Clinical trial NCT02004028
Conditions: Malignant Pleural Mesothelioma
Keywords: Mesothelioma adenoma Neoplasms, Mesothelial Focal Adhesion Kinase Inhibitor
Sponsor: Verastem, Inc.
Start date: 2013-12-12; Completion date: 2019-06-19
Enrollment: 35 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is an open label neoadjuvant (treatment with VS-6063 prior to mesothelioma surgery) study in subjects with malignant pleural mesothelioma who are eligible for surgery. Subjects will receive VS-6063 (defactinib) 400 mg twice daily for 12, 21, or 35 days or 100 mg formulation twice daily for 21 days. Pre- and post-treatment biopsies and blood samples will be collected. The purpose of this study is to assess biomarker responses from tumor tissue. The safety, pharmacokinetics, and tumor response rate to VS-6063 (defactinib) will be also be assessed.

Detailed description:

Arms: arm 1: Administered orally (BID) for 12, 21 or 35 days (+/- 2 days)
Interventions: intervention 1: VS-6063
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_SAP_000.pdf: 
Protocol Cover Page 
 
 
Verastem Protocol: VS-6063-203 
NCT: NCT02004028 
 
Coordinating Center: DFCI/BWH 
Protocol Version Date: 15-DEC-2017 
Protocol Version: 7.0 
 
 
 
 
Title: An Open Label Window of Opportunity Phase II Study of the FAK Inhibitor Defactinib 
(VS-6063) in Participants with Surgical Resectable Malignant Pleural Mesothelioma 




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INVESTIGATOR’S AGREEMENT  
 
I have read and understand the contents of this clinical protocol for Protocol VS-6063-203 
Version 7.0 and will adhere to the study requirements as presented, including all statements 
regarding confidentiality.  In addition, I will conduct the study in accordance with current 
International Conference on Harmonization (ICH) guidance, Good Clinical Practice (GCP) 
guidance, the Declaration of Helsinki 
 
Name of Clinical Investigator: ________________________________________ 
 
 
 
 
Investigator Signature 
 
Date 
 
 


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TABLE OF CONTENTS 
Abbreviations and Definitions of Terms ............................................................................................................ 7 
1. 
Introduction ................................................................................................................................................ 9 
2. 
OBJECTIVES ............................................................................................................................................. 9 
2.1 
Primary Objectives ........................................................................................................................................ 11 
2.2 
Secondary Objectives .................................................................................................................................... 11 
3. 
BACKGROUND ....................................................................................................................................... 11 
3.1 
Study Disease ................................................................................................................................................ 12 
3.2 
Rationale ....................................................................................................................................................... 19 
3.3 
Making the Case for personalized treatment by MPM Molecular diagnostic and predictive test................. 21 
4. 
PARTICIPANTS  SELECTION ............................................................................................................. 23 
4.1 
Inclusion Criteria .......................................................................................................................................... 23 
4.2 
Exclusion Criteria ......................................................................................................................................... 24 
4.3 
Prohibited Concomitant Treatment ............................................................................................................... 25 
4.4 
Inclusion of Women, Minorities and Other Underrepresented Populations ................................................. 26 
5. 
REGISTRATION PROCEDURES ......................................................................................................... 26 
5.1 
General Guidelines for DF/HCC and DF/PCC Institutions ......................................................................... 26 
6. 
TREATMENT PLAN ............................................................................................................................... 27 
6.1 
Pre-treatment Criteria ................................................................................................................................... 29 
6.2 
Administration of Defactinib ......................................................................................................................... 30 
6.3 
Surgery .......................................................................................................................................................... 31 
6.4 
General Concomitant Medication and Supportive Care Guidelines ............................................................. 32 
6.5 
Duration of Therapy ...................................................................................................................................... 32 
6.6 
Duration of Follow Up .................................................................................................................................. 32 
6.7 
Criteria for Removal from Study ................................................................................................................... 33 
7. 
TOXICITY MANAGEMENT AND DOSING DELAYS/DOSE MODIFICATIONS .......................... 33 
7.1 
Other Potential Risks .................................................................................................................................... 33 
7.2 
Toxicity Management .................................................................................................................................... 34 
7.3 
Supportive Care............................................................................................................................................. 34 
8. 
DRUG FORMULATION AND ADMINISTRATION ........................................................................... 34 
8.1 
Agent Defactinib (VS-6303) .......................................................................................................................... 34 
8.2 
Description .................................................................................................................................................... 35 


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8.3 
Form .............................................................................................................................................................. 35 
8.4 
Storage and Stability ..................................................................................................................................... 35 
8.5 
Compatibility ................................................................................................................................................. 35 
8.6 
Handling ........................................................................................................................................................ 35 
8.7 
Availability .................................................................................................................................................... 36 
8.8 
Administration ............................................................................................................................................... 36 
8.9 
Ordering ........................................................................................................................................................ 36 
8.10 
Accountability................................................................................................................................................ 36 
8.11 
Destruction and Return ................................................................................................................................. 37 
9. 
BIOMARKER STUDIES ......................................................................................................................... 37 
9.1 
Biomarker and Pharmacodynamic Sampling ................................................................................................ 37 
9.2 
Biomarker and Pharmacodynamic Endpoints ............................................................................................... 38 
10. 
STUDY CALENDAR ............................................................................................................................... 39 
11. 
MEASUREMENT OF EFFECT .............................................................................................................. 42 
11.1 
Antitumor Effect– Solid Tumors – Radiology and Biomarkers ..................................................................... 42 
11.2 
Definitions ..................................................................................................................................................... 42 
11.3 
Disease Parameters ....................................................................................................................................... 42 
11.4 
Methods for Evaluation of Measurable Disease ........................................................................................... 43 
11.5 
Response Criteria .......................................................................................................................................... 43 
12. 
ADVERSE EVENT REPORTING REQUIREMENTS ......................................................................... 44 
12.1 
Definitions ..................................................................................................................................................... 44 
12.2 
Procedures for AE and SAE Recording and Reporting ................................................................................. 46 
12.3 
Reporting Requirements ................................................................................................................................ 46 
12.4 
Serious Adverse Event Reporting .................................................................................................................. 47 
12.5   
Reporting to the Institutional Review Board (IRB) ....................................................................................... 48 
12.6 
Reporting to Hospital Risk Management....................................................................................................... 48 
12.7 
Monitoring of Adverse Events and Period of Observation ............................................................................ 48 
12.8  
Pregnancy ..................................................................................................................................................... 48 
13. 
DATA AND SAFETY MONITORING ................................................................................................... 49 
13.1 
Data Reporting .............................................................................................................................................. 49 
13.2 
Safety Meetings ............................................................................................................................................. 50 
13.3 
Monitoring ..................................................................................................................................................... 50 
14. 
REGULATORY CONSIDERATIONS ................................................................................................... 50 
14.1 
Protocol Review and Amendments ................................................................................................................ 50 
14.2 
Informed Consent .......................................................................................................................................... 51 


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14.3 
Ethics and Good Clinical Practice (GCP) .................................................................................................... 51 
14.4 
Study Documentation .................................................................................................................................... 52 
14.5 
Records Retention ......................................................................................................................................... 52 
15. 
STATISTICAL CONSIDERATIONS ..................................................................................................... 52 
15.1 
Study Design/Endpoints ................................................................................................................................ 52 
15.2 
Primary Objective ......................................................................................................................................... 52 
15.3 
Sample Size/Accrual Rate .............................................................................................................................. 53 
15.4 
Analysis of Secondary Endpoints .................................................................................................................. 53 
15.5 
Reporting and Exclusions .............................................................................................................................. 54 
16. 
PUBLICATION PLAN ............................................................................................................................... 54 
17. 
REFERENCES ......................................................................................................................................... 55 
18. 
APPENDICES .......................................................................................................................................... 61 
Appendix A: Performance Status Criteria ...................................................................................................... 61 
Appendix B:  Examples of Substrates OF CYP2C9 and CYP3A4 ................................................................. 62 
Appendix C:  Examples of strong Inhibitors and Inducers of CYP2C9 and CYP3A4 ................................. 63 
 
 


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ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
adverse event 
ALT 
alanine transaminase (SGPT) 
ANC 
Absolute neutrophil count 
AST 
aspartate transaminase (SGOT) 
ATP 
adenosine-5'-triphosphate 
AUC 
area under the curve 
BID 
twice daily 
BOR 
best overall response 
BP 
blood pressure 
BSC 
best supportive care 
CI 
confidence interval 
Cave 
average plasma concentration in steady state  
Ceff 
efficacious concentration 
Cmax 
peak plasma concentration 
CP 
conditional power 
CR 
complete response 
CRO 
contract research organization 
CRF 
CSC 
case report form 
cancer stem cell 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DCR 
disease control rate 
DOR 
duration of response 
DLT 
dose limiting toxicity 
DSMB 
Data and Safety Monitoring Committee 
EC50 
half maximal effective concentration 
ECG 
Electrocardiogram 
ECM 
extracellular matrix 
FAK 
focal adhesion kinase 
FDA 
Food and Drug Administration 
FIH 
first in human 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
HR 
hazard ratio 
IC50 
half maximal inhibitory concentration 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
ITT 
intent to treat 
IWRS 
interactive Web Response System  
Merlin 
moesin-ezrin-radixin-like protein 


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MPM 
malignant pleural mesothelioma 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
NF2 
neurofibromatosis type 2 gene 
NOAEL 
no observed adverse effect level 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PR 
partial response 
PK 
pharmacokinetic 
PFS 
progression-free survival 
Pyk2 
proline-rlch tyrosine kinase-2 
PP 
per protocol 
QoL 
quality of Life 
QTc 
corrected QT interval 
RBC 
red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
SD 
stable disease 
SOC 
system organ class 
SOP 
standard operating procedures 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
treatment emergent adverse event 
t1/2 
terminal half-life 
Tmax 
time of peak plasma concentration 
TTP 
time to progression 
ULN 
upper limit of normal 
WBC 
white blood cell 
 
 


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1. INTRODUCTION 
 
The reality is that Malignant Pleural Mesothelioma (MPM) treatment in the US is variable and 
based on regional preferences, varying expertise, physician choice and patient preference.  The 
Brigham and Women’s Hospital’s International Mesothelioma Program (IMP) has been one of 
the largest international centers for surgical treatment for MPM in the world.  Hundreds of 
patients come here every year to be considered for surgical therapy.  As a consequence, the IMP 
leadership has developed a clinical and research program focusing on improving care for MPM 
patients including collaborative clinical care, research infrastructure and all types of support 
including a house to provide accommodations to patients treated here.  The majority of patients 
who come to the BWH are eligible for surgical resection.  This patient population is largely 
chemotherapy naïve and has good functional status.  As part of the IMP, large funds have been 
invested in tumor collection and annotation as well as in refining staging and pre-treatment 
stratification.  As new biological agents with promise for response in MPM come on line, the 
IMP has been engaging to examine these drugs to better the lot of patients.  We hypothesize that 
the most rational manner to develop therapeutic strategies for patients with MPM is to take 
promising drugs and use them in short course in patients who come here for surgical evaluation.  
These patients generally have as part of their staging, pleural biopsies and multiple staging tests 
as part of standard approach and in parallel with consented tissue acquisition for research.   
 
The proposal herein is to offer these patients enrollment in brief phase II trials to evaluate 
promising drugs for 12-35 days as defined in specific cohorts, in biomarker driven studies, 
determine their response, define the predictive biomarker for response, and then after an 
adequate period to clear the drug and any potential side effects, offer them surgery for which 
they have come to the BWH in the first place.  This specific protocol is to study a promising drug 
which is a FAK inhibitor in this fashion.    
 
The drug proposed in this protocol, defactinib (VS-6063) was demonstrated to be a potent and 
selective ATP-competitive, reversible inhibitor of recombinant human Focal Adhesion Kinase 
(FAK) and proline-rich tyrosine kinase-2 (Pyk2) in biochemical and cell based assays.  This 
drug, defactinib, is an orally bioavailable, small-molecule FAK inhibitor with potential anti-
angiogenic and antineoplastic activities. The FAK pathway is a critical regulator of the survival 
of cancer stem cells, which are an underlying cause of cancer recurrence and metastasis [1].  
Therefore, defactinib can prevent the integrin-mediated activation of several downstream signal 
transduction pathways, including ERK, JNK/MAPK and PI3K/Akt (most of which have been 
implicated in mesothelioma), thus inhibiting tumor cell migration, proliferation and survival.  
 
2. OBJECTIVES 
 
Aim 1: 
The purpose of this study is to determine biomarker responses to the Focal Adhesion Kinase 
(FAK) inhibitor, defactinib (VS-6063, formerly PF-04554878) in Malignant Pleural 
Mesothelioma (MPM). This study is a biomarker driven study, and the primary endpoint in this 
Phase II trial is biological response to defactinib, including tumor and other surrogate tissue 
(Platelet Rich Plasma, PRP) phospho-FAK (pFAK) inhibition, change in cancer stem cells, 
tumor immune cells, and the tumor microenvironment.  Ultimately, the goal is to define the 


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biomarker best suited to predict the response to defactinib which is expected to result in 
therapeutic response. 
 
Aim 2:  
To quantify the toxicity of the investigational drug administered as neoadjuvant prior to 
conventional MPM multi modality therapy to chemotherapy naïve patients. As this trial is 
positioned to be offered for patients eligible and interested in surgical treatment for MPM, many 
may undergo surgery after induction therapy.  This surgery and subsequent treatment may 
consist of excisional surgery by Extrapleural Pneumonectomy (EPP) or Pleurectomy 
Decortication (P/DC) followed by intra operative intra thoracic/intra peritoneal heated 
chemotherapy and adjuvant treatment as necessary.  However, some patients may not undergo 
surgery and may opt for chemotherapy or other therapies.  The endpoint will be to determine 
how many patients at day 30-35 are still eligible to undergo surgery should they choose to. 
 
Aim 3: 
To procure samples to evaluate the pharmacokinetics of the investigational drug by measuring 
plasma concentrations of defactinib and potential metabolites. The established recommended 
daily dose of defactinib is 400 mg PO BID.  This drug has been dosed as high as 750 mg PO BID 
without reaching the MTD.   
 
Aim 4: 
To evaluate radiographic and metabolic response to the defactinib by comparing the pre-
treatment PET CT to a PET CT performed at the end of therapy.  We will measure tumor volume 
and FDG activities in the pre and post treatment studies.  The PET CT will also guide the post-
treatment biopsy by demonstrating the locations of tumor activity and bulk. 
 
Study Design 
 
This is an open label neoadjuvant study in subjects with malignant pleural mesothelioma who are 
eligible for extirpative surgery based on functional, pathologic and clinical parameters.  Patients 
eligible for this study can have either epithelial or non epithelial histology, negative mediastinal 
lymph nodes (by PET-CT or mediastinoscopy) and at least 100 cc tumor volume by chest PET-
CT.  They should not have contralateral or metastatic disease (defined as evidence of cancer 
outside the ipsilateral chest cavity) at staging as defined by PET-CT or biopsy.  The objectives of 
this Phase II clinical trial are to assess the ability of the Focal Adhesion Kinase (FAK) inhibitor, 
defactinib, to modulate key biological markers and mesothelioma cell populations, to define the 
pharmacodynamic in this population, to investigate tumor response by PET CT, to define the 
best predictive biomarker for response, to determine whether patients undergoing this therapy 
can remain candidates for surgical treatment and to describe any associated adverse reactions 
(toxicities) in this patient population.  
 
Defactinib will be administered at 400 mg twice daily for 12 (cohort 1), 35 (cohort 2), 21 (cohort 
3) +/- 2 days, or at 100 mg twice daily for 21 (cohort 4) +/- 2 days with up to 43 participants. 
Each participant will already have a pre-study drug biopsy as an entry criteria which will be 
accomplished during the routine work up of any mesothelioma patient at BWH/DFCI and then as 
part of the trial undergo a post treatment biopsy on Day 12 (cohort 1), Day 35 (cohort 2), Day 21 


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(cohort 3) or Day 21 (cohort 4) of treatment. After at least 10, 33, or 19 days of defactinib 
administration, the post treatment biopsy will be collected within 2-4 hours post the last dose of 
study drug. This will be obtained via core needle biopsy that is imaged-guided. Specifically, the 
patient will undergo a PET CT in Radiology or the AMIGO suite at BWH. The scan will be used 
to define areas consistent with tumor best suited for biopsy. The biopsy will be planned using 
guidance of the CT and/or Ultrasound at the same time and location and be undertaken by a team 
composed of a thoracic surgeon and radiologist. At least 4 cores will be obtained, to be analyzed 
by both the sponsor and Dr. Bueno’s lab. 
 
To assess the pharmacokinetics of defactinib in this patient population, plasma concentrations of 
the study drug will be determined over a 24 hour period beginning on Day 11 of the study. A 
single plasma sample will also be collected on Day 12 (+/- 2 days), within 30 minutes of the 
second biopsy (Cohort 1 patients only).  Additional samples will be collected on Day 35 and 42 
in cohort 2 and Day 21 and 28 in cohort 3 and cohort 4 subjects. Exposures of VS-6063 in the 
tumor biopsy may be examined. 
 
The definitive surgery will occur no earlier than 30 (cohort 1) or 7 (cohort 2, 3 and 4) days after 
the last dose of study drug to minimize any risk to the patient from potential surgery.  It is 
expected that the drug will completely clear the patient within 7 days of cessation of therapy 
based on the terminal t½ following a single dose averaged about 9 hours across all treatment 
groups in the FIH Phase I study. The safety of defactinib will be assessed continually until 30 
(cohort 1) or 7 (cohort 2, 3 and 4) days post last dose of study drug.  All treatment related AEs 
should be followed until resolution, stabilization, or for 30 days, whichever is least.  Any SAE 
occurring after the reporting period must be reported as soon as possible, but no later than 24 
hours, if a causal relationship to the investigational drug is suspected.  Death must always be 
reported when it occurs during the 30-day reporting period irrespective of intervening treatment. 
2.1 
Primary Objectives 
 
The primary objectives of this Phase II trial are to assess biomarker responses in patient derived 
tumor and other surrogate tissues, including but not limited to inhibition of phospho-FAK, 
alterations in markers of cell cycle and apoptosis, changes in cancer stem cells, tumor immune 
cells, and the tumor microenvironment. Specifically, we will assess percent pFAK inhibition in a 
tumor specimen as the primary objective.   Specimens will also be profiled genetically and 
immunologically to discover potential predictive biomarkers. 
2.2 
Secondary Objectives 
 
 
a.  To evaluate the safety of defactinib in subjects with malignant mesothelioma.  
b. To evaluate the pharmacokinetics of defactinib in plasma of subjects with malignant 
mesothelioma. 
c. To evaluate tumor response by PET/CT  
3. BACKGROUND 


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3.1 
Study Disease 
 
Malignant pleural mesothelioma (MPM) is a rare thoracic tumor that develops from transformed 
cells originating in the pleural mesothelium and is associated with asbestos dust and fibers 
exposure [1]. MPM progresses primarily by local extension to involve the ipsilateral lung and 
mediastinal structures causing death by such locoregional extension. Malignant pleural 
mesothelioma is often unresectable at diagnosis, is refractory to most conventional therapies 
including cytotoxic agents and is frequently complicated by pleural effusion [2].  Clinical 
behavior of the malignancy is affected by the continuous mesothelium surface of the pleural 
cavity that enable local metastasis via exfoliated cells, invasion to underlying tissue and other 
organs within the pleural cavity [3]. Prognostic scoring systems from our mesothelioma center at 
BWH, the EORTC and CALGB have shown that the most important predictors of poor 
prognosis for patients with MPM are: poor performance status; patient's age; tumor stage, male 
gender; low hemoglobin; high platelet count; high white blood cell count; high lactate 
dehydrogenase (LDH) and the histological subtype [4,5,6].  Our group has also validated these 
parameters and are in the process of submitting a manuscript proposing pre-operative staging. 
 
The management of the disease by single modality treatment did not achieve higher results than 
supportive care [7]. Complete responses to systemic treatment are rarely observed and the 
common responses are of short duration. Presently available chemotherapy regimens achieved a 
response rate of 30–40%, a median progression free of 6 months and an overall survival of 12 
months [8,9]. The epithelioid histology responds better to treatment and has a survival advantage 
over nonepithelioid sarcomatoid histology [10,11].  Radiation therapy alone is also ineffective. 
 
The current treatment paradigm for any solid tumors in the absence of metastatic disease is first 
to remove all macroscopic disease with surgical resection [12] and then to eradicate residual 
microscopic disease and prevent the development of micrometastatic recurrence with adjuvant 
local and systemic treatment with chemotherapy and radiation therapy. Successful application of 
this treatment strategy depends on both appropriate patient selection of those with favorable 
conditions for resection and on the efficacy of additional modalities used to control microscopic 
disease. Surgeons, oncologists and radiation oncologists at the BWH and DFCI pioneered the use 
of surgery for mesothelioma and developed new techniques to accomplish surgical extirpation.  
We also established the benchmark in terms of expected outcome as well as research protocols 
adding multimodality therapies to the treatment of this disease.  Extrapleural pneumonectomy is 
an aggressive treatment option which removes all tumor.  Pleurectomy and decortication (PD) is 
indicated for patients with earlier disease where the lung can be spared resection.  EPP based 
multimodality therapy for MPM in surgical candidates with resectable tumors has been 
associated with increase in median survival and with approximately 20% of selected number of 
patients experiencing long-term survival [5,13,14].  
 
Despite initial success for most patients, early recurrence and a short disease free interval are 
observed in over 50% of the patients with MPM [14]. The most common sites of recurrence are 
the contralateral hemithorax, abdomen, ipsilateral hemithorax, and distant regions. The median 
survival from time of recurrence to death is about 3 months [14].   However, there are patients 
who represent approximately 20% of the cohort who benefit long term survival after surgical 
therapy for MPM. 


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Due to the fact that the overall prognosis from MPM is usually dismal, many different 
approaches have been proposed and different centers treat patients in radically different manners.  
Certainly, a number of first line chemotherapy options exist.  In addition to surgery followed by 
chemotherapy and radiotherapy as practiced at our centers, other centers recommend 
neoadjuvant therapy with a variety of agents followed by restaging and surgery as well as the 
addition to surgery of other innovative techniques including immunotherapy, heated intra-pleural 
chemotherapy and photodynamic therapy.   
 
Furthermore, there is the understanding now that it is important to stratify patients upfront to 
protocol-driven care. We have led this strategy at BWH/DFCI by defining a pre-treatment 
evaluation of both the patient’s cardiorespiratory status as well as the oncologic status using 
lymph node staging, defining the subtype of the cancer, measuring serum markers and testing for 
a prognostic gene expression-based test developed here.  
 
To conclude the prognosis for MPM remains poor although there have been some modest 
improvements in survival from newer chemotherapies and multimodality treatments [11,13,14]. 
However, this improvement has occurred longer than 12 years ago and no other agents has 
shown improvement to-date. Surgery has shown improved survival in a selected subset of 
patients. However, additional therapy is required to extend survival. It must be clarified that 
Mesothelioma is almost universally a fatal illness for which we do not yet have adequate 
therapy. The mortality overall remains at 95-99%. Urgent new therapies are required and 
hope is focused on biologically driven compounds.  
 
The rationale for this study is based on the fact that tumor biology appears to be a major 
determinant of extended survival [15]. Therefore tailored treatment based on patient's individual 
tumor biology, as is currently studied in Breast Cancer [16,17], will most likely contribute to the 
existing treatment of Malignant Pleural Mesothelioma.  This protocol is to study a biological 
drug with a promising target in mesothelioma and is supported by pre-clinical studies.  
 
Study Agent 
 
Defactinib was demonstrated to be a potent and selective ATP-competitive, reversible 
inhibitor of recombinant human Focal Adhesion Kinase (FAK) and proline-rich tyrosine 
kinase-2 (Pyk2) in biochemical and cell based assays.  
 
The drug defactinib is an orally bioavailable, small-molecule FAK inhibitor with potential 
antiangiogenic and antineoplastic activities.  
 
FAK pathway is a critical regulator of the survival of cancer stem cells, which are an 
underlying cause of cancer recurrence and metastasis [1].  Therefore, defactinib can 
prevent the integrin-mediated activation of several downstream signal transduction 
pathways, including ERK, JNK/MAPK and PI3K/Akt (most of which have been implicated 
in mesothelioma), thus inhibiting tumor cell migration, proliferation and survival.  
 


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A comprehensive evaluation of selectivity against a large panel of other kinases in enzyme 
assays demonstrated that defactinib was highly selective for FAK and Pyk2 kinases 
strongly suggesting that its predominant pharmacologic activity is mediated by inhibition 
of FAK and Pyk2 kinases. Defactinib also demonstrated antitumor efficacy in three human 
tumor xenograft models in nude mice including glioma, colon, and pancreatic carcinoma 
models. In these studies, oral administration of defactinib resulted in significant growth 
inhibition or regression of established tumors at well-tolerated dose levels. In addition, 
studies investigating the dose- and time-dependent inhibition of FAK activity following 
oral administration of defactinib provided insight towards the relationship of inhibition of 
FAK to antitumor efficacy and the PK/PD relationship for this compound. The PK/PD 
relationship and subsequent target efficacious plasma concentration was determined by 
measuring defactinib in plasma samples isolated from the same individual mice in which 
target inhibition data was generated. Collectively, the combination of studies to assess the 
relationship between defactinib exposure in plasma, inhibition of FAK activity and tumor 
growth established several conclusions relevant to the evaluation of clinical efficacy 
[Presented at ASCO 2011 by S.F. Jones.  Phase I study of VS-6063, a second-generation 
focal adhesion kinase (FAK) inhibitor, in patients with advanced solid tumors. 2011 ASCO 
Annual Meeting   Abstract No: 3002].  Namely that the drug is relatively safe with the 
MTD not reached at 700 BID dosing and that biochemical effects are seen very rapidly. 
 
The main purpose of the trial proposed herein is to evaluate the activity of defactinib for 
future trials in MPM patients.    
 
Focal Adhesion Kinase (FAK)  
 
FAK protein is a member of the non-receptor protein tyrosine kinases (PTKs) subfamily 
that was first described in the early 90s [2]. FAK protein is encoded by the Protein 
Tyrosine Kinases PTK2 gene located on the long (q) arm of chromosome 8 [3, 4] and is 
expressed in sub-membranous structures called focal adhesions (FAs) involved in cellular 
adhesion and spreading processes. 
 
Obstructing FAK may prevent the integrin-mediated activation of several downstream 
signal transduction pathways, including ERK, JNK/MAPK and PI3K/Akt, thus inhibiting 
tumor cell migration, proliferation and survival. The tyrosine kinase FAK is a signal 
transducer for integrins that is up-regulated in many tumor cell types and is involved in 
tumor cell invasion, migration and proliferation. [1] 
 
The FAK is activated by several stimuli including integrins, cellular substances, receptors, 
and various pathological conditions. Increased FAK expression and activity has been 
observed in a variety of solid human tumors and is frequently correlates with metastatic 
disease and poor prognosis [11]. In Breast Cancer, FAK is important for progression and 
invasion and is necessary for the dynamic turnover of focal adhesions [12]. It has been 
shown that when FAK was blocked, breast cancer cells became less metastatic due to 
decreased mobility [11,12].    
 


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Src family kinases (SFK) 
 
A variety of PTK families have been identified in mammalian cells. The Src family kinases 
(SFK) are non-receptor (cytoplasmic) tyrosine kinases comprising nine known kinases 
members: blk, c-fgr, fyn, hck, lck, lyn, c-src, c-yes and yrk [5], of which three, c-src, fyn 
and c-yes are widely expressed. Members of this kinase family have several common 
features: 1) unique N-terminal domains, 2) attachment to cellular membranes through a 
myristylated N-terminus, and 3) homologous SH2, SH3, and catalytic domains, 
phosphotyrosines and proline-rich regions, by which, postactivation, interacts with various 
proteins [6,7,8]. The nonreceptor PTK c-Src is probably the most important enzyme 
interacting with FAK. It is characterized by the ability to bind and interact with 
phosphortyrosine residues of other molecules, such as c-Met and FAK, through its SH2 
domain [6,7]. The FAK/Src complex regulates various basic cellular functions and the 
behavior of terminally differentiated, post-mitotic cell types, such as cellular proliferation 
and growth, protection from apoptosis, adhesion, spreading, invasion, and migration. 
[9,10]. The FAK/Src complex binds and phosphorylates many downstream molecules such 
as p130Cas, Grb2, and PI3K, transducing signals down for many different pathways [9]. 
FAK/Src complex is activated in many tumor cells and generates signals leading to tumor 
growth and metastasis [10]. 
 
Epithelial-mesenchyme transition (EMT) in Human Cancer 
 
Epithelial-mesenchyme transition (EMT) is an epithelial plasticity characterized by long-
lasting morphological and molecular changes in epithelial cells as a result of differentiation 
towards a mesenchymal cell type [13].  
 
EMT was first recognized as a feature of embryogenesis, which is vital for morphogenesis 
during embryonic development as is the case of mesoderm formation, neural tube 
formation and the myocardium induce endothelial transformation into prevalvular 
mesenchyme [14]. Several oncogenic pathways like peptide growth factors; Src, Ras, Ets, 
Integrin, Wnt/beta-catenin and Notch may induce EMT. In addition, initiation of metastasis 
involves invasion, which has many phenotypic similarities to EMT including a loss of cell-
cell adhesion mediated by E-cadherin repression and an increase in cell mobility. It has 
been shown that EMT can generate cells with properties of stem cells. Those stem-like 
cells express markers associated with EMT and inducing phenotypes associated with 
cancer stem cells [15]. The epithelial-mesenchymal transition that generates cells with 
properties of stem cells was reported in varies human organs: uterus, breast, lung, gastro-
intestinal tract, pleura and ovary [16-21].  
 
Therefore, EMT may play a role in transforming normal cells to malignant ones and in 
metastasis. The morphological patterns of malignant mesothelioma may be the outcome of 
different steps in an epithelial–mesenchymal transition process resulting in mesothelioma 
histological classification of epithelioid (mostly composed of epithelial-shaped cells), 
sarcomatoid (mostly composed of spindle-shaped cells), or biphasic (composed of both 
types of cell) [22]. 
 


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EMT and Drug Resistance 
 
In advanced disease or diseases like pancreatic carcinoma where often curative surgery is 
not feasible, chemotherapy could be theoretically an attractive option in managing the 
disease [23]. However, a major problem preventing chemotherapy success is drug 
resistance, which is often acquired during treatment [24].  Recent studies have shown that 
EMT is associated with drug resistance and cancer cell metastasis [25]. Three observations 
support this notion: (i) Cells which have undergone EMT tend to be more resistant to 
drugs; (ii) When cells are cultured in the presence of a certain drug, specific drug-resistant 
cells will have a selective advantage; these cells will often have undergone EMT; (iii) 
Targeting EMT pathways not only leads to a decrease in invasive potential, but also to an 
increase in drug sensitivity [23]. When pancreatic cancer cells were cultured in serially 
increasing concentrations of gemcitabine, they gained up to 50-fold increase in drug 
resistance and they also showed hallmarks of EMT [26]. Gene expression profiling of 
pancreatic cancer cell lines revealed that cells resistant or sensitive to three 
chemotherapeutic agents (gemcitabine, 5-fluorouracil, and cisplatin) formed two distinct 
groups, with features of EMT in the drug-resistant group [27]. Our group reported 
chemoresistance in Mesothelioma specimens, both in vitro [28] and in vivo [29]. A 
significant proportion of mesothelioma tumors exhibited extreme/intermediate resistance to 
cisplatin, gemcitabine, or vinorelbine. Chemoresistance to cisplatin (27%), gemcitabine 
(31%), or vinorelbine (59%) and 11% had extreme/intermediate resistance to all 3 drugs 
[28].  
 
EMT therefore has impact on both the neoplastic progression and patient survival, as well 
as the on resistance of cancers to therapeutics such as taxol, vincristine, oxaliplatin, EGF-R 
targeted therapy and radiotherapy. New therapeutic combinations using genotoxic agents 
and/or EMT signaling inhibitors expected to circumvent the chemotherapeutic resistance of 
cancers characterized by transient or sustained EMT signatures [30].  
 
FAK and Mesothelioma  
 
There is accumulating evidence supporting the role of FAK up-regulation on the neoplastic 
transformation of different types of cells [31] and increased FAK expression/activity is 
frequently correlated with highly malignant or metastatic tumors having a poor prognosis 
like MPM [31]. 
 
a. Merlin is a tumor suppressor frequently inactivated in malignant mesothelioma (at 
least 40% of cases) (MM)(neurofibromatosis type 2 NF2 gene product). Merlin 
inactivation is a critical step in mesothelioma pathogenesis and is related with up-
regulation of FAK activity [32].   Merlin negative breast cancer cells are most 
sensitive to FAK Inhibition and Merlin negative mesothelioma cell lines are 
especially sensitive to FAK Inhibition. (AK  Inhibitor VS-4718 Preferentially 
Attenuates Growth of Malignant Mesotheliomas with  NF2 Mutation: Role of Cancer 
Stem Cells. Shapiro IM, Kolev VN et al, Poster  presented at IMIG 2012, Boston: 
 http://www.verastem.com/attachments/VSTM_iMig_poster_2012.pdf) 
 


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b. Mesothelin is a glycoprotein expressed on normal mesothelial cells and is  over-
expressed in several histologic types of tumors including pancreatic adenocarcinomas 
and MPM. Silencing Mesothelin induces a significant decrease in  activation 
(phosphorylation) of ERK1 and phospho-AKT and the expression of β- catenin, a 
known EMT marker, was reduced [33]. 
 
c. Membrane chondroitin sulphate proteoglycan 4 (CSPG4), has been successfully 
 targeted in melanoma and breast cancer, and was found highly expressed in 
Malignant Mesothelioma, but not in normal mesothelium [34]. CSPG4 was expressed 
on 75% of  MM cell lines and in 61% of MM biopsies, with minimal expression in 
surrounding  healthy cells. Mesothelioma cell adhesion is mediated by CSPG4 and 
inhibited by  CSPG4 mAb-based immunotherapy resulting in decreased 
phosphorylation of focal adhesion kinase (FAK), AKT and reducing apoptosis [34]. 
 
Pre-clinical work by Verastem and by our BWH research group 
 
 
A significant number of experiments at many levels has been recently completed first  at 
Verastem and then at BWH in collaboration with Verastem. 
  
There are many preclinical data supporting this trial.  NF2 mutations which affect the 
Merlin protein levels have been demonstrated previously in mesothelioma.  Furthermore, 
we recently conducted a deep sequencing study of 100 mesothelioma tumors (unpublished 
and confidential).  We found that at least 40% of the cases had NF2 mutations which 
included chromosomal loss, reduced copy number, point mutations and loss by other novel 
mechanisms.  The other two major recurrent mutations were in Bap1 and P53 with minimal 
overlap.   
 
We also performed extensive analysis of hundreds of mesotheliomas linked to clinical 
outcomes for chromosomal deletions using FFPE specimens and tissue microarrays, NF2 
deletions, Merlin levels and related proteins.  We found that 54% of the tumors had 
chromosome 22 loss (where NF2 is located), 1% had NF2 deletions, and 50% had low 
Merlin levels.  The overall merlin levels were even lower in non-epithelial mesothelioma 
tumors which have worse prognosis in general and truly have no reliable therapy.  
 
The FAK inhibitor drug defactinib was developed to treat triple negative breast cancer 
based on stem cell sensitivities.  When explored with cell lines of all tumors it was shown 
to be particularly effective with mesothelioma and ovarian cell lines which are related 
malignancies.  The figures below show in red the sensitivities of mesothelioma cell lines 
with low Merlin level and the decreased sensitivities to the drug with high Merlin levels.  
Merlin is known by many other studies to be an important interrelated pathway in 
mesothelioma so this effect makes biological sense.  The protein levels were measured by a 
Western Blot. 
 
 
 
 


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We also created CSC in mesothelioma using fresh tumors from surgery and showed good 
response to the study drug as seen in the below figure. 
 
 
 
 
 
The preclinical work described above suggests that this drug defactinib and other FAK inhibitors 
have good response in cases with low expression of Merlin.  However, the cutoff is unknown and 
not every mesothelioma with low Merlin has a good response and vice versa, necessitating a 
broad study of mesothelioma patients. 
 
 
0
0.5
1
1.5
2
2.5
3
Control
VS-4718
VS-5584
VS-6063


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3.2 
Rationale 
 
3.2.1 Defactinib in solid tumors 
 
Defactinib was demonstrated to be a potent and selective ATP-competitive, reversible 
inhibitor of recombinant human FAK and Pyk2 kinase in biochemical and cell based 
assays. A comprehensive evaluation of selectivity against a large panel of other kinases in 
enzyme assays demonstrated that defactinib was highly selective for FAK and Pyk2 
kinases strongly suggesting that its predominant pharmacologic activity is mediated by 
inhibition of FAK and Pyk2 kinases. 
 
3.2.2 Clinical Summary of defactinib, second generation FAK/Pyk2 inhibitor 
 
Phase I safety, pharmacokinetics, and pharmacodynamics trial of the focal adhesion 
kinase (FAK) inhibitor defactinib was conducted at 2 sites including DFCI, Boston 
(protocol 08-383). This phase 1 dose escalation study of defactinib given as continuous 
oral dosing in 21-day cycles in patients with solid tumors had several endpoints include 
safety, pharmacokinetics (PK), and response by RECIST. The enrollment included 
patients with advanced non-hematologic malignancies, including patients with 
malignancies appropriate for serial biopsy. Screening consisted of medical history, 
physical examination ECOG performance status, blood draws, a pregnancy test for 
female patients of childbearing potential tumor imaging. Treatment consisted of 
defactinib pills continued until progression of disease, unacceptable toxicity, or patient 
request.  
 
In this study 46 patients received doses ranging from 12.5 mg to 750 mg BID on a fasted 
schedule. The most frequently reported treatment-emergent adverse events were nausea 
(19/46 [41.3%] subjects) followed by fatigue (18/46 [39.1%] subjects), vomiting (15/46 
[32.6%] subjects) and unconjugated hyperbilirubinemia (15/46 [32.6%] subjects). 
Adverse events were generally Grade 1/2 in severity. A total of 5 subjects were reported 
with DLTs, 1 subject had a DLT of headache (in the 200 mg BID fasting cohort); 1 
subject had a DLT of fatigue (in the 425 mg BID fed cohort) and 3 subjects had a DLT of 
hyperbilirubinemia (1 in the 300 mg BID fasting cohort, 1 in the 425 mg BID fasting 
cohort and 1 in the 425 mg fed cohort). In all cases of hyperbilirubinemia, AST and ALT 
were within normal limits. No treatment related serious adverse events were reported.  
 
Overall, 16 subjects had 17 cases of abnormal blood bilirubin. In all cases, AST and ALT 
were within normal limits. Reports of hyperbilirubinemia were asymptomatic and 
reversible (on or off drug) with no evidence of other liver function abnormalities or 
hemolysis. 
 
A total of 9 (19.6%) subjects had a maximum increase from baseline ≥30 mmHg in 
supine systolic blood pressure and 9 (19.6%) subjects had a maximum increase from 
baseline ≥30 mmHg in standing systolic blood pressure. A total of 8 (17.4%) subjects had 
maximum increase from baseline ≥20 mmHg in supine diastolic blood pressure and 5 
(10.9%) subjects had maximum increase from baseline ≥20 mmHg in standing diastolic 


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blood pressure. 
 
No subjects experienced an increase in QTc interval from baseline ≥60 msec. 
 
PK analysis supports the BID-dosing regimen and shows that doses above 100 mg BID 
lead to exposures above the minimal efficacious concentration predicted preclinically. 
Increasing the dose beyond 425 mg BID did not increase drug exposure. Following single 
oral doses of defactinib under fasted conditions (at doses ranging from 12.5 mg to 
750 mg), defactinib was rapidly absorbed and maximum serum defactinib concentrations 
were generally achieved 1 to 2 hours post dose.  Mean terminal elimination half-life was 
approximately 9 hours across the dose groups. Hepatic metabolism was predicted to be 
the major clearance pathway for VS 6063 in humans. See Section 4.3 for possible drug-
drug interactions with substrates for CYP3A4 and CYP2C9. 
 
Stable disease was achieved in 16 of 37 subjects (43%) treated at doses ≥100 mg BID. 
Stable disease was not achieved at doses <100 mg BID (N=9). Of note, eight subjects 
enrolled in this study had ovarian cancer which is biologically similar to mesothelioma. 
Of these subjects, four subjects achieved stable disease (three for ≥6 months) and the 
duration of stable disease with VS-6063 was equal to or exceeded that reported with prior 
therapy. 
 
Phase II, randomized, double blind, placebo controlled study in subjects with malignant 
pleural mesothelioma (protocol VS-6063-202) was conducted at ~75 sites across 16 
countries and enrolled 344 subjects. Prior to entry and randomization to the study, tumor 
moesin-ezrin-radixin-like protein (Merlin) status for each subject was determined by 
immunohistochemistry performed at a central laboratory. Subjects were randomized in a 
1:1 ratio to receive oral VS-6063 400 mg twice daily (BID) or matched placebo.  
Randomization was stratified by tumor Merlin status (high versus low). The study 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 
VS-6063 was generally well tolerated, but that there was not a sufficient level of efficacy 
in this patient setting (maintenance setting in malignant pleural mesothelioma subjects 
with stable disease after >/= 4 cycles of pemetrexed/platinum chemotherapy) to warrant 
continuation of the study. 
Study VS-6063-103 compared a modified prototype formulation (new formulation) with 
the current clinical formulation (reference) of defactinib and evaluated the effect of food 
(high fat) on both formulations. The study was conducted in 24 healthy volunteer male 
subjects who received a single dose of 200 mg reference formulation of defactinib and 
single dose of 100 mg new formulation defactinib. There was a statistically significant 
food effect for the reference formulation of defactinib. Exposure increased by 
approximately 2 to 3-fold following dosing of defactinib reference formulation tablet in 
the fed state compared to the fasted state. The geometric mean ratio (GMR) and 90% CIs 
for AUC(0-t), AUC(0-inf) and Cmax of 273.36 (215.19%, 347.26%), 457.73 (275.75%, 
759.79%), and 192.52 (146.67%, 252.71%), respectively. The time taken to reach 
maximum plasma concentrations of defactinib was 2 to 4 times longer in the fed state 


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than in the fasted state, indicating a food effect on the rate of absorption. An approximate 
4-fold increase in exposure was observed following dosing of defactinib new formulation 
tablet in the fasted state in comparison to the reference formulation tablet in the fasted 
state. The GMR and 90% CIs for AUC(0-t), AUC(0-inf) and Cmax of 433.05 (366.77%, 
511.32%), 617.39 (387.20%, 984.42%) and 421.33 (348.42, 509.51), respectively. In 
conclusion, the 100 mg new formulation gave exposure potentially similar to 400 mg 
reference formulation when dosed to healthy volunteers as a single dose in fasted state. 
VS-6063 was well tolerated when administered in both fasted and fed states as a 200 mg 
reference formulation tablet and as a 100 mg new formulation tablet. There were no 
deaths, serious adverse events (SAEs) or severe AEs reported during the study, and no 
subject was withdrawn as a result of an AE. 
 
Based on both preclinical and clinical data the recommended Phase 2 dose schedule is 
400 mg BID (current clinical formulation).  Given the specific timeline of the protocol 
and the need for a week-day only availability of the PET/CT and biopsy, we will only 
start patient treatments on Monday, Tuesday, or Wednesday.  Based on the results of the 
VS-6063-103 study described above, the new 100 mg defactinib formulation will be 
evaluated in Cohort 4 of this study. 
3.3 
Making the Case for personalized treatment by MPM Molecular diagnostic and 
predictive test 
 
3.3.1 Patient and Tumor Variation 
 
Given the wide range of survival among MPM patients with similar tumors and treatment 
and the wide range of chemoresistance, there is a keen need for directing drugs to 
molecular pathways that characterize the disease in subsets of patients will improve 
treatment efficacy [3,22]. 
 
Though most of the MPM patients have poor survival, a subset of patients who 
underwent multimodality therapy with an aggressive surgical approach yield disease-free 
for over 3 years [5,6].  Among 636 patients who underwent extrapleural pneumonectomy 
at Brigham and Women’s Hospital, 117 (18%) survived at least 3 years following 
surgery. The median survival of the 117 patients who survived 3-years was 59 months.  
 
On the other hand, the prevalence of in vitro chemotherapeutic drug resistance in MPM is 
substantial. In a cohort of 203 MPM specimens resected at out center [4], a significant 
proportion of tumors had drug resistance to cisplatin, gemcitabine, or vinorelbine or even 
extreme resistance to all 3 drugs as measured in primary cell cultures. No significant 
differences in chemoresistance were found in tumors of patients who had received 
neoadjuvant chemotherapy compared with those who had not [4] and these findings 
support the need for new agents and this trial plan. 
 
As far as clinical trials for drugs, CALGB has conducted over 18 multi-center drug trials 
for mesothelioma without a single positive trial.  In fact, the only positive drug trial is 
from over 10 years ago showing a 2 months benefit in survival (10 to 12 months) for the 


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combination of Alimta and Cisplatin.  This is still the standard of care.  There is an urgent 
need for new drugs, particularly biological drugs for this cancer and we propose that our 
population is the best for it. 
 
This study is proposed with a promising drug which is biologically designed based on 
mutations that are present in over 50% of patients with mesothelioma.  We propose a 
short course to look at response and have available tissue before and after to hone in and 
define the best patient population.  This is somewhat similar to I SPY 2 in breast cancer 
and is a new paradigm for clinical trial.  We believe that in this very lethal disease it is 
justifiable.  There is always potential harm to patients in any clinical trial, but we believe 
that a short course will demonstrate those who may benefit and they will have access to 
the drug should and when they recur.   
 
As to the risk of a biopsy, we can address that risk because we have open an accruing 
study to do fine needles and core biopsy for mesothelioma patients for diagnosis and 
prognosis (04-349) for which we performed needle biopsies under image guidance on 
approximately 133 patients to date with no complications.  The benefit of the biopsy is 
that it will rapidly inform us of the response and provide an opportunity to develop 
integral biomarkers for this drug.  
 
3.3.2 MPM basic and Translational Research at BWH/DFCI 
 
Our group has pioneered genomic and predictive studies in MPM using our resources of 
the tumor bank.  We have developed diagnostic and prognostic tests based on gene 
expression analysis and have established expertise in developing biomarkers at the RNA 
and DNA levels.  In addition, we have described the first transcriptome and genome 
sequencing projects in MPM.   
 
We have also looked at the NF2 gene in MPM and find that there are some nucleotide 
altering mutations or NF2 loss in nearly 60% of the cases.  We have recently discovered 
evidence for novel mechanisms of NF2 inhibition is a subset of MPM which can be 
possibly utilized to alter NF2 wt tumors into NF2 negative tumors (confidential 
preliminary results).   Therefore, establishing which types of mutations may be associated 
with response in MPM becomes important. 
 
Recent pathway analysis done in our lab showed that co-regulation networks related to 
the cross talk between MPM and its micro-environment, in particular involving the 
adhesion molecules, integrins, and cytokines, as well as progression related to genes 
related to EMT might have an important role in MPM (De Rienzo et al. Clin Cancer Res 
In Press).  This is consistent with the expected role of the study drug.  Our experience is 
presented to demonstrate our capabilities to study and develop biomarkers for this drug. 
 
3.3.3 Tailoring drugs to MPM molecular pathways 
 
By using microarray platform and sequence analysis for the specimens before and after 
the neoadjuvant treatment of defactinib and comparing them to the outcome we will be 


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able to better characterize the role played by these genes in MPM. We will also perform 
DNA sequencing on these specimens to relate specific NF2 mutations and look for other 
mutations in the DNA and RNA of pre-operative specimens for additional clues to novel 
biomarkers associated with response.  Directing drugs to molecular pathways that 
characterize the disease in subsets of patients will most definitely improve treatment 
efficacy. This clinical trial will follow-up patients with newly diagnosed locally advanced 
MPM to test the effect of this investigational drug. The trial will use the information from 
each participant who completes the study treatment to help decide treatment for future 
patients.  
 
3.3.4 Current clinical experience with defactinib 
 
The Sponsor (Verastem) is currently conducting multiple clinical trials with defactinib.  
Patients participating in this study who are perceived to have received clinical benefit 
from defactinib administration will be eligible to participate in ongoing studies providing 
other entry criteria are met. 
 
4. PARTICIPANTS  SELECTION 
4.1 
Inclusion Criteria 
 
Participants must meet the following criteria on screening examination to be eligible to 
participate in the study: 
 
4.1.1 Participant must have histologically confirmed malignant pleural mesothelioma at 
BWH that is not metastatic or unresectable.   
 
4.1.2 Participants should be evaluated by a surgeon and a medical oncologist. 
 
4.1.3 Participants are eligible to undergo excisional surgery such as extrapleural 
pneumonectomy (EPP) or pleurectomy/decortication (P/DC) or any other 
mesothelioma surgery.  
 
4.1.4 Localized disease. The malignancy is confined to one affected hemithorax.   
Mediastinal N2 lymph nodes via cervical mediastinoscopy or endobronchial 
ultrasound (EBUS) are allowed.  
 
4.1.5 Completed preoperative evaluation including: chest MRI, pulmonary function tests, 
echocardiogram (ejection fraction >30% for P/DC), and PET-CT within 45 days 
prior to registration.  
 
4.1.6  Grossly normal pulmonary, cardiac function, renal, hepatic, hematologic and 
performance functions:    
 


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a. ECOG 0-1 or Karnofsky >80%  
 
b. Normal contralateral pulmonary function as evidenced by a chest radiograph that 
fails to show acute infiltrates and a minimum postoperative predicted FEV1 of 0.8L 
or % predicted FEV-1 of greater than 35%. 
 
c. Renal and hepatic function (serum Creatinine level less than upper limit of 
normal, SGOT (AST) of < 80 IU/L and total bilirubin of < 1.9 mg/dL) within 7 
days of registration. 
 
d. Hematology: Pre-operative WBC of  > 4 K/uL, hemoglobin > 8 mg/dl and 
platelet count of > 80 K/mm3 within 7 days of registration. 
 
4.1.7 Male or non-pregnant female (based on pregnancy test within 2 weeks of initial 
drug administration for premenopausal women).  
 
4.1.8 Age  ≥ 18 years of age. 
 
4.1.9 This protocol requires patient’s tissue to be collected and stored at BWH tumor 
bank prior to enrollment. If patient was diagnosed outside BWH and we do not 
have his/her tissue, a pleural biopsy for frozen tissue collection is required.  
Currently all patients with mesothelioma are offered the opportunity to enroll in 98-
063 that allows consented storage of discarded tissue in the BWH tumor bank 
(enclosed). 
4.2 
Exclusion Criteria 
 
Participants who exhibit any of the following conditions at screening will not be eligible 
for admission into the study: 
 
4.2.1 Participants who have had chemotherapy or radiotherapy any time prior to entering 
the study or at any prior time for mesothelioma. Patients receiving chemotherapy 
type drugs for benign conditions can participate in this trial (e.g. methotraxate for 
arthritis).  
4.2.2 History of upper gastrointestinal bleeding, ulceration, or perforation within 12 
months prior to the first dose of study drug. 
4.2.3 Known history of Gilbert’s Syndrome or any current hyperbilirubinemia of any 
cause. 
4.2.4 Known history of stroke or cerebrovascular accident within 6 months prior to the 
first dose of study drug. 
4.2.5 Subjects with known infection with human immunodeficiency virus (HIV) or 
Acquired Immune Deficiency Syndrome (AIDS) (testing not required). 


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4.2.6 Subjects with confirmed Hepatitis A, B or C (testing not required). 
4.2.7 Subjects with other cancers who have not been continuously disease-free for at least 
3 years. Exceptions: subjects with prior history of in situ cancer that has been cured 
(e.g. cervical) or adequately treated basal or squamous cell skin cancer are eligible. 
Men under observation for local prostate cancer (defined as T1a-c, NO, MO 
Gleason grade ≤6, PSA <10 or T2a, NO, MO Gleason grade ≤6, PSA <10) are also 
eligible if they have had stable disease for at least 1 year. 
4.2.8 Use of an investigational drug within 28 days or 5 half-lives (whichever is shorter) 
prior to the first dose of study drug.  A minimum of 10 days between termination of 
the investigational drug and administration of the study treatment is required. In 
addition, any drug-related toxicity except alopecia should have recovered to grade 1 
or less. 
4.2.9 Pregnant or breastfeeding. The effects of defactinib on the developing human fetus 
at the recommended therapeutic dose are unknown. For this reason, women of 
child-bearing potential must agree to use adequate contraception (hormonal or 
barrier method of birth control, or abstinence) prior to study entry and for the 
duration of study participation. Should a woman become pregnant or suspect she is 
pregnant while participating in this study, she should inform her treating physician 
immediately.  Men on this study must also agree to use adequate contraception 
(barrier method of birth control) when sexually involved with women of child-
bearing potential. 
4.2.10 Uncontrolled or severe cardiovascular disease, including myocardial infarct or 
unstable angina within 6 months prior to study treatment, New York Heart 
Association (NYHA) Class II or greater congestive heart failure, serious 
arrhythmias requiring medication for treatment, clinically significant pericardial 
disease, or cardiac amyloidosis 
4.2.11 Known history of malignant hypertension 
4.2.12 Uncontrolled intercurrent illness including symptomatic congestive heart failure, 
cardiac arrhythmia, or psychiatric illness/social situations which in the opinion of 
the study investigators would be associated with undue risk of participation in the 
study.  
4.3 
Prohibited Concomitant Treatment 
Patients who are receiving anticoagulants (Coumadin, Plavix etc.) who cannot safely come off 
these drugs for at least a week prior to biopsy. 
 
In vitro studies have shown that defactinib 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.  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 


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defactinib may increase their exposure.  A list of examples of substrates for CYP2C9 and 
CYP3A4 can be found in Appendix B. Subjects taking warfarin for therapeutic anticoagulation 
should be monitored closely because treatment with VS-6063 may increase its exposure. If 
subjects can safely stop taking warfarin, they should do so. If subjects require anticoagulation an 
alternative to warfarin should be considered. Subjects who require anticoagulation but cannot 
discontinue warfarin should be monitored closely and have their INRs checked more frequently 
whilst on VS-6063. For subjects requiring the start of anti-coagulation therapy during the course 
of any VS-6063 trial, alternatives to warfarin are recommended. 
 
In addition, as 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. A list of examples of inducers of CYP2C9 and CYP3A4 can be 
found in Appendix C. 
4.4 
Inclusion of Women, Minorities and Other Underrepresented Populations 
 
4.4.1 This study is recruiting minorities, women and underrepresented population.  
Translational/Language services will be used as needed. 
 
4.4.2 The vast majority of mesothelioma patients are over 18 years of age and the median  
age at presentation is 70 making the exclusion of children not relevant.  
5. REGISTRATION PROCEDURES 
5.1 
General Guidelines for DF/HCC and DF/PCC Institutions 
 
Patients seen at DFCI or BWH Surgery clinic and have the diagnosis of MPM will be 
approached by the treating physician to participate in this study.  They will be 
evaluated by a study surgeon to determine if they meet eligibility for surgery and by a 
study medical oncologist to determine if they are deemed eligible to receive drug 
therapy. 
 
Institutions will register eligible participants with the DF/HCC Clinical Trials 
Management System (CTMS) OnCore. Registration must occur prior to the initiation of 
therapy. Any participant not registered to the protocol before treatment begins will be 
considered ineligible and registration will be denied.  
 
A member of the study team will confirm eligibility criteria and complete the 
protocol-specific eligibility checklist. 
 
Following registration, participants may begin protocol treatment. Issues that would 
cause treatment delays should be discussed with the Principal Investigator. If a 
participant does not receive protocol therapy following registration, the subject must be 
taken off-study in the CTMS (OnCore) with an appropriate date and reason entered. 
 
Applicable DF/HCC policy (REGIST-101) must be followed. 
 


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6. TREATMENT PLAN 
 
Oral Treatment will be administered on an outpatient basis. Potential risks as well as dose 
modifications for agent defactinib are described in Section 7 (Dosing Delays/Dose 
Modification). No investigational or commercial agents or therapies other than those 
described below may be administered with the intent to treat the participant’s malignancy. 
 
We will register and enroll participants with confirmed diagnosis of Malignant Pleural 
Mesothelioma at Brigham and Women’s Hospital and DFCI. Please see the detailed eligibility 
list in Section 4.1. All participants will have specimens and blood work, including a 
biomarker profile (molecular analysis including the tumor suppressor gene NF2) procured at 
BWH. Participants presenting from outside facilities without available specimens and 
biomarkers profile will undergo a pretreatment biopsy and blood analysis.  
 
Defactinib will be administered at 400 mg twice daily for 12 +/- 2 days through the Day 12 
morning dose in cohort 1, for 35 +/- 2 days through the Day 35 morning dose in cohort 2, for 
21 +/- 2 days through the Day 21 morning dose in cohort 3 and at 100 mg (new formulation) 
twice daily for 21 +/- 2 days through the Day 21 morning dose in cohort 4 for a total of ~43 
participants. Each participant will undergo both a pre and post treatment biopsy. The 
pretreatment biopsy will be collected prior to  the first dose of defactinib and the post 
treatment biopsy will be collected within 2-4 hours post the last dose of study drug on Day 12 
(+/- 2 days) in cohort 1, Day 35 (+/- 2 days) in cohort 2 and  Day 21 (+/- 2 days) in cohort 3 
and 4. Neoadjuvant treatment will be monitored with blood analysis at baseline, Day 12 (+/- 2 
days), Day 35 (+/- 2 days) in cohort 2, Day 21 (+/- 2 days) in cohort 3 and 4, and the end of 
study visit (4 weeks post-treatment in cohort 1 or 1 week post-treatment in cohort 2, 3 and 4). 
For subjects with ongoing laboratory adverse events related to defactinib, weekly laboratory 
assessments are required through resolution (including: CBC, CMP, and PT/INR). 
 
The follow up and biopsies will be performed at BWH site using PET/CT guidance either at 
AMIGO or another radiology site. 
 
On Day 11 (+/- 2 days) of the study, serial plasma samples will be collected (via IV catheter if 
possible) for defactinib pharmacokinetic analysis and to evaluate the presence of its potential 
metabolites. Additional samples will be collected on Day 35 and Day 42 in cohort 2 and on 
Day 21 and 28 in cohort 3 and 4 subjects.  Note: Initiation of PK sampling must occur the 
preceding Day 12 (cohort 1), Day 35 (cohort 2), or Day 21 (cohort 3 and 4) biopsy collection. 
Blood samples should be collected according to the time points listed below by the BWH 
Clinical Trials Center staff: 
Table 1.  Pharmacokinetic Sampling Time points 
Sample 
Study 
Day 
PK Sampling Time Points  
 
1 
11 
Pre-dose (within 30 minutes of dosing with defactinib) 
2 
11 
15 min (± 5 min) after dosing with defactinib  
3 
11 
30 min (± 5 min) after dosing with defactinib 


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Sample 
Study 
Day 
PK Sampling Time Points  
 
4 
11 
1 hour (± 10 min) after dosing with defactinib 
5 
11 
2 hours (± 10 min) after dosing with defactinib 
6 
11 
4 hours (± 10 min) after dosing with defactinib 
7 
11 
8 hours (± 1 hour) after dosing with defactinib 
8 
12 
24 hours (± 2 hours) after dosing with defactinib prior to any Day 12    
defactinib administration 
9 
12 
2-4 hours (± 10 min) after dosing with defactinib within 30 min (± 10 
min) of biopsy (cohort 1 only) 
10* 
35 
24 hours (± 3 hours) after Day 34 morning defactinib dose, prior to 
any Day 35 defactinib administration 
11* 
35 
2-4 hours (± 10 min) after dosing with defactinib within 30 min (± 10 
min) of biopsy 
12 
42 
End of Study visit 
10** 
21 
24 hours (± 3 hours) after Day 20 morning defactinib dose, prior to 
any Day 21 defactinib administration 
11** 
21 
2-4 hours (± 10 min) after dosing with defactinib within 30 min (± 10 
min) of biopsy 
12** 
28 
End of Study visit 
 
*cohort 2 subjects only 
**cohort 3 and 4 subjects only 
 
On Day 12, Day 35, or Day 21 (+/- 2 days), cohort 1, 2 or 3 and 4 respectively, post treatment 
core biopsies for specimens and biomarkers will be performed. This will be performed under 
PET/CT in the BWH’s AMIGO suite or another radiology suite.  The PET CT will allow (a) 
guidance into metabolically active tumor; (b) assessment of the overall response based on 
overall appearance of the PET and (c) assessment of the tumor volume to be compared to pre-
treatment CT for evaluation for response to therapy.  The biopsy should be obtained within 2-
4 hours post the last dose of study drug. Study drug can be held and administered at the 
clinical site to ensure biopsy is obtained with the preferred window. The trial and data 
collection ends 30 days post treatment (Cohort 1) or 7 days post treatment, (Cohorts 2, 3 or 4).  
Treatment related adverse events and serious adverse events will be followed until resolution 
as defined in Section 2 and Section 12.4.1. 
 
PRP biomarkers will be investigated at baseline prior to the first dose of defactinib and within 
2-4 hours post last dose on Day 12 (cohort 1), on Day 35 (cohort 2), or on Day 21 (cohort 3).  
Additional plasma biomarker samples will be collected on Day 12 and 42 for cohort 2 and 
Day 12 and 28 for cohort 3 and 4. Peripheral blood biomarkers from whole blood will be 
investigated for cohort 3 and 4 patients only at baseline prior to the first dose of Defactinib 
and within 2-4 hours post last dose on Day 21. 
 
An overall treatment period is approximately 4 to 6 weeks: in the absence of treatment delays.  
 


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• The treatment cycle will be 12, 21 or 35 +/- 2 days when defactinib is administered 
P.O. 400 mg BID or 100 mg BID. 
• Image directed core biopsy will be performed within 2-4 hours post the last dose of 
defactinib on Day 12, 35 or 21 (+/- 2 days), cohort 1, 2, 3 and 4 respectively.  
• Definitive Surgery if appropriate will occur 30 (cohort 1) or > 7 (cohort 2, 3 and 4) 
days after the last defactinib dose and not within this trial.    
 
Participants will be considered to have completed the trial 30 (cohort 1) or 7 (cohort 2, 3 and 
4) days post the last dose of study drug. 
 
Current adjuvant treatment for Malignant Pleural Mesothelioma includes chemotherapy and 
radiation therapy and will be discussed with the participant’s Oncologist. 
 
Table 2. Treatment Description 
Agent 
Pre-
medications; 
Precautions 
Dose 
Route 
Schedule 
Cycle Length 
 
defactinib 
Fasting 
 
 
400 mg 
 
PO 
 
BID  
12 +/- 2 days 
(cohort 1) 
 
defactinib 
 
Fasting 
 
400 mg 
 
PO 
 
BID  
35 +/- 2 days 
(cohort 2) 
defactinib 
Immediately 
after meals with 
a full glass of 
water 
400 mg 
PO 
BID 
21 +/- 2 days 
(cohort 3) 
 
defactinib* 
 
Fasting 
100 mg 
PO 
BID 
21 +/- 2 days 
(cohort 4)           
*New formulation 
6.1 
Pre-treatment Criteria 
 
Screening evaluations are to be completed prior to the start of protocol therapy (see Section 
10 Study Calendar for a complete list of evaluations). 
• Tissue biopsies 
• Medical History 
• Physical Examination 
• Complete blood count: WBC of > 4 K/uL, hemoglobin > 8 mg/dl and platelet 
count of > 80 K/mm3, PT and INR 
• Serum chemistry (including: Albumin, alkaline phosphatase, total bilirubin, BUN, 
calcium, chloride, glucose, LDH, phosphorus, potassium, total protein, SGOT   
[AST], SGPT [ALT], sodium).  Serum Creatinine level less than 2, SGOT (AST) 
of < 80 IU/L and total bilirubin of < 1.9 mg/dL 
• Blood for biomarker studies, including flow cytometry analysis and determination 
of phosphoFAK. 


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• Chest PET/CT scan, chest MRI, pulmonary function tests, and echocardiogram 
(ejection fraction >30% for P/DC). 
• Normal contralateral pulmonary function with a chest radiograph that fails to 
show acute infiltrates and a minimum postoperative predicted FEV1 of 0.8L or % 
predicted FEV-1 of greater than 35%.  
• Negative pregnancy test (in women of childbearing potential) by serum. 
6.2 
Administration of Defactinib 
 
6.2.1 Defactinib Dosing Information 
 
Defactinib will be administered at 400mg twice daily for 12 +/- 2 days in cohort 1, for 35 
+/- 2 days in cohort 2 or for 21 +/- 2 days in cohort 3.  Defactinib (new formulation) will 
be administered at 100 mg twice daily for 21 +/- 2 days in cohort 4 for a total of ~43 
participants in all cohorts.   The day 12 for cohort 1 subjects, day 35 for cohort 2 subjects 
or day 21 for cohort 3 and 4 subjects (+/- 2) morning dose will be the final dose 
respectively.  The drug will be supplied for oral dosing as either 200 mg tablets for 
cohorts 1, 2 and 3 or 100 mg tablets for cohort 4.  
6.2.2 Defactinib Dosing Instructions for Study Participants 
 
The following instructions should be reviewed with the participant and a written copy of 
the instructions provided to the participant: 
 
• Take defactinib tablets by mouth twice each day with the second dose about 12 hours 
after the first dose. For cohort 1, 2 and 4 subjects, take the tablets with a full glass of 
water (approximately 8 ounces) either one hour before or two hours after a meal. For 
cohort 3 subjects, take the tablets with a full glass of water (approximately 8 ounces) 
immediately after a meal. Swallow the tablets whole. 
 
• In the event of emesis occurring after trial medication ingestion, the participant 
should simply adhere to the dosing schedule and resume dosing at the next scheduled 
time with the prescribed dosage. Participants should record the time of the emesis in 
their dosing diary. 
 
• Each day record date and time the tablets were taken on the drug diary. If a dose is 
missed, include the reason the dose was not taken. 
 
• Return the drug diary to your study doctor at each visit.  
 
• Return opened and unopened bottles in which the tablets were dispensed.  
 
• Adherence with the study treatment regimen must be assessed at each visit by 
checking the returned drug supply and reviewing the drug diary.  
6.2.3 Compliance 


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Participant compliance will be assessed by pill counts performed at the end of the cycle 
as well as by review of the participant’s drug diary.  
 
6.2.4 Missed or Vomited Doses 
 
If a scheduled dose of study drug is missed and less than 6 hours have passed since the 
scheduled dosing time, immediately take the missed dose.  In the event that a patient fails 
to take the trial medication within 6 hours of the designated dosing time, that dose should 
be omitted. The patient should record any missed doses and resume dosing at next 
scheduled time with prescribed dose.  
 
In the event of emesis occurring after trial medication ingestion, the patient should simply 
adhere to the dosing schedule and resume dosing at the next scheduled time with the 
prescribed dosage.  Patients should record the time of the emesis. Under no circumstance 
should a patient repeat a dose or the dosing schedule. 
 
6.2.5 Overdose and Medication Error Instructions 
 
For this study, overdose is defined as a daily dose of defactinib, higher than the 
prescribed daily dose.  In the event of an overdose or medication error, the Sponsor 
should be contacted immediately to discuss the details and formulate a clinical 
management plan. Documentation must be included in the dosing log. 
 
No information regarding overdose of defactinib in humans is available. No specific 
antidotes exist for the treatment of defactinib overdose.  
 
In the event of an overdose, the subject should be immediately admitted and monitored 
for possible signs of toxicity. As there is no specific antidote for overdose of defactinib, 
general supportive care should be provided.  An overdose will only be considered SAEs 
criteria as defined in Section 12.1.4. 
 
6.3 
Surgery 
 
Definitive Surgery will occur after 30 days (cohort 1) or >7 days (cohort 2, 3 and 4) from 
the last defactinib dose.  If surgery is elected it will not be part of this study.  Definitive 
Surgery includes but is not limited to extrapleural pneumonectomy or 
pleurectomy/decortication, with or without adjuvant therapy.   
 
To alleviate the concern of potential delay in surgery due to this trial we examined the 
timeline of surgery in our center.  During the past 3 years, 194 patients underwent 
surgery for resection of mesothelioma at BWH.  Of these 27 had positive lymph nodes 
and 22 received neoadjuvant therapy prior to resection.  In the ones immediately resected, 
the wait between staging and surgery was mean 36 days and median 28 days.  The 


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argument that from day one of trial till day 42 after trial will substantially delay patient 
care is not very persuasive given these data thus.   
 
6.3.1 Follow-Up 
 
The study will include a follow-up period of 30 (cohort 1) or 7 days (cohort 2, 3 and 4) 
post final drug administration.  Cohort 1 participants will be evaluated weekly during the 
follow-up period.  Assessments will include adverse event and collection of concomitant 
medications.  For subjects with ongoing laboratory adverse events related to defactinib, 
weekly laboratory assessments are required (CBC including platelet count and 
differential, PT and INR, and a serum chemistry (including: Albumin, alkaline 
phosphatase, total bilirubin, BUN, calcium, chloride, glucose, LDH, phosphorus, 
potassium, total protein, SGOT   [AST], SGPT [ALT], sodium).  Cohort 1 subjects will 
complete an end of study visit 30 days post-treatment and cohort 2, 3 and 4 subjects will 
complete the visit 7 days post-treatment.  Assessments will include a physical exam, 
ECOG status, laboratory assessments, adverse events and collection of concomitant 
medications.  In addition, an ECG (in triplicate) and two plasma samples (PK and 
Biomarkers) will be collected in cohorts 2, 3 and 4 along with whole blood collection for 
flow cytometry in cohort 3 and 4 subjects only. 
6.4 
General Concomitant Medication and Supportive Care Guidelines 
 
Concomitant use of any other anti-cancer treatment is not allowed during the study to avoid 
confounding the assessment of trial medication.  
6.5 
Duration of Therapy 
 
The duration of drug therapy will depend on individual response, evidence of disease 
progression and tolerance. In the absence of treatment delays due to adverse events, oral 
treatment may continue for 12 (cohort 1), 35 (cohort 2), or 21 (cohort 3 and 4) +/- 2 
days unless one of the following occurs prior to completion of planned therapy: 
• Intercurrent illness that prevents further administration of treatment 
• Unacceptable adverse event(s) 
• Participant demonstrates an inability or unwillingness to comply with the oral 
medication regimen and/or documentation requirements 
• Participant decides to withdraw from the study 
• General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the opinion of the treating investigator 
6.6 
Duration of Follow Up 
 
Participants will be followed for 30 (cohort 1) or 7 +2 (cohort 2, 3 and 4) days after the last 
dose of the drug.  
 
Participants removed from study for unacceptable adverse events will be followed until 
resolution, stabilization, or for 30 days (whichever is least) of the adverse event. 


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6.7 
Criteria for Removal from Study 
 
Participants will be removed from study when any of the criteria listed in Section 6.5 
applies. The reason for study removal and the date the participant was removed must 
be documented in the study-specific case report form (CRF). Alternative care options 
will be discussed with the participant. 
 
In the event of unusual or life-threatening complications, participating investigators 
must immediately notify the Principal Investigator Dr. Raphael Bueno. 
7. TOXICITY MANAGEMENT AND DOSING DELAYS/DOSE MODIFICATIONS 
 
Toxicity assessments will be done using the CTEP Version 4.0 of the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) which is identified and located on the CTEP 
website at: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
If possible, symptoms should be managed symptomatically. In the case of toxicity, appropriate 
medical treatment should be used (including anti-emetics, anti-diarrheals, etc.). 
In the setting of any toxicities of grade 2 or less, drug is continued at the current dose and 
schedule, and symptom management is provided as applicable. 
 
For toxicities > grade 2, other than hyperbilirubinemia (see Section 7.1), that are not adequately 
managed by supported therapy, drug is discontinued and the subject will be removed from the 
study and replaced. The patients will be followed to the end of the trial but will not restart the 
drug. 
 
All adverse events experienced by participants will be collected from the time of the first dose 
until the final study visit. Participants continuing to experience toxicity at the off study visit may 
be contacted for additional assessments until the toxicity has resolved or is deemed irreversible. 
 
For a list of adverse events and potential risks associated with VS-6063, please refer to the 
Investigator’s Brochure. 
7.1 
Other Potential Risks 
 
Increased Bilirubin 
Overall, 15 subjects (32.6%) reported hyperbilirubinemia. In all these cases, aspartate 
aminotransferase and alanine aminotransferase were within normal limits.  This 
unconjugated hyperbilirubinemia was generally asymptomatic and reversible with dosing 
holiday or continued treatment. 
If the increase in bilirubin is grade ≤ 3 and is not associated with an increase in AST or 
ALT, continue treatment.  Cohort 2, 3 and 4 subjects with elevated bilirubin will be re-
tested weekly until resolution or return to baseline.  If the bilirubin increases to ≥ grade 2 
and is associated with a ≥ grade 2 increase in AST and/or ALT, permanently discontinue 
study drug.     


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Blood Pressure 
Minor, generally asymptomatic increases in blood pressure were observed in a single agent 
Phase I study of defactinib.  Subjects experiencing recurrent, persistent, or symptomatic 
increase by >20 mmHg (diastolic) or to >150/100 mmHg if previously within normal 
limits, should be initiated on antihypertensive therapy according to institutional policies. 
Study drug does not need to be interrupted if hypertension can be controlled.  
For subjects with persistent systolic BP >= 160 mm Hg or diastolic BP >= 100 mm Hg 
despite optimal antihypertensive therapy, study drug should be discontinued and the patient 
removed from the study.  
Genitorurinary 
Based on extrapolations from nonclinical toxicities, potential manifestations in humans 
may also include impaired fertility.   
Appropriate monitoring in humans includes serial liver function testing, routine blood 
biochemical, hematological parameters, urinalyses, vital signs, and ECG.  
7.2 
Toxicity Management 
If a participant experiences toxicities, the Investigator has the option of suspending 
treatment until resolution. Subjects failing to receive the 12 (cohort 1), 35 (cohort 2), or 21 
(cohort 3 and 4) days +/-2 days of defactinib will be replaced. Subjects may be replaced at 
the Investigators discretion following discussions with the Sponsor.   
7.3 
Supportive Care 
 
Supportive care (e.g., analgesics, antiemetics, antidiarrheal agents, antidepressants) may be 
administered prophylactically after the first dose or therapeutically at the Investigator’s 
discretion.  
 
8. DRUG FORMULATION AND ADMINISTRATION 
8.1 
Agent Defactinib (VS-6303) 
 
Treatment Description 
Agent 
Pre-medications; 
Precautions 
Dose 
Route 
Schedule 
Cycle Length 
Defactinib  
(VS-6063) 
Fasting 
400 mg 
PO 
BID  
12 +/- 2 days 
(cohort 1) 
Defactinib  
(VS-6063) 
Fasting 
400 mg 
PO 
BID  
35 +/- 2 days 
(cohort 2) 


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Defactinib  
(VS-6063) 
Immediately after 
meals with a full 
glass of water 
400 mg 
PO 
BID 
21 +/- 2 days 
(cohort 3) 
Defactinib * 
(VS-6063) 
Fasting 
100 mg 
PO 
BID 
21 +/- 2 days 
(cohort 4) 
*New formulation of defactinib 
8.2 
Description 
 
Defactinib (in the form of: N-methyl-4-({4-[({3-methyl(methylsulfonyl)aminopyrazin-
2-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzamide 
hydrochloride)  is an orally bioavailable, small-molecule focal adhesion kinase (FAK) 
inhibitor with potential antiangiogenic and antineoplastic activities. The molecular 
formula is  C20H22ClF3N8O3S with a Molecular Weight of 545.97 Daltons. 
 
Defactinib is rapidly absorbed under fasted conditions (at doses ranging from 12.5 mg to 
750 mg). Maximum serum defactinib concentrations are achieved within 1 to 2 hours 
post dose. Peak and total exposure (Cmax and AUC) increased with increasing dose 
from 12.5 mg to 425 mg BID; however, doses above 425 mg BID did not result in 
significant increases in exposure. Hepatic metabolism is expected to be the major 
pathway of elimination with a half life of approximately 9hrs following a single oral 
dose in man.   
8.3 
Form 
 
Defactinib will be supplied as 200 mg immediate release tablets for oral dosing (cohort 1, 
2 and 3). Tablets will be oval with a white to off-white appearance. Defactinib (new 
formulation) will be supplied as 100 mg tablets for oral dosing (cohort 4). Tablets will be 
oval with a white to off-white appearance and VS1 embossed on one side. 
The study drug will be packaged in bottles labeled with pill strength and other 
information as per local regulatory requirements.  
8.4 
Storage and Stability 
 
The drug product has been demonstrated to be stable when stored in the defined container 
closure (HDPE bottles). The labeled storage condition for the drug product is “Store 
between 15 and 25°C (59 and 77°F)”. Bottles labeled with pill strength and other 
information as per local regulatory requirements. 
8.5 
Compatibility 
 
N/A 
8.6 
Handling 
 


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Qualified personnel, familiar with procedures that minimize undue exposure to 
themselves and the environment, should undertake the preparation, handling, and safe 
disposal of defactinib per internal standard operating procedure. 
8.7 
Availability 
 
Defactinib is an investigational agent and will be supplied free-of-charge from 
Verastem. 
8.8 
Administration 
 
Defactinib is to be taken twice daily orally continuously for 12 +/- 2 days in cohort 1, for 
35 +/- 2 days in cohort 2 or for 21+/- 2 days in cohort 3 and 4. The final dose will be 
administered the morning of the scheduled biopsy on Day 12 (+/- 2) in cohort 1, Day 35 
(+/- 2) in cohort 2 or Day 21 +/- 2 days in cohort 3 and 4.  See Section 6.2 for additional 
information.  
 
The patient will get a bottle of pills. Each bottle will contain tablets of a single 
formulation. The tablets will be repackaged to the patient as a 14-day supply for cohort 1 
subjects, a 35 day supply for cohort 2 subjects or a 21 day supply for cohort 3 and 4 
subjects. Study drug is stored at room temperature. 
8.9 
Ordering 
 
Defactinib will be supplied by Verastem or its designee.  
The agent may be requested by contacting Verastem directly at: 
 
Drug Orders  
Verastem, Inc. 
117 Kendrick St, Suite 500, Needham, MA 02494 
 
   
8.10 Accountability 
 
The Investigator or an approved representative (e.g. Pharmacist) will ensure that 
defactinib is stored in a secured area under recommended storage conditions and in 
accordance with applicable regulatory requirements. The Investigator must maintain 
adequate records documenting the receipt, use, loss, or other disposition of the 
investigational product. Verastem may supply drug accountability forms that must be 
used or may approve use of standard institutional forms. In either case, the forms must 
identify the investigational product, including batch or code numbers, and account for its 
disposition on a subject-by-subject basis, including specific dates and quantities.  
 


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The individual who dispensed the drug must sign the forms, and copies will be provided 
to Verastem. At the end of the trial, Verastem will provide instructions as to disposition 
of any unused investigational product. If Verastem authorizes destruction at the trial site, 
the Investigator must ensure that the materials are destroyed in compliance with 
applicable environmental regulations, institutional policy, and any special instructions 
provided by Verastem. Destruction must be adequately documented. 
 
The investigator, or a responsible party designated by the investigator, must maintain a 
careful record of the inventory and disposition of the agent (investigational or free of 
charge) using the NCI Drug Accountability Record or another comparable drug 
accountability form. (See the CTEP website at http://ctep.cancer.gov/protocol 
Development  for the “Policy and Guidelines for Accountability and Storage of 
Investigational Agents” or to obtain a copy of the drug accountability form.) 
8.11 Destruction and Return 
 
At the end of the study, unused supplies of defactinib should be destroyed according 
to institutional policies. Destruction will be documented in the Drug Accountability 
Record Form. 
 
9. BIOMARKER STUDIES 
9.1 
Biomarker and Pharmacodynamic Sampling 
 
Tumor biopsy samples for pharmacodynamic biomarker analysis will be taken at baseline 
(prior to the first dose of defactinib, and at the end of the 12, 35-day, or 21 defactinib 
treatment course in cohort 1, cohort 2, or cohort 3 and 4 respectively). At least 4 core 
needle biopsies will be obtained and each collection will include two Fine Needle 
Aspirates, one tumor Core Needle Biopsy to be fresh frozen, one tumor Core Needle 
Biopsy to be FFPE processed. Fine Needle Aspirates will be collected for tumor immune 
cell measurements by flow cytometry. Core Needle Biopsies are to be collected from the 
same needle site following the Fine Needle Aspirate. Additional core needle biopsies will 
be collected and kept frozen and/or FFPE in Dr. Bueno’s lab for experiments. 
 
In the event that the tumor biopsy cannot be collected on Day 12 (cohort 1), 35 (cohort 2), 
or 21 (cohort 3 and 4), subjects should continue dosing with defactinib until the 2nd biopsy 
is collected (a +/- 2 day visit window is allowed for this visit). On the last day of the 
defactinib run-in, the morning dose of defactinib should be administered in-clinic, up to 4 
hours before the 2nd tumor biopsy is collected.  
 
Blood samples will be collected for Biomarker analysis and PK. Separate blood tubes will 
be collected for Platelet Rich Plasma (PRP) and plasma at baseline prior to the first dose of 
defactinib and within 2-4 hours post the last dose on Day 12 (cohort 1), Day 35 (cohort 2) 
or Day 21 (cohort 3 and 4 for plasma only).  In cohort 2, additional plasma biomarker 
samples will be collected pre-dose on Day 12 and at the end of study on Day 42 and on 
Day 12 and at the end of study on Day 28 for cohort 3 and 4.  


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In cohort 3 and 4 only, flow cytometry biomarkers will be investigated from whole blood 
collected at baseline prior to the first dose of defactinib and within 2-4 hours post the last 
dose on Day 21 and at end of study. 
 
Comprehensive information on tissue processing, handling, storage and sample shipments 
for PK, Biomarker and core biopsies can be found in the Laboratory Manuals.  
9.2 
Biomarker and Pharmacodynamic Endpoints 
 
Pharmacodynamic and predictive response biomarkers intended to demonstrate inhibition 
of the molecular target and determination of the mechanism of action will be assessed in in 
the tumor biopsies whole blood, plasma, and PRP. Key markers may include phospho-
FAK, as well as specific markers for immunomodulation, cell cycle inhibition, apoptosis 
and cancer stem cells. Key immune cell markers will include but are not limited to CD8, 
CD4, ICOS, PDL1, PDL2, PD1, CD25, FOXP3, and marker panels for MDSCs. Immune 
marker comparisons between tumor and blood will be evaluated. Cancer stem cell 
biomarkers such as ALDH1, CD44, CD133, SOX2, and Integrins may be investigated. 
 
Blood-based Biomarkers of response will be evaluated including chemokines, cytokines, 
growth and differentiation factors. Additional biomarkers may be identified and measured 
as appropriate. 
 
 
 


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10. STUDY CALENDAR 
Baseline evaluations are to be conducted within 1-week prior to start of protocol therapy. In 
the event that the participant's condition is deteriorating, laboratory evaluations should be 
repeated within 48 hours. 
All assessments must be performed prior to administration of any study medication. All 
study assessments and medications should be administered within + 2 days of the 
protocol-specified date, unless otherwise noted.  
 
Table 3: Schedule of Assessments Cohort 1 
  
Pre-
study 
Day 1 
(-2d) 
Day 8 
Day 11 
(+/-  2) 
Day 12 
(+/-  2) 
Follow-
up 
Week 1g 
Follow-
up 
Week 2g 
Follow-
up 
Week 3g 
Follow-
up 
Week 
4h 
Study Agent 
 
----------BID throughout --------- 
 
 
 
 
Biopsy /PRP 
 Biomarker 
Collection 
Xd 
 
 
 
Xd 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
History  
X 
 
 
 
 
 
 
 
 
Concurrent 
Medications a 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical 
Exam/Vital Signs 
(Ht, Wt, BSA) 
X 
 
 
 
X 
 
 
 
X 
Performance 
Status 
X 
 
 
 
X 
 
 
 
X 
Pulmonary 
Function test 
X 
 
 
 
 
 
 
 
 
CBC w/ diff, plts 
X 
X 
 
 
X 
 
 
 
X 
PT/INR  
X 
X 
 
 
X 
 
 
 
X 
Serum chemistry b 
X 
X 
 
 
X 
 
 
 
X 
PK Assessments 
 
 
 
Xf 
Xf 
 
 
 
 
ECG 
X 
 
 
 
X 
 
 
 
 
Adverse Event 
Evaluationc 
 
X 
X 
X 
X 
X 
X 
X 
X 
Tumor 
Measurement e 
X 
 
 
 
X 
 
 
 
 
Radiologic 
Evaluatione  
X 
 
 
 
Xe 
 
 
 
 
Pregnancy test 
X 
 
 
 
 
 
 
 
 
Off-study 
 
 
 
 
 
 
 
 
Xi 
a: Concurrent medications will be self-reported by participant throughout duration of study  
b: Albumin, alkaline phosphatase, total bilirubin, BUN, calcium, chloride, glucose, LDH, phosphorus, potassium, total protein, SGOT   
[AST], SGPT [ALT], sodium. 
c: Adverse event evaluation will be recorded as they are encountered by clinician or self-reported by participant. 
d: Biopsy and PRP biomarker samples obtained prior to the initiation of oral therapy and within 2-4 hours of the last dose of defactinib. 
e: Evaluations should occur within 8 weeks of Day 1 and after completion of the 12 day (+/- 2 days)  oral therapy treatment. 


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f: Refer to protocol Section 6 for serial PK sampling table. 
g: Weekly laboratory assessments (CBC, Chemistry, PT/INR) required for ongoing toxicities related to defactinib 
h. All week 4 follow-up assessments completed 30 days after the last dose of study drug. 
i: Off study after all week 4 follow-up assessments completed. 
Table 4: Schedule of Assessments Cohort 2 
  
Pre-
study 
Day 1 
(-2d) 
Day 8 
Day 11  
(+/- 2) 
Day 12  
(+/- 2) 
Day 35  
(+/- 2) 
End of 
Studyh 
Study Agent 
 
----------BID throughout --------- 
 
Biopsy / PRP Collection 
Xf 
 
 
 
 
Xf 
 
Plasma Collection 
Xf 
 
 
 
Xg 
 
Xg 
Informed Consent 
X 
 
 
 
 
 
 
History  
X 
 
 
 
 
 
 
Concurrent Medications a 
X 
X 
X 
X 
X 
X 
X 
Physical Exam/Vital Signs (Ht, 
Wt, BSA) 
X 
 
 
 
X 
X 
X 
Performance Status 
X 
 
 
 
X 
X 
X 
Pulmonary Function 
test/ECHOb 
X 
 
 
 
 
 
 
CBC w/ diff, plts 
X 
X 
 
 
X 
X 
X 
PT/INR  
X 
X 
 
 
X 
X 
X 
Serum chemistry c 
X 
X 
 
 
Xh 
X 
X 
PK Assessments 
 
 
 
Xi 
Xi 
Xi 
Xi 
ECG 
X 
 
 
 
X 
X 
X 
Adverse Event Evaluationd 
 
X 
X 
X 
X 
X 
X 
Tumor Measurement e 
X 
 
 
 
 
X 
 
Radiologic Evaluatione  
X 
 
 
 
 
Xe 
 
Pregnancy test 
X 
 
 
 
 
 
 
Off-study 
 
 
 
 
 
 
Xj 
a: Concurrent medications will be self-reported by participant throughout duration of study.  
b: Evaluations should occur within 45 days of Day 1 and must be repeated within 1 week of Day 1 if results were abnormal and clinically 
significant or for any new clinically significant abnormalities per Investigator assessment. 
c. Albumin, alkaline phosphatase, total bilirubin, BUN, calcium, chloride, glucose, LDH, phosphorus, potassium, total protein, SGOT   [AST], 
SGPT [ALT], sodium. 
d: Adverse event evaluation will be recorded as they are encountered by clinician or self-reported by participant. 
e: Evaluations should occur within 8 weeks of Day 1and after completion of the Day 35 (+/- 2 day) oral therapy treatment.                  
f: Biopsy, PRP biomarker samples obtained prior to the initiation of oral therapy and within 2-4 hours of the morning Day 35 dose.  
g. Plasma biomarker samples obtained prior to initiation of oral therapy, prior to the morning dose of defactinib on Day 12 and the End of Study 
Visit (Day 42). 
h. Weekly retesting of Bilirubin, ALT, and AST is required for subjects with increased bilirubin (Grade 1-2 per CTCAE V4.0) on Day 12.  Local 
laboratory testing is permitted.  
i: Refer to protocol section 6 for serial PK sampling table. 
j. End of Study assessments completed 7 days after the last dose of study drug. 
 
 


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Table 5: Schedule of Assessments Cohort 3 and 4 
  
Pre-study 
Day 1 
(-3d) 
Day 8 
Day 11  
(+/- 2) 
Day 12  
(+/- 2) 
Day 21  
(+/- 2) 
End of 
Studyj 
Study Agent Cohort 3 
 
Orally, immediately after a meal BID throughout --------- 
 
Study Agent Cohort 4 
 
-------------BID THROUGHOUT------------- 
 
Tumor Fine Needle Aspirate 
and Core Needle Biopsyk 
X 
 
 
 
 
X 
 
Platelet Rich Plasma Collection 
(Cohort 3 only) 
Xf 
 
 
 
 
Xf 
 
Plasma Collection 
Xg 
 
 
 
Xg 
 
Xg 
Whole Blood Collectionl  
Xf 
 
 
 
 
Xf 
X 
Informed Consent 
X 
 
 
 
 
 
 
History  
X 
 
 
 
 
 
 
Concurrent Medications a 
X 
X 
X 
X 
X 
X 
X 
Physical Exam/Vital Signs (Ht, 
Wt, BSA) 
X 
 
 
 
X 
X 
X 
Performance Status 
X 
 
 
 
X 
X 
X 
Pulmonary Function 
test/ECHOb 
X 
 
 
 
 
 
 
CBC w/ diff, plts 
X 
X 
 
 
X 
X 
X 
PT/INR  
X 
X 
 
 
X 
X 
X 
Serum chemistry c 
X 
X 
 
 
Xh 
X 
X 
PK Assessments 
 
 
 
Xi 
Xi 
Xi 
Xi 
 ECG 
X 
 
 
 
X 
X 
X 
Adverse Event Evaluationd 
 
X 
X 
X 
X 
X 
X 
Tumor Measurement e 
X 
 
 
 
 
X 
 
Radiologic Evaluation, PET-
CT & MRI e  
X 
 
 
 
 
Xe 
 
Serum Pregnancy test 
X 
 
 
 
 
 
 
Off-study 
 
 
 
 
 
 
Xj 
a: Concurrent medications will be self-reported by participant throughout duration of study.  
b: Evaluations should occur within 45 days of Day 1 and must be repeated within 1 week of Day 1 if results were abnormal and clinically 
significant or for any new clinically significant abnormalities per Investigator assessment.  
c. Albumin, alkaline phosphatase, total bilirubin, BUN, calcium, chloride, glucose, LDH, phosphorus, potassium, total protein, SGOT   [AST], 
SGPT [ALT], sodium. 
d: Adverse event evaluation will be recorded as they are encountered by clinician or self-reported by participant. 
e: Evaluations should occur within 45 days of Day 1and after completion of the Day 21 (+/- 2 day) oral therapy treatment.(PET-CT and MRI)                  
f: Biopsy, PRP and whole blood collection samples obtained prior to the initiation of oral therapy and within 2-4 hours after the last dose (Day 21 
± 2 days) (PRP collection in Cohort 3 only).  
g. Plasma biomarker samples obtained prior to initiation of oral therapy, prior to the morning dose of defactinib on Day 12 and the End of Study 
Visit (Day 28). 
h. Weekly retesting of Bilirubin, ALT, and AST is required for subjects with increased bilirubin (Grade 1-2 per CTCAE V4.0) on Day 12.  Local 
laboratory testing is permitted.  
i: Refer to protocol section 6 for serial PK sampling table. 
j. End of Study assessments completed 7 days after the last dose of study drug. 
k. Tumor biopsy by Fine Needle Aspirate and Core Needle Biopsy at Pre-study and post the morning dose Day 21.  
l. Whole Blood collection for Flow cytometry analysis 


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.  
11. MEASUREMENT OF EFFECT  
 
Although response is not the primary endpoint of this trial, participants with measurable 
disease will be assessed by measuring the Tumor Volume.  
11.1 Antitumor Effect– Solid Tumors – Radiology and Biomarkers 
For the purposes of this study, participants should be evaluated for response prior to Day 
1 oral treatment and again after the end of the oral treatment.  Response and progression 
will be evaluated using the modified RECIST criteria for mesothelioma as established by 
Byrne and Nowak (Modified RECIST criteria for assessment of response in malignant 
pleural mesothelioma, Ann Oncol 2004) to evaluate response using the PET CT obtained 
at approximate day 12 (+/- 2 days) for subjects in cohort 1 and at the end of study 
treatment for subjects in cohort 2, Day 35 (+/- 2) and for subjects in cohort 3 and 4, Day 
21 (+/- 2).  For cohort 3 and 4 subjects only, this will also include a MRI. 
11.2 Definitions 
Evaluable for toxicity. All participants who receive at least one dose of study treatment 
will be evaluable for toxicity from the time of their first treatment. 
Evaluable for objective response. Only those participants who have measurable 
disease present at baseline, have received at least the oral cycle of therapy, and have 
had their disease re-evaluated will be considered evaluable for response. These 
participants will have their response classified according to the definitions stated 
below. (Note: Participants who exhibit objective disease progression or die prior to the 
end of the oral cycle will also be considered evaluable.) 
11.3  Disease Parameters 
Measurable disease. Measurable disease is the presence of at least one (1) lesion that 
can be accurately measured in at least one dimension with longest diameter >10 
millimeters (mm) using conventional techniques (CT, PET/CT) or >10 mm with spiral 
CT scan. Measurable lesions must be at least 2 times the slice thickness in mm. All 
tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). Lesions must be accurately measured in 1 dimension with a minimum 
size of 10 mm by CT (slice thickness no greater than 5 mm), 20 mm by CT scan. 
Nodes must have a short axis > 15 mm. The short axis should be included in the sum 
of the lesions in the calculation of response. Nodes that shrink to < 10 mm are 
considered normal. Target lesions should be selected on the basis of their size, be 
representative of all the involved organs, and should be lesions that can be followed 
with reproducible repeated measurements. 
 


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Malignant lymph nodes. To be considered pathologically enlarged and measurable, a 
lymph node must be >15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm). At baseline and in follow-up, 
only the short axis will be measured and followed. 
11.4  Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation, using a ruler, calipers, or 
digital measurement tool. All baseline evaluations should be performed as closely as possible 
to the beginning of treatment and never more than 8 weeks before the beginning of the 
treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination when both methods have 
been used to assess the anti-tumor effect of a treatment. 
 
FDG PET and PET/CT.  The acquisition of FDG PET and FDG PET/CT scans should 
follow the NCI Guidelines for using FDG PET as an indicator of therapeutic response 
(L.K. Shankar, J.M. Hoffman, S. Bacharach, M.M. Graham, J. Karp, A.A. Lammertsma, S. 
Larson, D.A. Mankoff, B.A. Siegel, A. Van den Abbeele, J. Yap, D. Sullivan. Consensus 
recommendations for the use of 18F-FDG PET as an indicator of therapeutic response in 
participants in National Cancer Institute Trials. J Nucl Med, 47(6):901-903, 2006). 
Participants should avoid strenuous exercise and be on a low carbohydrate diet for 24 
hours prior to the scan. Participants should fast for 4 hours or longer prior to the FDG 
injection and should have a serum glucose of less than 200 mg/dL at the time of FDG 
injection. A 10-20 mCi dose of FDG should be injected for typical adult participants. For 
longitudinal studies with multiple scans, particular attention should be paid to ensure 
consistent participant preparation and acquisition parameters between the follow-up scan 
and the baseline scan. When designing a study where PET scans are going to be utilized as 
one of the modalities to evaluate efficacy, it is important to consult with physicians in 
nuclear medicine in designing the appropriate criteria to be utilized. 
 
MRI. MRIs should be acquired according to RECIST criteria prior to start of oral 
treatment and after last day of oral treatment and according to other institutional MRI 
research procedures/policies. 
11.5 Response Criteria  
11.5.1 Evaluation of Target Lesions: 
This is a brief trial driven by imaging and biomarkers.  We will use the modified 
RECIST criteria for mesothelioma as established by Byrne and Nowak (Modified 
RECIST criteria for assessment of response in malignant pleural mesothelioma, 
Ann Oncol 2004 to evaluate response using the PET CT obtained at the end of 
therapy. 


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11.5.2 Definitions 
Complete Response (CR): 
Disappearance of all target lesions. Any pathological lymph node must have 
reduction in short axis to < 10 mm. 
Partial Response (PR):  
At least a 30% decrease in the volume of target lesions, taking as reference the 
baseline measurements. 
Progressive Disease (PD): 
At least a 20% increase in the volume of target lesions, taking as reference the 
baseline measurements. Or, new measurable lesions are detected.  
 
Stable Disease (SD): 
 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD, taking as reference the smallest sum LD since the treatment started. 
 
Unknown (UN): 
 
Assessment of target lesions cannot be made due to insufficient or unevaluable 
data. In this case, a concise explanation must be given. 
11.5.3 Evaluation of Biomarkers 
 
The primary objective of this trial is to measure biomarker response to the treatment. 
We will measure inhibition of phospho-FAK, alterations in markers of tumor immune 
populations, tumor microenvironment, cell cycle and apoptosis, and additional 
changes in cancer stem cells in the pre and post treatment specimens. Ultimately, 
these patients with response based on RECIST criteria, PET and pathological features 
(degree of tumor necrosis and viable tumor in the post-treatment biopsy) will be 
compared with non-responders on the basis of profiling as discussed in a previous 
section to define the best biomarker for response.  All samples will be evaluated with 
genomic analytical platforms such as sequencing and other profiling tools to 
determine potential predictive biomarkers.   
 
 
12. ADVERSE EVENT REPORTING REQUIREMENTS 
12.1 Definitions 
12.1.1 Adverse Event (AE) 
 
Adverse event means any untoward medical occurrence associated with the use of a 
drug in humans, whether or not considered drug related. An adverse event (AE) is 
any unfavorable and unintended sign, symptom or disease temporarily associated 
with the use of a drug and does not imply any judgment about causality. 


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12.1.2 Suspected Adverse Reaction 
Suspected adverse reaction means any adverse event for which there is a 
reasonable possibility that the drug caused the adverse event. For the purposes of 
IND safety reporting, ‘reasonable possibility’ means there is evidence to suggest a 
causal relationship between the drug and the adverse event. A suspected adverse 
reaction implies a lesser degree of certainty about causality than adverse reaction. 
12.1.3 Adverse Reaction 
An adverse reaction means any adverse event caused by a drug. Adverse reactions 
are a subset of all suspected adverse reactions where there is reason to conclude 
that the drug caused the event. 
12.1.4 Serious adverse event (SAE) 
An adverse event or suspected adverse event is considered serious if, in the view of 
the investigator or sponsor, it results in any of the following outcomes::  
• Death 
• A life-threatening event. Life-threatening means that the person was at 
immediate risk of death from the reaction as it occurred, i.e., it does not 
include a reaction which hypothetically might have caused death had it 
occurred in a more severe form. 
• Inpatient hospitalization or prolongation of existing hospitalization (i.e., the 
event required at least a 24-hour hospitalization or prolonged a hospitalization 
beyond the expected length of stay). Hospitalization admissions and/or 
surgical operations scheduled to occur during the study period, but planned 
prior to study entry are not considered SAEs if the illness or disease existed 
before the person was enrolled in the trial, provided that it did not deteriorate 
in an unexpected manner during the trial (e.g., surgery performed earlier than 
planned). 
• A persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions. 
• A congenital anomaly or birth defect; or 
• An important medical event when, based upon appropriate medical judgment, 
it may jeopardize the participant and require medical or surgical intervention 
to prevent one of the outcomes listed above. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home; blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug 
abuse. 
 
Events not considered to be serious adverse events are hospitalizations for: 
• Routine treatment or monitoring of the studied indication, not associated with 
any deterioration in condition, or for elective procedures 
• Elective or pre-planned treatment for a pre-existing condition that did not 
worsen 
• Emergency outpatient treatment for an event not fulfilling the serious criteria 
outlined above and not resulting in inpatient admission 


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• Respite care 
12.1.3 Expectedness 
Adverse events can be 'Expected' or 'Unexpected.'  
12.1.3.1 Expected adverse event 
Expected adverse events are those that have been previously identified as resulting 
from administration of the agent. For the purposes of this study, an adverse event is 
considered expected when it appears in the current Reference Safety Information 
section in the Investigator’s Brochure.  
12.1.3.2 Unexpected adverse event 
For the purposes of this study, an adverse event is considered unexpected when it 
varies in nature, intensity or frequency from information provided in the current 
Reference Safety Information section of the Investigator’s Brochure. 
12.1.4 Attribution 
Attribution is the relationship between an adverse event or serious adverse event and the 
study treatment. Attribution will be assigned as follows: 
 
• Definite – The AE is clearly related to the study treatment. 
• Probable – The AE is likely related to the study treatment. 
• Possible – The AE may be related to the study treatment.  
• Unlikely - The AE is doubtfully related to the study treatment. 
• Unrelated - The AE is clearly NOT related to the study treat. 
12.2 Procedures for AE and SAE Recording and Reporting 
 
Participating investigators will assess the occurrence of AEs and SAEs at all participant 
evaluation time points during the study.  
 
All AEs and SAEs whether reported by the participant, discovered during questioning, 
directly observed, or detected by physical examination, laboratory test or other means, will 
be recorded in the participant’s medical record and on the appropriate study-specific case 
report forms.  
 
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. All 
appropriate treatment areas should have access to a copy of the CTCAE version 4.0. 
A copy of the CTCAE version 4.0 can be downloaded from the CTEP website at: 
 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
12.3 Reporting Requirements 
 


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The study must be conducted in compliance with FDA regulations, local safety reporting 
requirements, and reporting requirements of the sponsor.  
 
Each investigative site will be responsible for reporting SAEs that occur at that institution 
to their respective IRB. It is the responsibility of each participating investigator to report 
SAEs to the study sponsor and/or others as described below.  
 
The study sponsor or designee will notify investigators of all suspected, unexpected serious 
adverse reactions (SUSAR; 7 / 15 Day Safety Reports) that occur during any clinical 
studies that are using the investigative compound. Each investigator is responsible for 
reviewing each SUSAR and is responsible for notifying his/her IRB of these external 
SUSARs.  
 
All serious adverse events that occur after the initial dose of study treatment, during 
treatment, or within 30 days of the last dose of treatment must also be reported. Any SAE 
occurring after the reporting period must be promptly reported if a causal relationship to 
the investigational drug is suspected.  
 
In addition, the following AEs, including serious and non-serious events, meeting the 
criteria below, will be recorded on the toxicity CRF and are to be reported to the Sponsor 
and the DFCI IRB per the Adverse Event Reporting Policy: 
 
• Grade 2 (moderate) and Grade 3 (severe) Events – Only events that are 
unexpected and possibly, probably or definitely related/associated with the 
intervention. 
 
• All Grade 4 (life-threatening or disabling) Events – Unless expected AND 
specifically listed in the protocol as not requiring reporting. 
 
• All Grade 5 (fatal) Events – When the participant is enrolled and actively 
participating in the trial OR when the event occurs within 30 days of the last dose 
of study drug. 
 
12.4 Serious Adverse Event Reporting 
 
The investigator is responsible for ensuring that all AEs and SAEs (as defined in Section 
12.1.1 and Section 12.1.2) are recorded on the eCRF and reported to the Sponsor in 
accordance with protocol instructions. 
 
Investigators will submit reports of all SAEs, regardless of attribution, to Verastem’s 
designated Pharmacovigilance representative within 24 hours of learning of the events.  For 
initial SAE reports, investigators should record all case details that can be gathered within 
24 hours on the study specific SAE form and faxed or emailed immediately upon 
completion to Verastem’s Drug Safety:  
 


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by FAX to PAREXEL Safety: 
 
or 
by email to 
 
 
The participating investigator must provide follow-up information on the SAE as soon as 
additional information becomes available and must report the follow up information to 
Verastem within 24 hours of becoming aware of the follow up. Follow-up information 
should describe whether the event has resolved or continues, if and how the event was 
treated, and whether the participant will continue or discontinue study participation. 
12.5 Reporting to the Institutional Review Board (IRB) 
 
Investigative sites within DF/HCC will report all serious adverse events, and non-serious 
events as outlined in section 12.3, directly to the DFCI Office for Human Research Studies 
(OHRS). 
12.6  Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any subject 
safety reports or sentinel events that require reporting according to institutional policy. 
12.7 Monitoring of Adverse Events and Period of Observation 
 
All adverse events, both serious and non-serious, and deaths that are encountered from the 
time the subject signs the informed consent, throughout the study, and within 30 days of 
the last study intervention should be followed to their resolution, or until the 
participating investigator assesses them as stable, or the participating investigator 
determines the event to be irreversible, or the participant is lost to follow-up. The 
presence and resolution of AEs and SAEs (with dates) should be documented on the 
appropriate case report form and recorded in the participant’s medical record to facilitate 
source data verification.  
 
For some SAEs, the study sponsor or designee may follow-up by telephone, fax, and/or 
monitoring visit to obtain additional case details deemed necessary to appropriately 
evaluate the SAE report (e.g., hospital discharge summary, consultant report, or autopsy 
report).  
 
Participants should be instructed to report any serious post-study event(s) that might 
reasonably be related to participation in this study. Participating investigators should notify 
the DF/HCC Overall Principal Investigator and their respective IRB of any unanticipated 
death or adverse event occurring after a participant has discontinued or terminated study 
participation that may reasonably be related to the study.  
12.8 Pregnancy 
 


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The effects of defactinib on conception, pregnancy, and lactation are unknown. 
Pregnancies occurring in patients or partners of male patients during the study treatment 
period are considered immediately reportable events. If a pregnancy occurs in a patient, 
study treatment must be discontinued immediately. The pregnant woman should be 
referred to an obstetrician/gynecologist experienced in reproductive toxicity for further 
evaluation and counseling and the pregnancy reported to the Sponsor within 24 hours of 
the investigator’s knowledge of the pregnancy. 
 
13. DATA AND SAFETY MONITORING 
13.1 Data Reporting 
 
13.1.1 Method  
The study staff will collect, manage, and monitor data for this study. Research staff 
will assist with project compliance, data collection, abstraction and entry, data 
reporting, regulatory monitoring, problem resolution and prioritization, and 
coordinate the activities of the protocol study team. The data collected for this 
study will be entered into a secure database. Source documentation will be 
available to support the computerized subject record.  Case Report Forms (CRF’s) 
will be developed and updated by the Clinical Trials Research Informatics Office 
(CTRIO). These data forms will be sent to the Principal Investigator for his review 
and will be computerized and monitored for completeness and accuracy. Reports 
are provided as needed to the Study Team. 
13.1.2 Data Submission 
The schedule for completion and submission of case report forms (paper or 
electronic) to the Office of Data Quality (ODQ) is as follows: 
 
Form 
Submission Timeline 
Eligibility Checklist 
Complete prior to registration with QACT 
On Study Form 
Within 14 days of registration 
Baseline Assessment Form Within 14 days of registration 
Treatment Form 
Within 10 days of the last day of the cycle 
Adverse Event Report 
Form 
Within 10 days of the last day of the cycle 
Response Assessment 
Form 
Within 10 days of the completion of the cycle required 
for response evaluation 


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Off Treatment/Off Study 
Form 
Within 14 days of completing treatment or being taken 
off study for any reason 
Follow up/Survival Form 
Within 14 days of the protocol defined follow up visit 
date or call 
 
13.2 Safety Meetings 
 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor 
toxicity and accrual data from this trial. The committee is composed of clinical specialists 
with experience in oncology and who have no direct relationship with the study. 
Information that raises any questions about participant safety will be addressed with the 
Principal Investigator and study team. 
 
The DSMC will meet quarterly and/or more often if required to review toxicity and accrual 
data.  Information to be provided to the committee may include:  up-to-date participant 
accrual; current dose level information; DLT information; all grade 2 or higher unexpected 
adverse events that have been reported; summary of all deaths occurring within 30 days for 
Phase I or II protocols; for gene transfer protocols, summary of all deaths while being 
treated and during active follow-up; any response information; audit results, and a 
summary provided by the study team. Other information (e.g. scans, laboratory values) 
will be provided upon request. 
13.3 Monitoring 
 
Involvement in this study as a participating investigator implies acceptance of potential 
audits or inspections, including source data verification, by representatives designated by 
the DF/HCC Overall Principal Investigator (or Protocol Chair) or DF/HCC. The purpose 
of these audits or inspections is to examine study-related activities and documents to 
determine whether these activities were conducted and data were recorded, analyzed, and 
accurately reported in accordance with the protocol, institutional policy, Good Clinical 
Practice (GCP), and any applicable regulatory requirements. 
 
All data will be monitored for timeliness of submission, completeness, and adherence to 
protocol requirements. Monitoring will begin at the time of participant registration and 
will continue during protocol performance and completion.  
 
14. REGULATORY CONSIDERATIONS 
14.1 Protocol Review and Amendments 
This protocol, the proposed informed consent and all forms of participant information 
related to the study (e.g., advertisements used to recruit participants) and any other 


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necessary documents must be submitted, reviewed and approved by a properly 
constituted IRB governing each study location.  
 
Any changes made to the protocol must be submitted as amendments and must be 
approved by the IRB prior to implementation. Any changes in study conduct must be 
reported to the IRB. The DF/HCC Overall Principal Investigator (or Protocol Chair) 
will disseminate protocol amendment information to all participating investigators.  
All decisions of the IRB concerning the conduct of the study must be made in 
writing. 
14.2 Informed Consent 
 
All participants must be provided a consent form describing this study and providing 
sufficient information for participants to make an informed decision about their 
participation in this study. The formal consent of a participant, using the IRB approved 
consent form, must be obtained before the participant is involved in any study-related 
procedure. The consent form must be signed and dated by the participant or the 
participant’s legally authorized representative, and by the person obtaining the 
consent. The participant must be given a copy of the signed and dated consent 
document. The original signed copy of the consent document must be retained in the 
medical record or research file.  
14.3 Ethics and Good Clinical Practice (GCP) 
This study is to be conducted according to the following considerations, which 
represent good and sound research practice: 
• 
US Code of Federal Regulations (CFR) governing clinical study conduct and ethical 
principles that have their origin in the Declaration of Helsinki. 
o Title 21 Part 50 – Protection of Human Subjects 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr50_02.html 
o Title 21 Part 54 – Financial Disclosure by Clinical Investigators 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr54_02.html 
o Title 21 Part 56 – Institutional Review Boards 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr56_02.html 
o Title 21 Part 312 – Investigational New Drug Application 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr312_02.html 
• 
State laws 


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• 
DF/HCC research policies and procedures        
http://www.dfhcc.harvard.edu/clinical-research-support/clinical-research-unit-
cru/policies-and-procedures/ 
It is understood that deviations from the protocol should be avoided, except when 
necessary to eliminate an immediate hazard to a research participant. In such case, 
the deviation must be reported to the IRB according to the local reporting policy.  
14.4 Study Documentation 
 
The investigator must prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each 
research participant. This information enables the study to be fully documented and the 
study data to be subsequently verified. 
 
Original source documents supporting entries in the case report forms include but are 
not limited to hospital records, clinical charts, laboratory and pharmacy records, 
recorded data from automated instruments, microfiches, photographic negatives, 
microfilm or magnetic media, and/or x-rays.  
14.5 Records Retention 
 
All study-related documents must be retained for the maximum period required by 
applicable federal regulations and guidelines or institutional policies.  
15. STATISTICAL CONSIDERATIONS 
15.1 Study Design/Endpoints 
 
This is an open label neoadjuvant study in subjects with malignant pleural 
mesothelioma. Defactinib will be administered at 400 mg twice daily for 12+/- 2 days 
in cohort 1, for 35+/- 2 days in cohort 2, for 21+/- 2 days in cohort 3, or at 100 mg 
twice daily (new formulation) for 21+/- 2 days in cohort 4.  For each patient, a pre-
treatment biopsy will be collected prior to the first dose of defactinib and a post-
treatment biopsy will be collected within 2-4 hours post the last dose on Day 12 (+/-2 
days) in cohort 1, on Day 35 (+/-2 days) in cohort 2 or on Day 21 (+/-2 days) in cohort 
3 and 4. 
15.2 Primary Objective 
 
The primary aim is to assess the biomarker responses to a FAK inhibitor in tumor and 
surrogate tissues obtained from pre and post treatment biopsies, including inhibition of 
phospho-FAK, alterations in markers of cell cycle, immunomodulation, and apoptosis as 
well as changes in cancer stem cells.  
 
A useful biomarker must demonstrate very high activity in the molecularly targeted group 
while providing no information on other patients, thus a biomarker response rate of 10% 


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may be specified as an upper bound in the non-target group. The power available to 
detect a difference in biomarker response depends on the total number of pre- and post-
treatment biopsy pairs as well as the underlying frequency among untreated specimens. 
Assuming paired biopsies were obtained from 80% of patients, 83% power is achieved to 
detect a biomarker response rate of 55% in a molecular subgroup if the biomarker 
frequency were as high as 50%. In contrast, 81% power is attained to detect a biomarker 
response rate of 80% in a molecular subgroup if the biomarker frequency were as low as 
10%. A one-sided test is used at 0.10 level, as biomarker responses are expected only in 
molecular subgroups along the targeted pathways of defactinib. Due to longer exposure, 
cohorts 2 and 3 may show larger differences in biomarker change between pre- and post-
treatment biopsies. Thus, the three cohorts will be summarized separately as well as 
pooled based on the appropriateness of the biomarker data. 
 
Biomarker responses will be analyzed between histologic subtypes and by the extent of 
disease based on our published criteria. On the other hand, the other analyses will be 
considered exploratory due to limited power, as epitheliod tumors are the dominant 
histology and a majority of patients are classified with poor prognosis.   
15.3 Sample Size/Accrual Rate 
 
Patients may be replaced if they were terminated from the protocol due to failure to 
receive at least approximately 80% of the planned treatment within the 12, 21 or 35-day 
indicated period. The protocol will replace treated patients who do not proceed to the 
second biopsy post-treatment. In order to account for cases without paired biopsies as 
well as assay failures, the target accrual is a total of up to 43 patients. 
15.4 Analysis of Secondary Endpoints 
 
a. The safety of defactinib will be assessed until 30 (cohort 1) or 7 (cohort 2, 3 and 4) 
days following the last dose of defactinib or until definitive surgery, whichever occurs 
first. Adverse events will be graded by the CTCAE 4.0 and summarized according to 
the worst grade observed since the first treatment dose. The rates of specific toxicities 
will be reported with 95% exact confidence intervals based on the exact binomial 
distribution separately by cohort as well as across all treated patients. 
 
b. Plasma concentrations of defactinib will be determined over a 24-hour period on Day 
11 for pharmacokinetic analysis. Cohorts 1 and 2 will be pooled for pharmacokinetic 
analysis. Cohorts 4 pharmacokinetic analysis will be done separately. The additional 
Day 35 and 42 samples in cohort 2 and the Day 21 and 28 samples in cohort 3 and 4 
will be summarized separately.  The observed (e.g. peak and trough concentrations) and 
derived (e.g. AUC, clearance, elimination half-life) parameters will be characterized by 
average and variation summaries in the patient population. Samples collected may also 
be tested for potential defactinib metabolites. 
 
c. Tumor response will be assessed by the PET-CT performed in conjunction with the 
post-treatment core biopsy according to the criteria in Section 11.1. The response rate 


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will be reported for with 95% exact confidence intervals based on the exact binomial 
distribution separately by cohort as well as across all treated patients. 
15.5 Reporting and Exclusions 
15.5.1 Evaluation of toxicity. All participants will be evaluable for toxicity from the time 
of their first treatment dose. 
 
16. PUBLICATION PLAN 
 
The results should be made public within 24 months of the end of data collection. If a report is 
planned to be published in a peer-reviewed journal, then that initial release may be an abstract 
that meets the requirements of the International Committee of Medical Journal Editors. A full 
report of the outcomes should be made public no later than three (3) years after the end of data 
collection.  
 
 
 


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to paclitaxel. Cancer Res 2007;67:1979–87. 
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Section 3.3: 
[1] Siu L, Burris H, Mileshkin L, et al. A phase 1 clinical, pharmacokinetic (PK) and 
pharmacodynamic (PD) evaluation of PF-00562271 targeting focal adhesion kinase (FAK) in 
patients with advanced solid tumors, J Clin Oncol 26: 2008 (May 20 supplement); abstract 
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Semin Thorac Cardiovasc Surg. 2009 Summer;21(2):188-93. Review. 
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vitro chemotherapeutic drug resistance in primary malignant pleural mesothelioma: result in a 
cohort of 203 resection specimens. J Thorac Cardiovasc Surg. 2010 Aug;140(2):352-5. 
[5] D.J. Sugarbaker, R.M. Flores, M.T. Jaklitsch et al. Resection margins, extrapleural nodal 


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status, and cell type determine postoperative long-term survival in trimodality therapy of 
malignant pleural mesothelioma: Results in 183 patients. J Thorac Cardiovasc Surg, 117 
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Oncology, Williams and Wilkins, Baltimore, MD (1996), pp. 786–798 
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Characteristics of malignant pleural mesothelioma in women. Ann Thorac Surg. 2010 
Sep;90(3):949-56; discussion 956. 
[8] G.J.Gordon,R.V.Jensen,L.L.Hsiao,S.R.Gullans,J.E.Blumenstock,W.G.Richards,M.T. 
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Differentially expressed alternatively spliced genes in malignant pleural mesothelioma 
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[12] Gordon GJ, Jensen RV, Hsiao LL, et al: Translation of microarray data into clinically 
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[13] Gordon GJ, Deters LA, Nitz MD, et al: Differential diagnosis of solitary lung nodules 
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[14] Gordon GJ, Richards WG, Sugarbaker DJ, et al: A prognostic test for adenocarcinoma of 
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2003 41. 
[15] Ma XJ, Wang Z, Ryan PD, et al: A two-gene expression ratio predicts clinical outcome in 
breast cancer patients treated with tamoxifen. Cancer Cells 5:607-616, 2004 [16] Ankerst DP, 
Groskopf J, Day JR, et al: Predicting prostate cancer risk through incorporation of prostate 
cancer gene 3. J Urol 180:1303- 1308, 2008, discussion, 1308 [17]  Deras IL, Aubin SM, 
Blase A, et al: 3: A molecular urine assay for predicting prostate biopsy outcome. J Urol 
179:1587-1592, 2008. 
[18] Gordon GJ, Rockwell GN, Godfrey PA, et al: Validation of genomics- based prognostic 
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[19] Bueno R, Gordon GJ. Genetics of malignant pleural mesothelioma: molecular markers 
and biologic targets. Thorac Surg Clin. 2004 Nov;14(4):461-8. Review. 
[20] Melaiu O, Cristaudo A, Melissari E, Di Russo M, Bonotti A, Bruno R, Foddis R, 
Gemignani F, Pellegrini S, Landi S. A review of transcriptome studies combined with data 
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[21] De Rienzo A, Dong L, Yeap BY, Jensen RV, Richards WG, Gordon GJ, Sugarbaker DJ, 
Bueno R. Fine-needle aspiration biopsies for gene expression ratio-based diagnostic and 
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[22] Esserman LJ, Berry DA, Cheang MC, Yau C, Perou CM, Carey L, DeMichele A, Gray 
JW, Conway-Dorsey K, Lenburg ME, Buxton MB, Davis SE, van't Veer LJ, Hudis C, Chin K, 
Wolf D, Krontiras H, Montgomery L, Tripathy D, Lehman C, Liu MC, Olopade OI, Rugo HS, 
Carpenter JT, Livasy C, Dressler L, Chhieng D, Singh B, Mies C, Rabban J, Chen YY, Giri 
D, Au A, Hylton N; I-SPY 1 TRIAL Investigators. Chemotherapy response and recurrence-
free survival in neoadjuvant breast cancer depends on biomarker profiles: results from the I-
SPY 1 TRIAL (CALGB 150007/150012; ACRIN 6657). Breast Cancer Res Treat. 2012 
Apr;132(3):1049-62. Epub 2011 Dec 25. 
[23] Barker AD, Sigman CC, Kelloff GJ, Hylton NM, Berry DA, Esserman LJ. 
I-SPY 2: an adaptive breast cancer trial design in the setting of neoadjuvant chemotherapy. 
Clin Pharmacol Ther. 2009 Jul;86(1):97-100. Epub 2009 May 13. 
 


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18. APPENDICES 
Appendix A: Performance Status Criteria 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Description 
Percent 
Description 
0 
Normal activity. Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
1 
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; 
some signs or symptoms of 
disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active 
work. 
2 
In bed < 50% of the time. 
Ambulatory and capable of all self-
care, but unable to carry out any 
work activities. Up and about more 
than 50% of waking hours. 
60 
Requires occasional assistance, 
but is able to care for most of 
his/her needs. 
50 
Requires considerable assistance 
and frequent medical care. 
3 
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care 
and assistance. 
30 
Severely disabled, 
hospitalization indicated. Death 
not imminent. 
4 
100% bedridden. Completely 
disabled. Cannot carry on any self-
care. Totally confined to bed or 
chair. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly.  
5 
Dead. 
0 
Dead. 
 
 
 
 


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Appendix B:  Examples of Substrates OF CYP2C9 and CYP3A4 
 
Substrates of CYP2C9  
Substrates of CYP3A4 
Celecoxib 
Phenytoin 
Tolbutamide  
Warfarin 
 
Alprazolam 
Astemizole 
Buspirone 
Calcium Channel Blockers 
Carbamazepine 
Cisapride 
Cyclosporine 
Doxorubicin 
Erythromycin 
Etoposide 
Felodipine 
Fentanyl 
HIV protease inhibitors 
Ifosphamide 
Lovastatin (not prevastatin) 
Midazolam 
Nifedipine 
Pimozide 
Quinidine 
Quinine 
Simvastatin 
Tacrolimus 
Terfenadine 
Triazolam 
 
 
1Note that this is not an exhaustive list.  Additional information on drugs and possible interactions 
can be found at http://www.drugs.com. 
 
 
 
 


VS-6063-203 V7.0 
 
 
15DEC2017 
 
Confidential                                                                                                                 Page 63 of 63 
Appendix C:  Examples of strong Inhibitors and Inducers of CYP2C9 and CYP3A4  
 
Inhibitors of CYP2C9  
Inhibitors of CYP3A4 
fluconazole 
miconazole 
amentoflavone   (constituent of 
Ginkgo biloba and St. John’s Wort) 
sulfaphenazole 
valproic acid 
 
ritonavir 
indinavir 
nelfinavir 
saquinavir 
clarithromycin 
telithromycin 
chloramphenicol  
ketoconazole 
itraconazole 
nefazodone 
 
Inducers of CYP2C9 
Inducers of CYP3A4 
rifampicin 
secobarbital 
 
carbamazepine 
phenytoin 
oxcarbazepine 
phenobarbital 
St. John's wort 
rifampicin 
rifabutin 
efavirenz 
nevirapine 
pioglitazone 
troglitazone 
glucocorticoids 
modafinil 
 
 
1Note that this is not an exhaustive list.  Additional information on drugs and possible interactions 
can be found at http://www.drugs.com.