
actions are to be developed by the study staff and implemented promptly. 
 
All deviations from the protocol must be addressed in study participant source documents 
and promptly reported to the IRB and other regulatory bodies according to their 
requirements.  
 
Eligibility waivers are strictly prohibited. Protocol deviations will be recorded, will be 
considered at the time of study analysis and where appropriate, will be documented in 
the clinical study report. 
 


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Amendments to the protocol may only be made with the approval of the IRB. Amendments 
will be subject to review by the sponsor. Non-substantial amendments do not require FDA 
approval. Urgent safety measures may be implemented immediately where necessary 
but the sponsor should be informed immediately (see section 8.4). 
15 Study Finances 
15.1 Funding Source 
The study will be funded by Verastem Oncology, Inc, as well as institutional funds 
(Metastatic Uveal Melanoma Research Fund) at Thomas Jefferson University.  
 
15.2 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, 
or financial gain greater than the minimum allowable by their institution, etc.) must have 
the conflict reviewed by a properly constituted Conflict of Interest Committee with a 
Committee-sanctioned conflict management plan that has been reviewed and approved 
by the study sponsor prior to participation in this study. All Jefferson University 
Investigators will follow the TJU Conflicts of Interest Policy for Employees (107.03). 
15.3 Participant Stipends or Payments 
There is no compensation for participation in this study. 
16 Publication and Data Sharing Policy 
This study will comply with the NIH Public Access Policy, which ensures that the public 
has access to the published results of NIH funded research. It requires scientists to submit 
final peer-reviewed journal manuscripts that arise from NIH funds to the digital archive 
PubMed Central upon acceptance for publication. 
 
The International Committee of Medical Journal Editors (ICMJE) member journals have 
adopted a clinical trials registration policy as a condition for publication. The ICMJE 
defines a clinical trial as any research project that prospectively assigns human 
participants to intervention or concurrent comparison or control groups to study the cause-
and-effect relationship between a medical intervention and a health outcome. Medical 
interventions include drugs, surgical procedures, devices, behavioral treatments, 
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related measures obtained in patients or participants, including pharmacokinetic 
measures and adverse events. The ICMJE policy requires that all clinical trials be 
registered in a public trials registry such as ClinicalTrials.gov, which is sponsored by the 
National Library of Medicine. Other biomedical journals are considering adopting similar 
policies. The ICMJE does not review specific studies to determine whether registration is 
necessary; instead, the committee recommends that researchers who have questions 
about the need to register err on the side of registration or consult the editorial office of 
the journal in which they wish to publish. 
 
U.S. Public Law 110-85 (Food and Drug Administration Amendments Act of 2007 or 
FDAAA), Title VIII, Section 801 mandates that a "responsible party" (i.e., the sponsor or 
designated principal investigator) register and report results of certain "applicable clinical 
trials:"  
 
Trials of Drugs and Biologics: Controlled, clinical investigations, other than Phase I 
investigations, of a product subject to FDA regulation;  
 
Trials of Devices: Controlled trials with health outcomes of a product subject to FDA 
regulation (other than small feasibility studies) and pediatric postmarket surveillance 
studies. 
 
NIH grantees must take specific steps to ensure compliance with NIH implementation of 
FDAAA. 
 
 


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Harbour JW. The genetics of uveal melanoma: an emerging framework for 
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et al. First-in-human, phase I dose-escalation study of the safety, 
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MEK/RAF inhibitor in patients with solid tumors. Clin Cancer Res. 2012 Sep 
1;18(17):4806-19. 
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Honda K, Yamamoto N, Nokihara H, Tamura Y, Asahina H, Yamada Y, et al. 
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Cancer Chemother Pharmacol. 2013 Sep;72(3):577-84. 
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growth factor receptor inhibitor-associated cutaneous toxicities: an evolving 
paradigm in clinical management. Oncologist. 2007 May;12(5):610-21. 
33. 
Kaliki S, Shields CL. Uveal melanoma: relatively rare but deadly cancer. Eye 
(Lond). 2017 Feb;31(2):241-57. 
34. 
van Nimwegen MJ, van de Water B. Focal adhesion kinase: a potential target in 
cancer therapy. Biochem Pharmacol. 2007 Mar 1;73(5):597-609. 
35. 
Siesser PM, Hanks SK. The signaling and biological implications of FAK 
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Compensatory role for Pyk2 during angiogenesis in adult mice lacking endothelial 
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Gerber DE, Camidge DR, Morgensztern D, Cetnar J, Kelly RJ, Ramalingam SS, 
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Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 
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39. 
Banerji U, Camidge DR, Verheul HM, Agarwal R, Sarker D, Kaye SB, et al. The 
first-in-human study of the hydrogen sulfate (Hyd-sulfate) capsule of the MEK1/2 
inhibitor AZD6244 (ARRY-142886): a phase I open-label multicenter trial in 
patients with advanced cancer. Clin Cancer Res. 2010 Mar 1;16(5):1613-23. 
40. 
LoRusso PM, Krishnamurthi SS, Rinehart JJ, Nabell LM, Malburg L, Chapman 
PB, et al. Phase I pharmacokinetic and pharmacodynamic study of the oral 
MAPK/ERK kinase inhibitor PD-0325901 in patients with advanced cancers. Clin 
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41. 
Ishii N, Harada N, Joseph EW, Ohara K, Miura T, Sakamoto H, et al. Enhanced 
inhibition of ERK signaling by a novel allosteric MEK inhibitor, CH5126766, that 
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42. 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. 
New response evaluation criteria in solid tumours: revised RECIST guideline 
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44. 
Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 
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45. 
 Clinical Trial Facilitation Group (CTFG). (2014). Recommendations related to 
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Appendices 
The following documents are officially affiliated with the protocol and will be submitted to the IRB 
as a part of the protocol. As such, changes to these items require a protocol amendment. 
APPENDIX A: SCHEDULE OF EVENTS 
APPENDIX B: MEASUREMENT OF DISEASE 
APPENDIX C: RECOMMENDATIONS RELATED TO CONTRACEPTION AND PREGNANCY 
TESTING IN CLINICAL TRIALS 
APPENDIX D: PROTOCOL HISTORY 
 
 


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APPENDIX A: SCHEDULE OF EVENTS 
Observation/Investigation Baseline/Pre-study 
Cycles 1 & 2** 
Cycles 
3 & 4 
** 
Cycle 5 
onwards 
** 
Off study and Follow-up 
1 cycle = 28 days* 
Within 4 
weeks 
prior to 
first dose 
Within 2 
weeks  
prior to 
first dose 
Day 1 
Day 8 Day 15 Day 22 Day 1 
Day 1 
Off study: 
within 28 
days after 
last dose 
 
Monthly safety 
follow-up(a) 
 
Survival 
Follow-up 
Written informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographics &  
                 medical history 
X 
 
 
 
 
 
 
 
 
 
 
Adverse event evaluation 
X 
Continually review 
X 
Until  
resolution (a) 
 
Concomitant treatments 
X 
Continually review 
X 
 
 
Echocardiogram or MUGA 
X 
 
 
 
 
 
 
 
 
 
 
Radiological (CT, MRI)  
      disease assessment (b) 
X 
 
 
 
 
 
X C3D1 
X (b) 
X 
 
 
Clinical disease assess. (b) 
 
X 
 
 
 
 
X C3D1 
X (b) 
X 
 
 
Ophthalmological exam (c) 
X 
 
X C2D1 
 
 
 
X C3D1 X C5D1(c) 
X 
 
 
Triplicate ECG 
 
X 
X C2D1 
 
 
 
 
 
X 
 
 
Pregnancy test (d) 
 
X 
X 
 
 
 
X 
X 
X 
 
 
Physical examination 
 
X 
X 
 
 
 
X 
X 
X 
 
 
ECOG performance status   
           and Vital Signs 
 
X 
X 
X 
X 
X 
 
 
Urinalysis 
 
X 
X 
 
 
 
X 
X 
X 
 
 
Laboratory tests:  
       Hematology and   
               biochemistry (e) 
 
X 
X 
X 
X 
X 
X 
X 
X 
To resolution 
of drug-related 
lab AEs 
 
Coagulation (f) 
X 
 
X 
 
 
X 
 
 
Tumor biopsy (f) 
X 
 
X(f) 
 
 
X 
 
 
Blood for   
     pharmacodynamic (PD)  
 
X 
 
 
 
 
X C3D1 
 
X 
 
 


Defactinib & VS-6766 
 
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page 96 of 99 
 
 
 
* There will be visit windows of +/-2 days in Cycle 1, or on Day 1 of any cycle. For interim safety visits (Cycle 2 onwards, Day 8, 15 or 
22) a window of +/- 2 days is acceptable. The cycle length must always remain 28 +/- 2 days. 
** Patients will be followed up weekly during Cycles 1 and 2, then seen on Day 1 of each cycle thereafter. These assessments can be 
performed within the 24 hours prior to dosing. 
a) Monthly follow-up required for all AEs regardless of causality present at time the patient comes off the trial. Monthly follow-up to 
continue until resolution, to baseline, stabilization or patient starts another anti-cancer treatment. 
b) Disease assessment must be performed at baseline and repeated every 2 cycle(s)/8 weeks of continuous treatment and at 
off study visit (unless assessment has been performed within previous 4 weeks). For patients who continue on treatment 
after 6 cycles frequency may be reduced. Clinical disease assessment and tumor markers should be assessed if applicable. 
c) Ophthalmological examination must be performed at baseline (within 28 days prior to first dose), end of Cycle 1 (between 
Cycle 1 Day 22 and pre-dose Cycle 2 Day 1), end of Cycle 2 (between Cycle 2 Day 22 and pre-dose Cycle 3 Day 1), end of 
Cycle 4 (between Cycle 4 Day 22 and pre-dose Cycle 5 Day 1) and every 3 cycles thereafter and within 28 days after the 
last dose of study drugs. Result must be available prior to dosing (Section 6.1.2). 
d) Pregnancy test only required if the patient is a woman of child bearing potential. 
e) In the event of a Grade 4 neutropenia or Grade 4 thrombocytopenia, a full blood count must be performed at least on Day 5 
after the onset of the event to determine if a dose limiting toxicity has occurred. Continue close monitoring until resolution to 
Grade 3 or less. 
f) Three tumor biopsy samples will be taken at the following time points: at baseline (within 4 weeks), after cycle 1 or 2, and 
within 28 days after the last dose of the study medications. Coagulation should be tested prior to each biopsy as per 
institutional standard practice (at minimum within 7 days prior to procedure). On-treatment biopsy should be performed 2-6 
hours after VS-6766 dose during day 1-21. Post-progression biopsy (if possible) should also be 2-6 hours after VS-6766 dose. 
g) Blood sample for PD analysis will be taken at the following time points: at baseline (within 14 days of first dose), on C3D1 prior 
to administration of study medication, and within 28 days after the last dose of the study medications 
h) Blood for ctDNA analysis will be taken at the end of every 2 cycles for up to 6 cycles, i.e. C3D1 & C5D1 (Section 6.6.2.2). 
i) 
Survival information will be collected via telephone or clinical record review every 12 weeks following the off-study visit and/or 
the completion of monthly safety follow-up (Section 6.4) 
            analysis (g) 
Blood for ctDNA analysis 
 
X 
 
 
 
 
X (h) 
X (h) 
X 
 
 
VS-6766 administration 
 
 
X 
X 
X 
 
X 
X 
 
 
 
Defactinib administration 
 
 
X 
X 
X 
 
X 
X 
 
 
 
Survival Contact 
 
 
 
 
 
 
 
 
 
 
X  


Defactinib & VS-6766 
 
Version 3.0 
IRB #20P.1113 
 
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Based on SKCC Interventional Protocol Template v.20170209 
 
page 97 of 99 
APPENDIX B: MEASUREMENT OF DISEASE (42, 43) 
Eisenhaur et al. (2009). New response evaluation criteria in solid tumours: 
Revised RECIST Guideline (version 1.1). Eur J Cancer, 45(2), 228-247. 
doi:10.1016/j.ejca.2008.10.026. (42) 
 
Schwartz et al. (2016). RECIST 1.1-Update and clarification: From the 
RECIST committee. Eur J Cancer, 62, 132-137. 
doi:10.1016/j.ejca.2016.03.081. (43) 
 
 
 


Defactinib & VS-6766 
 
Version 3.0 
IRB #20P.1113 
 
21JUN2022 
 
 
Based on SKCC Interventional Protocol Template v.20170209 
 
page 98 of 99 
APPENDIX C: RECOMMENDATIONS RELATED TO CONTRACEPTION AND 
PREGNANCY TESTING IN CLINICAL TRIALS (45) 
Clinical Trial Facilitation Group (CTFG). (2014). Recommendations related 
to contraception and pregnancy testing in clinical trials. Retrieved from 
https://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.
pdf. (45) 
 
 


Defactinib & VS-6766 
 
Version 3.0 
IRB #20P.1113 
 
21JUN2022 
 
 
Based on SKCC Interventional Protocol Template v.20170209 
 
page 99 of 99 
APPENDIX D: PROTOCOL HISTORY 
1. Version 1.0 (06/12/2020); written by Dr. Rino Seedor and modified by Dr. 
Takami Sato and was approved by TJU IRB as part of New Study Submission.  
 
2.  Version 2.0 (08/07/2021); modified by Dr. Rino Seedor. Revisions include: 
• Investigator and research staff changes; Title page, Signature page 
• Updated IND number; Title page 
• Clarification of radiologic disease assessments; Sec. 6.1.2 
• Modified AE/SAE reviewer; Sec. 6.2 
• Clarification of ophthalmological examination schedule; Sec. 6.2 
• Modified schedule for blood draws for PD testing; Schematic of study 
design, Sec. 6.1.3, 6.2, 6.6.2.1, Appendix A 
• Modified schedule for blood draw for ctDNA testing; Schematic of study 
design, Sec. 6.1.3, 6.6.2.2, Appendix A 
• Modified tumor biopsy schedule and procedure; Schematic of study design, 
Sec. 6.2, 6.6.2.1, Appendix A 
• Clarification of coagulation testing schedule; Sec. 6.1.2, 6.1.3, 6.6.1 
• Added External Laboratory to approved laboratories; Sec. 6.6.2.1 and 6.6.2.2 
• Removal of BAP1 testing; Sec. 6.6.2.2 
      3.   Version 2.1 (03/07/2022) 
• Investigator and research staff changes; Title page, Signature page 
 
      4.    Version 3.0 (06/21/2022) 
• Modified tumor biopsy timing; Sec. 6.2, 6.6.2.1, Appendix A 
• Added follow-up detail; Sec. 6.4, Appendix A