A Phase 2 Study of Defactinib and Avutometinib, in Combination With Nivolumab for Patients With Anti-PD1 Refractory LKB1-Mutant Advanced Lung Adenocarcinoma
Phase: PHASE2
Conditions: Advanced Lung Adenocarcinoma, Refractory Lung Adenocarcinoma, Stage III Lung Cancer AJCC v8, Stage IV Lung Cancer AJCC v8
Sponsor: Emory University

Protocol Title:  A Phase 2 Study of Defactinib and Avutometinib, in Combination with Nivolumab for 
patients with anti-PD1 refractory LKB1-Mutant Advanced Lung Adenocarcinoma 
 
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PROTOCOL TITLE: A Phase 2 Study of Defactinib and Avutometinib, in Combination with Nivolumab 
for patients with anti-PD1 refractory LKB1-Mutant Advanced Lung Adenocarcinoma 
 
WINSHIP PROTOCOL #: WINSHIP5947-23 
 
COORDINATING CENTER: Winship Cancer Institute at Emory University 
 
 
 
PRINCIPAL INVESTIGATOR:  
 
 
CO-PRINCIPAL INVESTIGATOR:       
Suresh S. Ramalingam, MD 
Professor 
Director of the Winship Cancer Institute 
Emory University 
Winship Cancer Institute 
1365 Clifton Road NE 
Atlanta, GA 30322 
Phone: 404-778-5378 
Fax: 404-778-5520 
Email: suresh.ramalingam@emory.edu 
 
 
Conor E. Steuer 
Associate Professor 
Emory University 
Winship Cancer Institute 
1365 Clifton Road NE 
Atlanta, GA 30322 
Phone: 404-778-5378 
Fax: 404-778-5520 
Email: csteuer@emory.edu 

Protocol Title:  A Phase 2 Study of Defactinib and Avutometinib, in Combination with Nivolumab for 
patients with anti-PD1 refractory LKB1-Mutant Advanced Lung Adenocarcinoma 
 
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CO-INVESTIGATORS: 
Jennifer Carlisle, MD 
Ticiana Leal, MD 
Badi El-Osta, MD 
Wei Zhou, PhD 
Adam Marcus, PhD 
Department of Hematology and Medical Oncology 
Emory University 
Atlanta, GA 
 
STATISTICIAN: 
Yuan Liu, PhD 
Biostatistics Core 
 
Winship Cancer Institute  
 
 
 
VERSION: 4; 9/9/2025 
 
 
 
FUNDING SOURCE: NCI Lung Cancer P01 CA257906; Project 003(003) 
 
STUDY SUPPORTER: Verastem, Inc. (providing Defactinib and Avutometinib) 
 
INVESTIGATIONAL PRODUCT (IP): Defactiniband Avutometinib,   
OTHER AGENT(S): Nivolumab  
 
SPONSOR -INVESTIGATOR (IND HOLDER): Conor Steuer, MD 
 
IND # 168683 
 
 
REVISION HISTORY 
 
Revision # 
Version 
Date 
Summary of Changes 
1 
5-13-24 
Page 11: Reference to how Nivolumab will be supplied. 
Page 14: Sentences removed related to Avutometinib 
Page 17: Risks add to does modifications and management 
guidance for specific toxicities 
Page 18: Management addition regarding 
hyperbilirubinemia 
Page 19: Removal of maximum number of dose reductions 
related to creatine phosphokinase elevation 

Protocol Title:  A Phase 2 Study of Defactinib and Avutometinib, in Combination with Nivolumab for 
patients with anti-PD1 refractory LKB1-Mutant Advanced Lung Adenocarcinoma 
 
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Page 20: Removal of dose modification instruction for 
Grade2 other toxicities; Grade 1, 2, 3, 4 footnotes added. 
Page 22: Grades 1-4 added to Ocular findings in Retinal 
Toxicities table 
Page 25: BCRP Inhibitors/Inducers row added to 
Concomitant Therapies Restrictions table 
Page 6: stk11 is equal to 1kb 1 
Page 36: Participants must receive prior authorization from 
their insurance companies to cover nivolumab prior to 
enrollment on study. 
 
 
 
 
2 
5-20-25 
Opened enrollment to any line of therapy after platinum 
chemotherapy and immunotherapy. 
3 
9-9-25 
Decrease CRCL inclusion to 50, and increase qtc to 470  
 
 
 

Protocol Title:  A Phase 2 Study of Defactinib and Avutometinib, in Combination with Nivolumab for 
patients with anti-PD1 refractory LKB1-Mutant Advanced Lung Adenocarcinoma 
 
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Table of Contents 
1. 
Study Summary ...................................................................................................................................... 5 
2. 
Objectives (and Endpoints) ..................................................................................................................... 8 
3. 
Background ............................................................................................................................................ 8 
4. 
Study Intervention/Investigational Agent ............................................................................................. 11 
5. 
Procedures Involved ............................................................................................................................. 13 
6. 
Statistical Considerations ...................................................................................................................... 30 
7. 
Sharing of Results with Participants ...................................................................................................... 33 
8. 
Study Timelines .................................................................................................................................... 33 
9. 
Inclusion and Exclusion Criteria ............................................................................................................. 34 
10. Vulnerable Populations ........................................................................................................................ 37 
11. Local Number of Participants ................................................................................................................ 37 
12. Recruitment Methods ........................................................................................................................... 37 
13. Withdrawal of Participants ................................................................................................................... 38 
14. Study Stopping Criteria ......................................................................................................................... 38 
15. Risks to Participants .............................................................................................................................. 38 
16. Potential Benefits to Participants .......................................................................................................... 39 
17. Data Management and Confidentiality ................................................................................................. 39 
18. Provisions to Monitor the Data to Ensure the Safety of Participants ..................................................... 41 
Adverse Event Characteristics ............................................................................................................... 44 
19. Provisions to Protect the Privacy Interests of Participants ..................................................................... 47 
20. Economic Burden to Participants .......................................................................................................... 48 
21. Consent Process .................................................................................................................................... 48 
22. Setting…………………………………………………………………………………………………………………………………………………50 
23. Resources Available .............................................................................................................................. 50 
24. References ………………………………………………………………………………………………………………………………………….51 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ....................................................................................... 55 
APPENDIX B  
Drug Diary .......................................................................................................................... 56 
APPENDIX C   Abbreviations and definition of terms ..................................................................................... 56 
Appendix D. GUIDANCE on Inhibitors, Inducers, and Substrates .................................................................... 60 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol Title:  A Phase 2 Study of Defactinib and Avutometinib, in Combination with Nivolumab for 
patients with anti-PD1 refractory LKB1-Mutant Advanced Lung Adenocarcinoma 
 
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1. Study Summary 
1.1 Synopsys 
Title: 
A Phase 2 Study of Defactinib and Avutometinib, in Combination with Nivolumab 
for patients with anti-PD1 refractory LKB1-Mutant Advanced Lung 
Adenocarcinoma 
Study 
Description: 
 
Two cohorts of patients will be enrolled: Cohort A: patients with LKB1 and KRAS mutation; 
Cohort B: LKB1 mutation without concomitant KRAS mutation. The efficacy of the 
combination regimen will be evaluated in both cohorts individually.  
Objectives: 
 
Primary Objective:    
The primary objective of the phase II study is to determine the efficacy (6-months 
PFS rate) of Defactinib and Avutometinib when combined with the, Nivolumab in 
patients with LKB1 mutated lung adenocarcinoma.  
Secondary Objectives: 
1. To determine the toxicity profile of defactinib and  avutometinib  in combination 
with nivolumab  
2. To assess the response rate (RECIST) and overall survival 
3. To identify biomarkers in tumor tissue that predict for a favorable or unfavorable 
outcome  
Exploratory Objective: 
To evaluate the effect of treatment on selected biomarkers (Pyk2/FAK and 
MEK/ERK) in the tumor microenvironment and systemic circulation. 
 
Endpoints: 
Primary Endpoint:   
Efficacy as measured by 6-month PFS rate 
 
Secondary Endpoints:  
Safety, PFS, OS, duration of overall response (DOR) 
Study 
Population: 
25 patients will be enrolled in each of the two cohorts; The initial 10 patients will be used 
for a safety-run if deemed to be safe. For each cohort separately, a time-to-Event Bayesian 
optimal phase 2 (TOP) design will be carried out with two planned interim analyses for 
futility assessment. The design holds a maximum statistical power of 85% under 0.1 type I 
error to reject null hypothesis of 25% 6-mo PFS rate if the underlying rate is over 50%. 
Histological confirmation of non-squamous NSCLC, LKB1 mutation, disease progression on 
prior immune checkpoint inhibition, ECOG Performance status of 0/1, adequate hepatic, 
renal and bone marrow function, ability to take oral medications on a regular basis, and 
willingness to sign informed consent.  Patients with treated and stable brain metastasis 

Protocol Title:  A Phase 2 Study of Defactinib and Avutometinib, in Combination with Nivolumab for 
patients with anti-PD1 refractory LKB1-Mutant Advanced Lung Adenocarcinoma 
 
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Study Population 
 
- 
LKB1-Mutant Lung 
Adenocarcinoma 
- 
Advanced 
- 
Measurable disease 
- 
Refractory to prior PD1 
therapy 
 
 
**STK11 =’s LBK1 
 
 
 
1.2  Schema 
 
                                                          
 
 
Nivolumab  
480mg intravenously once on 
Day 1 of each 28-day cycle  
 
 
will be eligible. Patients that suffered a clinically significant immune AE with prior 
immunotherapy will be excluded. This study is hypothesis generation, not a registrational 
study.  
 
Phase: 
Phase II 
Description of 
Sites/Facilities 
Enrolling 
Participants: 
Winship Cancer Institute of Emory University (Atlanta, GA).  
Description of 
Study 
Intervention: 
Eligible patients will be initiated on therapy with defactinib (oral administration) 200mg 
orally twice daily for 21 days of each 28-day cycle,  Avutometinib 3.2 mg orally twice weekly 
for 21 days of each  28-day cycle,  in combination with nivolumab 480 mg iv on day 1 of 
each cycle.  Treatment cycles will be repeated every 4 weeks. Treatment will be continued 
until disease progression or unacceptable toxicity.  
During treatment, scans will be every 8 weeks (2 cycles) for cycles 1-4, then every 3 cycles 
afterwards. The RECIST criteria will be utilized (version 1.1) for response assessment. 
Toxicity will be graded by NCI CTC version 5.0.  
Archived tumor samples will be obtained from all the study participants, but is not a 
requirement for study entry; on study repeat biopsy will be optional in each cohort 
during the second stage of accrual (statistical design). Biomarker studies will be 
conducted on the tumor samples and peripheral blood collections.  
Study Duration: 
How long subjects remain on study treatment depends on how well the cancer responds 
and how well subjects are able to tolerate any side effects. Subjects will continue to receive 
study drug as long as there is a benefit from it. Subjects will be contacted every 3 months 
for up to 5 years upon leaving the study. 
Defactinib 
200mg orally twice daily for 21 
days of each 28-day cycle 
Avutometinib 
3.2 mg orally twice weekly for 
21 days of each  28-day cycle 

Protocol Title:  A Phase 2 Study of Defactinib and Avutometinib, in Combination with Nivolumab for 
patients with anti-PD1 refractory LKB1-Mutant Advanced Lung Adenocarcinoma 
 
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1.3 Schedule of Assessments 
 
Pre-Study 
Cycle 1f 
All Subsequent cycles 
EOT 
 
28 days 
Wk 1 
Wk 2 
Wk 3 
Wk 1 
Wk 2 
Wk 3 
 
Defactinib (twice daily) 
 
X 
X 
X 
X 
X 
X 
 
Nivolumab (day 1)  
 
X 
 
 
X 
 
 
 
Avutometinib (twice 
weekly) 
 
X 
X 
X 
X 
X 
X 
 
Informed consent 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
Concurrent meds 
--------------X---------------- 
 
Physical exam 
X 
X 
 
X 
X 
 
 
X 
Vital signs 
X 
X 
 
X 
X 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
X 
 
 
X 
Performance status 
X 
X 
 
 
X 
 
 
X 
CBC w/diff, plts 
X 
X 
 
X 
X 
 
 
X 
Serum chemistry, TSH, 
CPK 
X 
X 
 
X 
X 
 
 
X 
PT, PTT and INR 
X 
 
 
 
 
 
 
 
EKG  
X 
 
 
 
 
 
 
 
Adverse event 
evaluation 
---------------------X--------------------- 
X 
Tumor measurements 
X 
Xe 
 
Radiological evaluation 
X 
Xe 
 
Pregnancy test 
Xa 
 
 
 
Xa 
 
 
Xa 
Ophthalmologic 
examination 
Xg 
C2D1, C5D1, and every 3 cycles (+/- 5 days)g 
Tumor biopsy  
Xb 
 
 
X 
 
 
 
 
Tumor Genomic 
testing 
Xd 
 
 
 
 
 
 
 
Peripheral blood 
X 
X 
 
 
Xc 
 
 
 
a: In women of reproductive age and have not undergone hysterectomy. Urine or blood test is acceptable 
b; Baseline tumor samples will be provided from archived tissue or optional biopsy. This is not a requirement to enter study. 
Optional biopsy can be performed at c2d1 +/- 1 week 
c: will be collected during screening on day 1 of cycle 1, 2, 3, 4 and at progression for correlative studies 
d. This will be done as per clinical standard of care, and previous results acceptable demonstrating LKB1 and/or KRAS as per 
cohort. This will be done on validated next generation sequencing platforms. Any FDA approved NGS will be acceptable. 
These will typically be commercially available platforms, most common at our institution will be Caris testing 
e. Scans include PET scans or ct chest and abdomen. During treatment, scans will be every 8 weeks (2 cycles) for cycles 1-4, 
then every 3 cycles afterwards. 
f. All on treatment assessments have a +/- 2 day window 
g. Ophthalmological examination by an ophthalmologist must be conducted. If an ophthalmologist is not available, a qualified 
optometrist may conduct the examination, but the results must be reviewed by an ophthalmologist within 72 hours. This 
must be performed at Baseline (within 28 days prior to first dose, at C2D1, C5D1, and every 3 cycles thereafter), and urgently 

Protocol Title:  A Phase 2 Study of Defactinib and Avutometinib, in Combination with Nivolumab for 
patients with anti-PD1 refractory LKB1-Mutant Advanced Lung Adenocarcinoma 
 
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at any time on-treatment as clinically indicated. The results of the baseline examination must be available prior to dosing. 
Ophthalmologic examination must include visual acuity testing, slit lamp examination of the anterior eye segment, 
intraocular pressure, dilated fundoscopy, and retinal optical coherence tomography (OCT). 
 
 
2. Objectives (and Endpoints) 
 
OBJECTIVES 
ENDPOINTS 
Primary 
 
 
- 
The primary objective of the phase II study is 
to determine the efficacy (6-months PFS 
rate) of defactinib and avutometinib when 
combined with nivolumab in patients with 
LKB1 mutated lung adenocarcinoma. 
 
The primary endpoint is the 6m PFS rate. 
The rate will be calculated with an 95% 
confidence interval using Kaplan-Meier 
method based on the efficacy evaluable 
population. Patients who fail to have a 
response assessment for other reasons 
(e.g., refusal due to travel constraints) will 
be considered unevaluable and will not be 
included 
in 
the 
denominator 
when 
calculating the rate. 
 
Secondary 
 
 
- 
To evaluate response rate, overall survival 
and toxicity assessment.  
 
For progression-free survival (PFS) and 
overall survival (OS), the Kaplan-Meier 
method will be used to estimate the median 
event-free time with 95% confidence 
interval. For the duration of overall 
response, summary statistics will be used to 
describe the mean and median duration of 
response. 
 
Tertiary/Exploratory  
 
 
Biomarker evaluation will be conducted on 
archived tumor samples and on-study 
biopsies obtained in a subset of patients. 
         
Analysis of Biomarker Correlative  
 
 
3. Background 
 

Protocol Title:  A Phase 2 Study of Defactinib and Avutometinib, in Combination with Nivolumab for 
patients with anti-PD1 refractory LKB1-Mutant Advanced Lung Adenocarcinoma 
 
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Lung cancer is the leading cause of cancer related deaths in the United States with more than 225,000 cases 
diagnosed annually. More than 85% of the patients have non-small cell lung cancer that includes 
adenocarcinoma, squamous cell carcinoma, large cell carcinoma and bronchioloalveolar carcinoma. Nearly 50% 
of the patients with advanced NSCLC present with advanced stage disease.  
 
Systemic therapy remains the mainstay of treatment of advanced stage NSCLC. Combination chemotherapy with 
a platinum-based regimen had remained as the standard therapy for patients with advanced stage disease until 
recently 1. Improvements in overall survival and quality of life have been demonstrated with platinum-based 
regimens over supportive care alone in randomized clinical trials 2. Among the platinum compounds, both 
cisplatin and carboplatin have been extensively studied for the treatment of NSCLC. In general, carboplatin-based 
regimens have a favorable tolerability profile over cisplatin-based regimens 3, 4. Despite the marginally higher 
response rate with cisplatin-based regimens, considering the palliative intent of therapy, carboplatin-based 
regimens have found wide applicability in routine care. 
 
The optimal duration of treatment for patients with advanced NSCLC has been the subject of study ever since 
the role of chemotherapy was established 5, 6. Randomized studies that compared the use of combination 
chemotherapy for a defined number of cycles versus continuation until progression or higher number of courses 
failed to demonstrate an advantage for the latter approach. Therefore, administration of 4 to 6 cycles of 
combination chemotherapy followed by observation became the standard of care for first-line therapy of 
advanced NSCLC. With the advent of well-tolerated novel chemotherapeutic and molecularly targeted agents, 
recent studies have shown benefit of single agent maintenance therapy after achievement of maximal disease 
control with combination regimens.  
3.1 Study Rationale 
Personalized therapy for advanced NSCLC 
 
In recent years, the emergence of immune checkpoint inhibitors and novel targeted therapies have resulted in 
substantial improvements in outcome for advanced NSCLC. For patients with lung adenocarcinoma, molecular 
testing for treatable genetic alterations in EGFR, ALK, ROS1, B-RAF, RET, HER2, MET, KRAS and NTRK is considered 
the standard of care; for patients with these ‘treatable’ genetic alterations, molecularly targeted therapies 
provide high response rates and robust progression-free survival. We recently demonstrated that Osimertinib, 
an EGFR tyrosine kinase inhibitor, improves overall survival when used for the treatment of patients with EGFR 
exon 19 or 21 mutation 7. 
 
For patients without a ‘treatable’ genetic alteration, assessment of PD-L1 expression is routinely done by immune 
histochemistry; for tumors with PD-L1 expression > 50%, pembrolizumab used as monotherapy is a standard of 
care; for tumors with PD-L1 expression < 50%, pembrolizumab or atezolizumab are used in combination with 
platinum-based chemotherapy. These approaches have been shown to improve overall survival when compared 
to platinum-based chemotherapy alone 8, 9. Despite these improvements, robust and durable benefit is limited 
to approximately 20% of these patients.  
 
For patients that develop disease progression after immune checkpoint inhibition, the current standard approach 
is docetaxel in combination with ramucirumab, a VEGF-R2 targeted monoclonal antibody. This regimen provides 

Protocol Title:  A Phase 2 Study of Defactinib and Avutometinib, in Combination with Nivolumab for 
patients with anti-PD1 refractory LKB1-Mutant Advanced Lung Adenocarcinoma 
 
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modest improvements in PFS and OS. Development of more effective salvage therapy options for patients who 
develop disease progression on first line immunotherapy (+/- chemotherapy) remains a major research priority. 
Nivolumab currently is approved in the both the first and second line NSCLC space. 
 
Resistance to immune checkpoint inhibition 
 
A number of investigators are conducting research to determine the reasons behind why only a subset of patients 
respond to immune checkpoint inhibitors. For instance, patients with EGFR mutation do not achieve clinical 
benefit with immune checkpoint inhibition as monotherapy 10. Skoulidis et al 11 have demonstrated an intrinsic 
resistance to immune checkpoint inhibition in LKB1 and KRAS co-mutated NSCLC; LKB1 mutated tumors 
promoted resistance to PD-1 inhibition, while tumors with KRAS mutation alone responded well to immune 
checkpoint inhibition.  
 
Role of LKB1 and FAK in lung cancer 
 
The tumor suppressor LKB1 is a serine/threonine kinase that regulates lung cancer motility and metastasis. LKB1 
is mutated in 30% of NSCLC tumors and cell lines. LKB1 ranks as the 3rd most frequently mutated gene in lung 
adenocarcinoma after p53 and Ras12-14.  LKB1 activity is regulated by the pseudokinase STRADα and the 
scaffolding protein MO25 through a phosphorylation-independent mechanism. Our data show that LKB1 
regulates NSCLC cell polarity15 and phosphorylated focal adhesion kinase (FAK) during cell motility to oversee cell 
adhesion. FAK regulates cell migration and invasion through adhesion signaling16. FAK signals through integrins 
and growth factor receptors to relay cues from the extracellular matrix through the plasma membrane, and into 
the cytoplasm. FAK acts as a signaling node at cell adhesion sites called focal contacts to promote cytoskeletal 
reorganization, adhesion, migration, and survival16. A series of tyrosine phosphorylations controls FAK activation 
whereby ligand binding to a FAK-associated integrin autophosphorylates Y397-FAK17. This reveals a binding motif 
for SH2-domain-containing proteins such as Src, which further phosphorylates FAK at Y861, Y925, Y576, and Y577 18-
20. Thus, FAK phosphorylation at Y861 and Y397 are markers for FAK activation21. FAK mRNA and protein expression 
are increased in most cancers including colon, breast, and ovarian, and are most often associated with a more 
invasive phenotype22-26. In lung cancer, a retrospective analysis on 172 patients with lung adenocarcinoma 
showed that FAK positive patients (total FAK and not pY-FAK) had worse survival than FAK negative patients, 
where 88% of the cases were FAK positive27. Currently, there are several small molecule FAK inhibitors in 
development and Phase I clinical trials for the treatment of non-hematologic malignancies28-31  
3.2 Clinical Experience 
The combination of the 3.2 mg BIW avutometinib and 200 mg BID defactinib, administered 3 weeks of every 4-
week cycle, was selected based on the results of an IST (VS-6063-003, FRAME) that compared the safety of 3.2 
mg BIW avutometinib + 200 mg BID defactinib, 3.2 mg avutometinib + 400 mg BID defactinib and 4.0 mg 
avutometinib + 200 mg BID defactinib. There was a DLT of Grade 2 rash in 2 of 3 patients in receiving 3.2 mg 
avutometinib + 400 mg defactinib, while there were no DLTs with the other two regimens. Due to chronic 
Grade 2 toxicities in patients on treatment >6 months, the dose of 3.2 mg BIW avutometinib + 200 mg BID 
defactinib for 3 of 4 weeks was selected as the RP2D. The response rate in patients with KRAS mt low-grade 
serous ovarian cancer (LGSOC) was 64% (7 of 11 subjects with PR) and it was 46% (11 of 24 patients with PR) for 
all patients with recurrent LGSOC. Estimated median PFS across all LGSOC was 23 months (Banerjee et al., 

Protocol Title:  A Phase 2 Study of Defactinib and Avutometinib, in Combination with Nivolumab for 
patients with anti-PD1 refractory LKB1-Mutant Advanced Lung Adenocarcinoma 
 
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2021). Of the 18 evaluable patients with KRAS mt NSCLC, 3 patients (2 with KRAS G12V and 1 with KRAS G12C) 
achieved PR. Median PFS was 16 weeks and 7 patients received treatment for ≥24 weeks (Krebs et al., 2021). 
 
 
4. Study Intervention/Investigational Agent 
4.1 Description 
DEFACTINIB and AVUTOMETINIB are non-covalent Pyk2/FAK and RAF/MEK kinase inhibitors respectively, with 
nanomolar potency. Avutometinib and Defactinib are to be taken orally as capsules and as tablets, respectively. 
Nivolumab- will be given by infusion. All drugs will be given in a 28-day cycle. A study diary must be kept by 
patients when taking avutometinib and defactinib to determine their compliance in taking the investigational 
agents. 
The intracellular RAS-regulated RAF/MEK/ERK (MAPK) signaling cascade is the most mutated oncogenic pathway 
in human malignancies. Aberrant signaling through the RAS/RAF/MEK/ERK pathway drives tumor cell 
proliferation, differentiation, survival, and migration. 
Avutometinib is a dual inhibitor of RAF and MEK in the MAPK pathway and blocks both MEK kinase activity and 
the ability of RAF to phosphorylate MEK, in contrast to other MEK inhibitors in development and/or registered. 
This mechanism of sequential blockade enables avutometinib to block MEK signaling more consistently without 
the compensatory and paradoxical activation of MEK that precludes the efficacy of other small molecule 
inhibitors of MEK and RAF. 
Avutometinib was active in nonclinical in vitro and in vivo models against the validated anticancer targets RAF 
and MEK and combines these anticancer inhibitory activities in a single orally available compound. Avutometinib 
as a monotherapy has also demonstrated anticancer activity in two single-agent Phase 1 studies and two 
Investigator-sponsored studies (see the Avutometinib Investigator’s Brochure [IB] for details). 
Defactinib and other FAK inhibitor compounds (VS-6062 and VS-4718), as surrogates, have shown synergistic 
activity with BRAF and MEK inhibitors in both in vitro and in vivo preclinical solid tumor models (see the defactinib 
IB for details). In mouse models of BRAF-mutant (mut) melanoma, KRAS mut ovarian cancer, or uveal melanoma, 
FAK inhibition has been shown to induce tumor regression when combined with RAF, MEK or RAF/MEK inhibitors, 
respectively, while the single agents have only induced tumor stasis. 
The combination of avutometinib and defactinib has demonstrated nonclinical and clinical anticancer activity 
(see avutometinib IB for details). In vitro it was shown to produce additive or synergistic activity against solid 
tumors in several cell lines screening for synergy. The addition of defactinib to avutometinib therapy may also 
reduce the FAK -mediated adaptive resistance to MAPK inhibitors (Diaz Osterman 2019, Kang 2013, Tong 2019). 
Proof-of-concept safety and activity data in patients with advanced cancer are being gathered in Investigator-
sponsored trials (ISTs). In a Phase 1 clinical study (IST-VS-6766-002; CCR3808), avutometinib as a monotherapy 
has shown preliminary efficacy in patients with RAS/RAF-mut solid tumors, including gynecological cancers. In 5 
patients with RAS/RAF-mut gynecological cancers treated at a dose of 4 mg twice-weekly, 3 patients achieved a 
partial response (PR), including patients with KRAS mut LGSOC, BRAF mut LGSOC, and KRAS-mut endometrial 
cancer. The responses were greater than 6 months in duration. 
The combination of avutometinib and defactinib is currently being evaluated in patients with advanced solid 
tumors, including LGSOC, in the Investigator Sponsored FRAME study (IST-VS-6063-003; CCR4642, FRAME; 
EudraCT: 2017-001035-39). In the FRAME proof-of-concept study, there have been durable objective responses 
in patients with LGSOC with and without KRAS mutations following treatment with avutometinib 3.2 mg twice 

Protocol Title:  A Phase 2 Study of Defactinib and Avutometinib, in Combination with Nivolumab for 
patients with anti-PD1 refractory LKB1-Mutant Advanced Lung Adenocarcinoma 
 
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weekly for 3 weeks out of every 4 weeks and defactinib 200 mg twice daily for 3 weeks out of every 4 weeks 
(Banerjee 2021, Banerji 2020, Shinde 2020). 
Preliminary efficacy results from the FRAME study, as of an April 2021 data cut-off date, are available for a total 
of 24 LGSOC patients (Banerjee 2021). Specific observations included the following: 
• 
Overall response rate (ORR): 
o ORR in all patients with LGSOC = 46% (11 of 24 patients with confirmed partial response [PR] [2 
additional patients with unconfirmed PR]). 
o ORR in patients with KRAS-mut LGSOC = 64% (7 of 11 patients with confirmed PR [1 additional 
patient with unconfirmed PR]). 
o ORR in patients with KRAS-wt LGSOC = 44% (4 of 9 patients with confirmed PR). 
o ORR in patients with KRAS-undetermined LGSOC = 0 of 4 patients with confirmed PR and 1 of 4 
patients with unconfirmed PR. 
• 
Median progression-free survival (PFS) of 23 months. 
• 
Eight of the 11 patients with PR remained on study interventions as of the April 2021 data cut-off date. 
• 
Among the 13 patients with best response of stable disease (SD), 5 remained on study interventions as 
of the April 2021 data cut-off date. 
• 
Ten of 24 patients with LGSOC had previously received MEK inhibitors, including 4 patients with PRs (3 
confirmed, 1 unconfirmed). 
The developing results from the FRAME study support the potential of the avutometinib -defactinib combination 
for the treatment of patients with both KRAS-mut and -wt LGSOC. Overall, the demonstrated nonclinical and 
clinical anticancer activity of avutometinib monotherapy and in combination with defactinib in LGSOC justifies 
their comparison in the current study. 
Nivolumab, a monoclonal anti-PD-1 immunotherapeutic checkpoint inhibitor, is FDA approved for the 
treatment of squamous and non-squamous NSCLC. Of the second line treatment options currently available, 
immunotherapies more often result in prolonged benefit for a population of patients, with about 20% of 
patients having >12 month PFS. Despite this efficacy, there is an unmet need to find drugs which synergize 
immunologically to allow a larger proportion of patients to benefit long term from therapy. 
Nivolumab is active in the second line treatment of non-squamous NSCLC, as demonstrated in the trial 
CheckMate 057, Nivolumab versus Docetaxel in advanced non-squamous NSCLC. In this trial, nivolumab had an 
overall survival benefit compared with docetaxel. 
4.2 Drug/Device Handling 
The control of AVUTOMETINIB, DEFACTINIB will be accomplished by following an established approved 
Standard Operation Procedure (SOP) at Emory University Investigational Pharmacy (IDS). IDS will be used 
according to the pharmacist supplier to control handling, storage, ordering, receiving, and control of drugs and 
assure compliance with the standards of the U.S. Food and Drug Administration (FDA) and of the study sponsor. 
An Emory Investigator holds the IND and is considered to be a Sponsor-Investigator. 
 
NIVOLUMAB will be provided commercially. We have received IDS exemption for Nivolumab to be sourced via 
commercial pharmacy.  
 
4.3 Accountability 

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Drug accountability may be noted by the internal monitor during site visits and at the completion of the study. 
The study drug supply will be disposed of per Winship’s Investigational Drug Service (IDS) SOP. 
Compliance will be assessed by the investigator and/or study personnel at each patient visit. This information 
must be captured in the source document at each patient visit.  
 
Dose changes and interruptions of study drug must be specifically documented in the patient source 
documents and eCRF. 
 
The designated site personnel will be responsible for maintaining accurate records of the quantity and dates of 
all study drug supplies received, dispensed, and returned, in accordance with applicable regulations and the 
site’s SOPs.  The quantity of study drug lost, destroyed, or otherwise unaccounted for must also be accounted 
for and documented. The patient will be required to maintain a medication diary of each dose of medication.  
The medication diary (Appendix B) will be returned to clinic staff at the end of each cycle. 
Dose changes and interruptions of study drug must be specifically documented in the patient source 
documents and eCRF. 
 
 
5. Procedures Involved 
5.1 Study Design 
This is a phase II study to determine the efficacy of avutometinib and defactinib with nivolumab in patients with 
LKB1 mutated lung adenocarcinoma. Two cohorts of patients will be enrolled.  
 
Cohort A: Patients with LKB1 and KRAS co-mutation 
 
Cohort B: Patients with LKB1 mutation without KRAS mutation 
 
Enrollment to each cohort will proceed concurrently. 
 
25 patients will be enrolled in each of the two cohorts; The initial 10 patients will be used for a safety-run-in (5 
pts/cohort); if deemed to be safe. For each cohort separately, a time-to-Event Bayesian optimal phase 2 (TOP) 
design will be carried out with two planned interim analyses for futility assessment. The two planned interim 
analyses will be implemented after 10 and 20 patients have been treated.  
5.2 Dosing and Administration 
Treatment will be administered on an outpatient basis.  Reported adverse events and potential risks are 
described in Section 21.  Appropriate dose modifications are described below.  No investigational or commercial 
agents or therapies other than those described below may be administered with the intent to treat the patient's 
malignancy. 
 
Avutometinib  
 
• 
Avutometinib will be administered BIW PO (e.g., Monday/Thursday, Tuesday/Friday, or 
Wednesday/Saturday) for 3 weeks, followed by a 1-week rest period, in each 4-week (28-day) cycle. 
• 
Avutometinib should be swallowed whole with a glass of water (approximately 8 ounces or 240 mL). 
Patients should be advised not to open, break, or chew the capsules. 

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• 
Avutometinib should be administered with or without a meal.  
• 
In the event of emesis occurring after Avutometinib 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 date and time of the emesis in their dosing diary. 
• 
If a scheduled dose of Avutometinib is missed and less than 24 hours has passed the dose can be made 
up. If more than 24 hours have passed the patient should not attempt to make up the dose and should 
proceed to the next scheduled dose. Patients should enter any missed or made-up doses including the 
reason the dose was missed in the dosing diary, as applicable. 
• 
Patients must avoid grapefruit, grapefruit juice, St. John’s Wort and other medications (with or without 
prescriptions), supplements, herbal products or foods that are strong inhibitors or inducers of CYP3A4 
while on Avutometinib. Please see table 7 for additional information on restrictions on the use of CYP 
3A4 inhibitors, inducers, and substrates, and Appendix D for a list CYP3A4 inhibitors, inducers, and 
substrates. 
• 
Refer to the Pharmacy Manual for additional instructions regarding Avutometinib administration. 
 
Defactinib 
 
• 
Defactinib will be administered BID PO for 3 weeks, followed by a 1-week rest period, in each 4-week 
(28-day) cycle. 
• 
Defactinib should be swallowed whole with a glass of water (approximately 8 ounces or 240 mL). Advise 
patients not to break or chew the tablets 
• 
Defactinib should be administered within 30 minutes following a meal.  
• 
In the event of emesis occurring after defactinib 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 date and time of the emesis in their dosing diary. 
• 
If a scheduled dose of defactinib is missed and less than 6 hours have passed since the scheduled dosing 
time, patient should immediately take the missed dose. If more than 6 hours have passed since the 
scheduled dosing time, patient should not take the missed dose. Patient should wait and take the next 
regularly scheduled dose. 
• 
Patients must avoid grapefruit, grapefruit juice, St. John’s Wort and other medications (with or without 
prescriptions), supplements, herbal products or foods and that are strong inhibitors or inducers of 
CYP2C9, CYP3A4, or P-gp while on defactinib. Please see Table 7 for additional information on restrictions 
on the use of CYP2C9, CYP 3A4, and P-gp inducers, and substrates, and Appendix D for lists of CYPC9, 
CYP3A4, and P-gp inhibitors, inducers, and/or substrates. 
• 
Refer to the Pharmacy Manual for additional instructions regarding defactinib administration. 
 
Defactinib will be given on a twice-daily oral schedule at a dose of 200 mg. The drug is to be taken with food. 
Each treatment cycle will include four weeks of therapy. Defactinib will be administered on a continuous daily 
schedule for 3 of 4 week cycle. Avutometinib, as a dose of 3.2mg, must be taken by mouth twice weekly for 3 
weeks of every 4 week cycle. Avutometinib is to be taken with or without food. Patients will be asked to complete 
a pill diary to document compliance. The medication diary will be returned to clinic staff at the end of each course. 
Patients will be evaluated before initiation of each new cycle of therapy. Nivolumab will be administered at a 
dose of 480mg IV once every four weeks. Treatment cycles will be repeated every 4 weeks. 

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Table 1: Study Interventions 
Study Interventions Intervention 
Name  
Avutometinib 
Defactinib  
Dosage Level(s) and Frequency  
• 3.2 mg BIW (combined with 
defactinib), 3 weeks of every 4--
week cycle  
 
200 mg BID (combined with 
avutometinib), 3 weeks of every 4-
week cycle  
Route of Administration  
Oral  
Oral  
Dose Formulation  
Capsule  
Tablet  
Unit Dose Strength(s)  
0.8 mg  
200 mg  
Number of Capsules/Tablets per 
Dose  
 
• 3.2 mg: 4 capsules  
 
200 mg: 1 tablet  
Formulation Excipients  
Excipients (mannitol and magnesium 
stearate) that are listed in the US 
FDA Inactive Ingredients Database 
for approved drug products and/or 
GRAS  
Excipients (microcrystalline 
cellulose, lactose monohydrate, 
sodium starch glycolate, and 
magnesium stearate) that are listed 
in the US FDA Inactive Ingredients 
Database for approved drug 
products and/or GRAS  
Abbreviations: BID: twice daily; FDA: Food and Drug Administration; GRAS: Generally Regarded as Safe  
  
 
Nivolumab Treatment 
Nivolumab 480mg IV will be administered once on Day 1 of each 28-day cycle.  
 
5.3 Toxicities and Definition of Dose-Limiting Toxicity  
Avutometinib 
• 
The most commonly reported treatment-emergent adverse events (TEAEs) (≥25%) regardless of 
causality for avutometinib monotherapy in Phase 1 study NO21895 included dermatitis acneiform and 
rash (67%), diarrhea (65%), blood CPK increased (58%), asthenia (46%), peripheral oedema (40%), 
nausea (38%), vision blurred (37%), constipation (33%), hypoalbuminemia (33%), vomiting (29%), AST 
increased (27%), stomatitis (27%) and pyrexia (25%). While not a frequent AE in the Phase 1 study 
NO21895, mucositis/mouth ulcer was seen in 38% of patients in IST-CCR3808.  
• 
The most common treatment-related TEAEs reported in IST-CCR3808 were rash (91%), CPK elevation 
(66%), visual abnormalities (45%), mucositis/mouth ulcer (39%), diarrhea (34%), fatigue (34%), limb 
oedema (30%), hypoalbuminemia (27%), nausea (25%), dry skin (23%), and fissures (20%).  
• 
The identified risks for avutometinib treatment are skin toxicity, eye toxicity, CPK elevation, 
gastrointestinal tract toxicities, and edema.  
• 
The potential risks are effects on the bone and cartilage, hematological toxicity, drug-drug interactions, 
liver function abnormalities, and tissue mineralization.  
 
Defactinib 

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• 
Frequent TEAEs (≥20%) regardless of causality with defactinib monotherapy in solid tumor patients as 
reported in the current IB include nausea (29%), fatigue (26%), diarrhea (25%), hyperbilirubinaemia 
combined with blood bilirubin increased (23%), and dyspnea (20%). 
• 
GI disorders were the most common type of treatment-related TEAEs as reported in IB ed 12, with 
nausea being the most common individual treatment-related TEAE (23%) and diarrhea (21%), and 
vomiting (14%) being among the most common. Other common treatment-related TEAEs included 
hyperbilirubinemia (25%), fatigue (21%), and decreased appetite (10%). 
• 
The only identified risk for defactinib treatment is hyperbilirubinemia/increased bilirubin. 
• 
The important potential risks for defactinib treatment are GI effects, drug-drug interactions, most 
specifically with strong inhibitors or inducers of CYP3A4 or CYP2C9, and interaction with warfarin. 
 
Nivolumab 
• 
Please see Nivolumab Package Insert.  
 
Overlapping Toxicities 
In Phase 1 FRAME study, no toxicities unique to the combination of avutometinib + defactinib were observed in 
the preliminary data from 52 patients treated with the combination as of 18 Mar 2020. GI disorders, especially 
nausea and diarrhea, are frequent TEAEs common to both avutometinib and defactinib. 
The most common treatment-related AEs observed in patients receiving the combination were rash (90%), CPK 
elevation (56%), hyperbilirubinaemia (42%), AST elevation (38%), fatigue (31%), glossitis/oral mucositis/mouth 
ulcers (31%), ALT elevation (29%), diarrhoea (29%), visual disturbance (29%), nausea (25%) and peripheral 
oedema (21%), most of which were Grades 1 or 2 and reversible. 
GI toxicities and drug-drug interactions with inhibitors or inducers of CYP3A4 are overlapping risks for 
avutometinib and defactinib. 
The combination of avutometinib, defactinib, and nivolumab has not been studied previously. Overlapping 
toxicities for the three agents may not be known.  
 
DLT DEFINITIONS 
All adverse events will be graded according to NCI CTCAE v. 5.0 with attribution. To be evaluable for DLT, 
patient must receive at least 66% of the planned doses of defactinib, avutometinib, and nivolumab i.e. 14 of 28 
days in cycle 1. A DLT is defined as a clinically significant AE or laboratory abnormality that meets any of the 
following criteria within the first cycle: 
▪ Grade 4 hematologic toxicity (excluding anemia) lasting more than 7 days 
▪ Grade 3 anemia lasting more than 7 days or requiring blood transfusion 
▪ Grade 4 anemia regardless of duration 
Grade ≥3 thrombocytopenia if associated with clinically significant bleeding 
▪ Grade ≥3 fever with neutropenia of any duration 
▪ Grade ≥3 nausea and or vomiting lasting more than 72 hours in spite of standard supportive therapy 
▪ Grade ≥3 non-hematologic toxicity (exclude alopecia and skin rash that resolves to grade 2 or less with a 
treatment break not to exceed 10 days; also excluding fatigue or anorexia lasting < 7 days); Lab 
abnormalities will not be considered DLT if it is not of any significant clinical consequence requiring 
intervention and not directly attributed to the receipt of the investigational agents. Also, grade ≥3 

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amylase or lipase elevation NOT associated with symptoms or clinical manifestations of pancreatitis 
does not count as a DLT 
▪ Grade ≥3 electrolyte abnormality that lasts >72 hours, in the absence of clinical symptoms, or of any 
duration if associated with clinical symptoms. 
▪ Inability to re-treat patient within 14 days of scheduled treatment due to treatment-related toxicity 
(non-treatment related events that result in treatment delay will not be considered a DLT) 
▪ Inability to deliver 66% of the planned dose i.e. ≥14 days of treatment with defactinib and avutometinib 
within the first 28 days due to treatment discontinuation as a result of intolerable treatment-related toxicity 
5.4 Dose Modification 
In general, no dose modification will be needed for Grade 1 or 2 toxicities.. Any dose modification 
must be based on the maximum toxicity experienced during a cycle. No dose re-escalation is permitted. 
A maximum of one dose reduction is allowed prior to discontinuation of treatment.  
Study interventions may be held up to 28 days due to toxicity. Doses held for > 28 days due to 
treatment-related toxicity will result in permanent discontinuation, unless approved by the DSMC. . If 
there is a dose interruption due to toxicity, the missed doses will be skipped rather than delayed, with 
no extension of cycle length. Dosing resumes at the next scheduled administration. 
 
 
There are no dose reductions for nivolumab. 
 
Table 2: Dose Reductions for Toxicity: Avutometinib when Combined with Defactinib 
 
Abbreviations: BIW: twice a week 
Table 3: Dose Reductions for Toxicity: Defactinib when Combined with Avutometinib 
Dose Level 
Defactinib 
Starting Dose 
200 mg BID for 3 of 4 weeks 
Dose -1 
200 mg QD for 3 of 4 weeks 
Dose -2 
Discontinue 
Abbreviations: BID: twice a day; QD: once a day 
Table 4: Dose Modifications and Management Guidance for Specific Toxicities 
 
Dose Modifications and Management of Toxicities except Ocular 
Dose modification and clinical management guidance for specific toxicities (except Ocular) is provided below. 
 
Dose Modifications and Management Guidance for Specific Toxicities 
Dose Level 
Avutometinib 
Starting Dose 
3.2 mg BIW for 3 of 4 weeks 
Dose -1 
2.4 mg BIW for 3 of 4 weeks 
Dose -2 
Discontinue 

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Toxicity 
Adverse Reaction Grade (CTCAE v5.0) 
Dose Modification 
Management Guidelines and 
Dosing Notes 
Rasha 
Grade 1 (papules and/or pustules 
covering < 10% of body surface area 
[BSA], which may or may not be 
associated with symptoms of pruritis or 
tenderness) 
No change 
Treat with any of the following: 
minocycline (recommended 
dose: 200 mg BID [loading dose] 
followed by 100 mg PO BID x 7 to 
10 days), topical tetracycline, 
topical clindamycin, topical silver 
sulfadiazine, oral 
diphenhydramine, or oral 
prednisone (short course) at 
discretion of the Investigator 
Provide supportive care per 
institutional guidelines 
 
Patients who develop rash/skin 
toxicities should be seen by a 
qualified dermatologist and should 
receive evaluation for 
symptomatic/supportive care 
management, as clinically needed.  
General recommendations for 
symptomatic care include: 
• 
Pruritic lesions: cool 
compresses and oral antihistamine 
therapies 
• 
Fissuring lesions: Monsel’s 
solution, silver nitrate, or zinc oxide 
cream 
• 
Desquamation: thick 
emollients and mild soap 
• 
Paronychia: antiseptic bath, 
local potent corticosteroids in addition 
to antibiotics; if no improvement, 
consult dermatologist or surgeon 
• 
Infected lesions: 
appropriate bacterial/fungal 
culture-driven systematic or 
topical antibiotics 
Grade 2 (papules and/or pustules 
covering 10-30% of BSA, which may or 
may not be associated with symptoms of 
pruritus or tenderness; associated with 
psychosocial impact; limiting 
instrumental ADLb; papules and/or 
pustules 
covering > 30% BSA with or without 
mild symptoms) 
No change. If rash does not 
respond to supportive care or 
reoccurs after resolution to 
Grade ≤1, consult the DSMC 
regarding possible dose 
modification. 
Grade 3 (papules and/or pustules 
covering > 30% of BSA, with moderate 
or severe symptoms; limiting self-care 
ADLc; associated with local 
superinfection 
with oral antibiotics indicated) 
Interrupt dosing. Resume one 
dose level lower if resolution to 
Grade 2. 
Resume at current dose if 
resolution to Grade ≤ 1. 
Grade 4 (life-threatening 
consequences; papules and/or pustules 
covering any % of BSA, which may or 
may not be associated with symptoms 
of pruritus 
or tenderness and are associated with 
extensive 
superinfection with IV antibiotics 
indicated) 
Discontinue 
NA 
 
 
 
 
 
 
 
 
 
 
Grade 1 (> ULN to 1.5 x ULN if 
baseline was normal; > 1.0 to 1.5 x 
baseline if baseline was abnormal) 
 No change 
 
Hold defactinib and monitor at least 
weekly until return to baseline.  

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Toxicity 
Adverse Reaction Grade (CTCAE v5.0) 
Dose Modification 
Management Guidelines and 
Dosing Notes 
Grade 2 (> 1.5 x ULN to 3 x ULN if 
baseline was normal; > 1.5 x to 3 x 
baseline if baseline was abnormal) 
If patient has Gilbert’s syndrome 
and isolated Grade 2, no change. 
For isolated Grade 2 in the 
absence of Gilbert’s syndrome, 
hold until resolution to Grade 1, 
then resume at same dose. For 
Grade 2 hyperbilirubinemia (with 
or without Gilbert’s syndrome) 
with Grade 2 AST or ALT elevation, 
hold dose, then resume at same 
dose upon Grade 1 resolution. 
 
For Grade > 2 hyperbilirubinemia 
(with or without Gilbert’s 
syndrome) with Grade ≥ 2 AST or 
ALT elevation, (meeting the 
definition of Hy’s Law), 
permanently discontinue. 
Exclude other causes of 
hyperbilirubinemia. Exclude Hy’s 
law. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hyperbilirubinemia 
(Blood bilirubin 
increased)d 
Regardless of presence or absence 
of Gilbert’s syndrome, if increased 
bilirubin is not associated with 
increased ALT or AST, interrupt 
dosing until bilirubin returns to 
Grade ≤ 2.  
 
If on retreatment bilirubin returns 
to Grade ≥ 3, withhold treatment 
until toxicity is Grade ≤ 2 or 
bilirubin returns to baseline levels 
then decrease the dose by one 
dose level. 
Grade 3 (> 3 to 10 x ULN if baseline was 
normal; >3 to 10 x baseline if baseline was 
abnormal) 
 
If at any time bilirubin increases to 
Grade ≥ 2 and is associated with a 
Grade 
≥ 2 increase in AST and/or ALT, 
permanently discontinue.  
Grade 4 (> 10 x ULN if baseline was 
normal; > 10 x baseline if baseline was 
abnormal) 
Discontinue unless 
duration ≤ 1 week. 
If the event resolves to at least 
baseline in < 1 week, resume prior 
dose. 
Grade 1 (> ULN to 2.5 ULN) 
No change 
Monitor at least bimonthly until 
return to baseline or normal. 
Grade 2 (> 2.5 to 5 x ULN) 
No change 
Monitor at least weekly until 
return to baseline or normal. 

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Toxicity 
Adverse Reaction Grade (CTCAE v5.0) 
Dose Modification 
Management Guidelines and 
Dosing Notes 
Creatine 
Phosphokinase 
Elevatione 
Grade 3 (> 5 to 10 x ULN) 
Interrupt dosing until CPK 
returns to Grade 0-1 
within 3 weeks. 
Investigators should assess for 
myoglobinuria using dipstick or 
accurate urine analysis and 
consider additional diagnostic 
evaluation (e.g., CPK-MB, CPK 
electrophoresis, troponin) to 
help determine the etiology of 
the CPK abnormality and  to 
guide treatment. 
Investigators should check for 
any cardiac symptoms and 
conduct a muscle examination. 
Information regarding muscle 
symptoms, exercise, concomitant 
medications, and alcohol 
consumption should be 
recorded. 
CPK should be monitored at least 
weekly until levels return to 
baseline or normal. 
Grade 4 (> 10 x ULN) 
1st occurrence: interrupt dosing 
until CPK returns to Grade 0-1 
within 3 weeks. 
 
2nd occurrence (or 3rd occurrence 
if applicable): Interrupt dosing until 
CPK returns to Grade 0-1 within 3 
weeks, then decrease dose by 1 
dose level number. If with any 
occurrence the CPK level does not 
return to Grade 0-1 within 3 weeks, 
discontinue. Regardless of the 
grade, if at anytime a diagnosis of 
rhabdomyolysis or another 
medically significant event related 
to CPK elevation is made, 
discontinue study treatment. 
Investigators should assess for 
myoglobinuria using dipstick or 
accurate urine analysis and 
consider additional diagnostic 
evaluation (e.g., CPK-MB, CPK 
electrophoresis, troponin) to help 
determine the etiology 
of the CPK abnormality and to guide 
treatment.  
Investigators should check for any 
cardiac symptoms and conduct a 
muscle examination.  
Information regarding muscle 
symptoms, exercise, concomitant 
medications, and alcohol 
consumption should be recorded.  
CPK should be monitored at least 
weekly until levels return to baseline 
or normal. 
Any Grade 4 CPK elevation must be 
discussed with the Principal 
Investigatorr and study treatment  
continuation will be allowed only 
upon written agreement from the 
DSMC.  
 
 
 
 
 
 
 
Grade 1 
No change 
Supportive care per institutional 
guidelinesg 
Grade 2 
No change.  

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Toxicity 
Adverse Reaction Grade (CTCAE v5.0) 
Dose Modification 
Management Guidelines and 
Dosing Notes 
 
 
Other Toxicities 
EXCEPT Ocular 
Toxicities f, g 
Grade 3 
First occurrence: interrupt dosing 
until toxicity Grade ≤2 
Subsequent occurrences: 
interrupt dosing until toxicity 
Grade ≤2. Consult the DSMC 
regarding dose level for resumed 
dosing. 
Grade 4 
Discontinue 
NA 
Abbreviations: ADL: Activities of Daily Living; ALP = alkaline phosphatase, ALT: alanine aminotransferase; AST: aspartate 
aminotransferase; BID: twice daily; BSA: body surface area; CPK: creatine phosphokinase; CTCAE: Common Terminology 
Criteria for Adverse Events; GI = gastrointestinal; NA = not applicable; ULN: upper limit of normal. 
a Rash includes events such as acneiform rash (CTCAE grade definitions shown), which is a disorder characterized by an eruption 
of papules and pustules, typically appearing in face, scalp, upper chest and back, and macular papular rash, which is a disorder 
characterized by the presence of macules (flat) and papules (elevated). Macular papular rash, also known as morbilliform rash, 
frequently affects the upper trunk, spreading centripetally and associated with pruritis. Macular papular rash symptoms may 
include burning and tightness. Only up to Grade 3 is applicable for macular papular rash. 
b Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc. 
c Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden. 
d A finding based on laboratory test results that indicate an abnormally high level of bilirubin in the blood. Excess bilirubin is 
associated with jaundice. 
e A finding based on laboratory test results that indicate an increase in levels of creatine phosphokinase in a blood specimen. 
f Includes GI Toxicities (e.g., diarrhea). 
g Includes  clinical laboratory changes in the liver-related enzymes ALT, AST, and ALP. 
 
  h For GI Toxicities, interruption and/or reduction of dosing as well as supportive treatment will improve gastrointestinal toxicity. If          
gastrointestinal bleeding is suspected, interruption of dosing and a standard work-up of the gastrointestinal tract is required. 
Recommended diarrhoea management:  
Grade 1 (Increase of < 4 stools per day over baseline; mild increase in ostomy output compared to baseline): No change in study drug. 
Consider treatment with loperamide (4 mg at first onset, followed by 2 mg every 2-4 hours until diarrhoea free for 12 hours).  
Grade 2 (Increase of 4 - 6 stools per day over baseline; moderate increase in ostomy output compared to baseline; limiting 
instrumental ADL): no change in study drug. Manage as described for Grade 1.  
Grade 3 (Increase of ≥ 7 stools per day over baseline; hospitalization indicated; severe increase in ostomy output compared to 
baseline; limiting self-care ADL): decrease dose or interrupt dosing. Manage as described for Grade 1. Dose can be re-escalated 
when diarrhea is Grade ≤ 1.  
Grade 4 (Life-threatening consequences; urgent intervention indicated): discontinue patient from study or treat with a reduced dose 
(previous dose level or intermediate dose after approval of Verastem) according to clinical judgment. Manage as described for 
Grade 1. 
 
Table 5: Dose Modification Guidelines for Ocular Toxicities 
A special grading system rather than the CTCAE grading system should be used for the assessment of ocular toxicities. 
Where appropriate, abnormalities observed during the ophthalmologic examination as well as symptoms should be 
carefully monitored until improved. 
 
Corneal keratitis, Blurred vision, Conjunctivitis or Iritis 
Ocular 
abnormalitya 
Grading 
Description 
Management  
Corneal keratitisb 
Grade 1 
Nonconfluent superficial keratitis 
No dose interruption 

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Ocular 
abnormalitya 
Grading 
Description 
Management  
Grade 2 
 
Confluent superficial keratitis, cornea 
epithelial defect, or 3 line or more 
vision loss in best corrected distance 
visual acuity [Corneal examination 
finding(s): Moderate superficial 
keratopathy] 
Delay dose until resolved to ≤ Grade 1, 
then maintain dose 
Grade 3 
 
Sterile corneal ulcer or stromal opacity, 
or best corrected distance visual acuity 
20/200 or worse [Corneal examination 
finding(s): Severe superficial 
keratopathy] 
Delay dose until resolved to ≤ Grade 1, 
then reduce dose by 1 level. If more than 
the allowed dose reductions are needed, 
discontinue study drug 
Grade 4 
 
Corneal perforation or Infectious 
keratitis 
Discontinue study drug 
Blurred visionc 
Grade 1 
BCVA worse than baseline but no worse 
than 20/40 
Dosing not interrupted 
Grade 2 
BCVA worse than baseline but no worse 
than 20/200 
Delay dose until BCVA same as baseline 
or 20/40 whichever is worse, then 
maintain dose 
Grade 3 
BCVA 20/200 or worse 
Delay dose until BCVA same as baseline 
or 20/40 whichever is better, then 
reduce dose by 1 level 
Conjunctivitisd 
Grade 1 
Nonconfluent superficial punctate 
defects, mild vasodilation 
No dose interruption 
Grade 2 
Confluent superficial punctate staining 
moderate to severe vasodilation 
Delay dose until resolved to ≤ Grade 1, 
then maintain dose 
 
Grade 3 
Conjunctival ulcer or very severe 
injection 
Delay dose until resolved to ≤ Grade 1, 
then reduce dose by 1 level. If more than 
the allowed dose reductions are needed, 
discontinue study drug 
Iritise 
Grade 1 
Rare cell in anterior chamber 
No dose interruption 
Garde 2 
1-2 + Cell or Flare in anterior chamber 
Delay dose until resolved to ≤ Grade 1, 
then maintain dose 
Grade 3 
3+ Cell or Flare in anterior chamber 
Delay dose until resolved to ≤ Grade 1, 
then reduce dose by 1 level. If more than 
the allowed dose reductions are needed, 
discontinue study drug 
Grade 4 
Hypopyon 
Discontinue study drug 
a (1) Please assure that other causes are excluded particularly for common conditions (e.g. allergic conjunctivitis) prior to 
considering dose modification guidelines. (2) Dose modifications for corneal adverse reactions should be based on both 
corneal examination findings and changes in best-corrected visual acuity (BCVA). (3) Advise patients to use preservative-

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free lubricant eye drops and avoid contact lenses unless directed by an ophthalmologist. Consideration should be given 
to the use of ophthalmic topical steroids. 
b A normal corneal exam is considered a clear cornea and no epithelial defect 
c A normal vision exam is when the best corrected distance visual acuity (BCVA) same as baseline BCVA 
d A normal examination implies that the transparent membrane of the eye should not have any vasodilation or epithelial 
defects. Also, other common causes of conjunctivitis should be excluded (e.g. allergic conjunctivitis) 
e A normal eye exam implies that the iris should have a clear anterior chamber 
 
Uveitis 
Ocular 
abnormality 
Grading 
Description 
Management  
Uveitisa 
Grade 1 
Rare cell in anterior chamber 
Dosing not interrupted and monitor. 
Grade 2 
1-2 + Cell or Flare in anterior chamber 
Hold dose until resolved to Grade 1 or less 
and then Resume at the dose 
Grade 3 
3+ Cell or Flare in anterior chamber 
Delay dose until resolved to Grade 1 or less, 
then resume at reduce dose (1 level)  
Grade 4 
Hypopyon 
Discontinue study drug 
a Please assure that other causes are excluded particularly for common conditions prior to considering dose modification guidelines. 
 
Retinal Toxicities 
Ocular finding 
Grading a 
OCT Exam 
Management 
RPE detachment 
 
 
 
Grade 1-4 
First occurrence: No change in drug 
No dose modification 
A-Follow-up OCT examination in 2 weeks  
Grade 1-4 
Follow-up 1 OCT:  
RPE is still present in two weeks 
Reduce dose by one dose level 
OCT examination obtained again in 2 weeks  
Grade 1-4 
Follow-up 2 OCT:  
RPE is still present in two weeks and loss 
of 1 line in BCVA 
Hold until the RPE detachment is shown to 
be resolving 
If no resolution in two weeks, discontinue 
study drug 
Abbreviations: BCVA = Best-corrected visual acuity OCT: optical coherence tomography; RPE: Retinal pigment epithelium 
a For RPE detachment (defined as disorder characterized by the separation of the inner retina layers from the underlying pigment 
epithelium) CTCAE v5.0 should be applied. Definition of Grade 3 is: Macular sparing rhegmatogenous detachment, and Grade4 is: 
Macula-off rhegmatogenous retinal detachment.  
 
Table 6: Recommended Nivolumab Dosage Modifications for Adverse Reactions 
No dose reduction for nivolumab is recommended. In general, withhold nivolumab for severe (Grade 3) immune-
mediated adverse reactions. Permanently discontinue nivolumab for life threatening (Grade 4) immune-
mediated adverse reactions, recurrent severe (Grade 3) immunemediated reactions that require systemic 
immunosuppressive treatment, or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or 
equivalent per day within 12 weeks of initiating steroids.  
Adverse Reaction 
Severity 
Dosage 
Modification 

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Immune-Mediated Adverse Reactions  
 
Pneumonitis 
Grade 2 
Withholda 
Grades 3 or 4 
Permanently discontinue 
 
Colitis 
Grade 2 or 3 
Withholda 
Grade 4 
Permanently discontinue 
 
 
Hepatitis with no tumor 
involvement of the liver 
AST/ALT increases to >3 and ≤8 times ULN 
or Total bilirubin increases to >1.5 and ≤3 
times ULN. 
Withholda 
AST or ALT increases to >8 times ULN 
Or Total bilirubin increases to >3 times ULN. 
Permanently discontinue 
 
Hepatitis 
with 
tumor 
involvement of the liverb 
Baseline AST/ALT is >1 and ≤3 times ULN and 
increases to >5 and ≤10 times ULN 
or 
Baseline AST/ALT is >3 and ≤5 times ULN and 
increases to >8 and ≤10 times ULN. 
Withholda 
AST/ALT increases to >10 times ULN 
or 
Total bilirubin increases to >3 times ULN. 
Permanently discontinue 
Endocrinopathiesc 
Grade 3 or 4 
Withhold until clinically stable or 
Permanently discontinue 
depending on severity 
Nephritis 
with 
Renal 
Dysfunction 
Grade 2 or 3 increased blood creatinine 
Withholda 
Grade 4 increased blood creatinine 
Permanently 
discontinue 
Exfoliative Dermatologic 
Conditions 
Suspected SJS, TEN, or DRESS 
Withhold 
Confirmed SJS, TEN, or DRESS 
Permanently 
discontinue 
Myocarditis 
Grades 2, 3, or 4 
Permanently 
discontinue 
Neurological Toxicities 
Grade 2 
Withholda 
Grade 3 or 4 
Permanently 
discontinue 
Other Adverse Reactions 
Infusion-Related Reactions 
Grade 1 or 2 
Interrupt or slow 
the rate of infusion 
Grade 3 or 4 
Permanently 
discontinue 
a  Consider resuming in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper as 
per standard of care. Permanently discontinue if no complete or partial resolution within 12 weeks of last dose 
or inability to reduce prednisone to 10 mg per day (or equivalent) or less within 12 weeks of initiating steroids. 
b If AST and ALT are less than or equal to ULN at baseline, withhold or permanently discontinue nivolumab based 
on recommendations for hepatitis with no liver involvement. 

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c Depending on clinical severity, consider withholding for Grade 2 endocrinopathy until symptom improvement 
with hormone replacement. Resume once acute symptoms have resolved. 
ALT = alanine aminotransferase, AST = aspartate aminotransferase, DRESS = Drug Rash with Eosinophilia and 
Systemic Symptoms, SJS = Stevens Johnson Syndrome, TEN = toxic epidermal necrolysis, ULN = upper limit normal 
 
 
Concomitant Therapies Restrictions  
 
Table 7: Prohibited Concomitant Therapies  
Prohibited Concomitant 
Therapy 
Guidance 
Other Anticancer Therapy 
or Investigational Agents 
During the study intervention period, patients are not to receive any additional 
anticancer therapy or other investigational agents not outlined in the protocol. 
Radiotherapy is not permitted. 
Colony-stimulating factors 
(CSFs)  
Primary CSF prophylaxis is not permitted. Otherwise adhere to ASCO 
guidelines(1).  
Warfarin 
Due to the potential for drug-drug interaction with defactinib, the use of 
warfarin is prohibited. If patients require anticoagulation an alternative to 
warfarin should be used. Patients who require anticoagulation but cannot 
discontinue warfarin are excluded from this study.  
Strong CYP3A4 Inhibitors 
 
Use of a strong CYP3A4 inhibitor during treatment with avutometinib ± 
defactinib is prohibited. Co-administration with a strong CYP3A4 inhibitor could 
increase study intervention exposure, which may increase the risk of 
treatment-related toxicities. 
 
Strong CYP2C9 Inhibitors 
Use of a strong CYP2C9 inhibitor during treatment with defactinib is prohibited. 
Co-administration with a strong CYP2C9 inhibitor could increase study 
intervention exposure, which may increase the risk of treatment-related 
toxicities. 
 
Strong CYP3A4 Inducers 
Use of a strong CYP3A4 inducer during treatment with avutometinib ± 
defactinib is prohibited. Co-administration with a strong CYP3A4 inducer could 
decrease study intervention(s) exposure, which may reduce study 
intervention(s) efficacy. 
 
Strong CYP2C9 Inducers 
Use of a strong CYP2C9 inducer during treatment with defactinib is prohibited. 
Co-administration with a strong CYP2C9 inducer could decrease study 
intervention exposure, which may reduce study intervention efficacy. 
 

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Prohibited Concomitant 
Therapy 
Guidance 
CYP3A4 and CYP2C9 
substrates with narrow 
therapeutic index 
Use of CYP3A4 and CYP2C9 substrates with narrow therapeutic index during 
treatment with defactinib is prohibited, as defactinib could increase the risk of 
treatment-related toxicities of these drugs.  
Strong P-gp Inhibitors or 
Inducers 
Use of a strong P-gp inhibitor or inducer during treatment with defactinib is 
prohibited, as P-gp inhibitor or inducer co-administration could change study 
intervention exposure.  
Strong BCRP Inhibitors or 
Inducers 
Use of a strong BCRP inhibitor or inducer during treatment with 
avutometinib (VS-6766) is prohibited, as a strong BCRP inhibitor or 
inducer may change avutometinib (VS-6766) exposure, which may 
impact avutometinib (VS-6766) efficacy or treatment-related toxicities. 
Abbreviations: ASCO: American Society for Clinical Oncology; CSF: colony-stimulating factor ; regCYP: cytochrome P450; QD: once 
daily; P-gp: P-glycoprotein; PK: pharmacokinetic. 
 
 
 
Table 8: Concomitant Therapies: Use with Caution During Treatment with Avutometinib and Defactinib 
The study investigator should be contacted with any questions regarding concomitant use of these 
medications. 
 
Concomitant Therapy: Use 
with Caution 
Guidance 
Weak or Moderate CYP2C9 
or CYP3A4 Inhibitors 
Weak or moderate CYP3A4 inhibitors should be used with caution during 
treatment with avutometinib ± defactinib, as they could increase study 
intervention exposure, which may increase the risk of treatment-related 
toxicities 
Weak or moderate CYP2C9 inhibitors should be used with caution during 
treatment with defactinib, as they could increase study intervention exposure, 
which may increase the risk of treatment-related toxicities. 
 
Weak or Moderate CYP2C9 
or CYP3A4 Inducers 
Weak or moderate CYP3A4 inducers should be used with caution during 
treatment with avutometinib ± defactinib, as they could decrease study 
intervention(s) exposure, which may reduce study intervention(s) efficacy. 
Weak or moderate CYP2C9 inducers should be used with caution during 
treatment with defactinib, as they could decrease study intervention exposure, 
which may reduce study intervention efficacy.  
 
CYP2C9 or CYP3A4 
Substrates 
Substrates of CYP3A4 or CYP2C9 should be used with caution. Co-
administration of a CYP3A4 substrate with defactinib may increase the toxicity 
of these drugs. Co-administration of a CYP2C9 substrate with defactinib may 
increase the exposure of these drugs.  

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Concomitant Therapy: Use 
with Caution 
Guidance 
An alternative drug that is not a substrate of CYP2C9 or CYP3A4 should be 
considered.  
 
Weak or Moderate P-gp 
Inhibitors or Inducers 
Weak or moderate P-gp inhibitors or inducers should be used with caution 
during treatment with avutometinib ± defactinib, as they could change study 
intervention(s) exposure.  
UGT1A1 substrates 
Substrates of UGT1A1 substrates should be used with caution. Co-
administration of a UGT1A1 substrates substrate with defactinib may increase 
the toxicity of these drugs. (See Appendix D). 
An alternative drug that is not a substrate of UGT1A1 substrates should be 
considered. 
 
P-gp substrates 
Substrates of P-gp (See Appendix D) should be used with caution. Co-
administration of a P-gp substrate with defactinib may increase the toxicity of 
these drugs. 
An alternative drug that is not a substrate of P-gp should be considered. 
 
OATP1B1 or OATP1B3 
substrates  
Substrates of OATP1B1 or OATP1B3 should be used with caution.(SeeAppendix 
D). Co-administration of a OATP1B1 or OATP1B3 substrates with defactinib 
may increase the toxicity of these drugs. 
An alternative drug that is not a substrate of OATP1B1 or OATP1B3 should be 
considered. 
 
Medications that modify 
gastric pH 
The effect of medications that modify gastric pH on study intervention activity 
and exposure has not been clinically evaluated. Therefore, avoid concomitant 
use of gastric acid reducing agents (proton-pump inhibitors, H2-receptor 
antagonists, antacids).  
Abbreviations: AUC: area under the curve; CYP: cytochrome P450; QD: once daily. 
 
Additional information can be found at: https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-
drug-interactions-table-substrates-inhibitors-and-inducers and https://www.drugbank.ca/categories/DBCAT002635 
(CYP2C9 inhibitors). 
5.6 Study Procedures 
Baseline evaluations are to be conducted within 4 weeks prior to start of protocol therapy.  Scans must be done 
<4 weeks prior to the start of therapy.  See schedule of events 
 
 
 
 

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General Concomitant Medication and Supportive Care Guidelines 
 
All appropriate supportive care measures for adverse events related to therapy will be utilized according 
to standard of care guidelines. No prophylactic therapy will be given unless clinically indicated. 
 
Rash Prophylaxis and Symptomatic Care 
Prophylactic medications must be used during the first 2 cycles of avutometinib and defactinib dosing 
and will be optional starting with Cycle 3 to mitigate against dermatologic toxicities. Hydrocortisone 1% 
cream, moisturizer and sunscreen (sun protection factor [SPF]≥30) should be applied topically twice 
daily, along with a systemic antibiotic (minocycline 100 mg daily or doxycycline 100 mg BID). 
Application of topical agents should include the most commonly affected skin areas such as face, scalp, 
neck, upper chest, and upper back.  
In addition, patients should be advised to avoid unnecessary exposure to sunlight. For patients who 
cannot tolerate a component of the prophylaxis, that component may be eliminated; the reason for the 
change will be documented in the eCRF. 
Patients who develop rash/skin toxicities should be seen by a qualified dermatologist at the 
investigator’s clinical discretion and should receive evaluation for symptomatic/supportive care 
management.  
General recommendations for symptomatic care include: 
• 
Pruritic lesions: cool compresses and oral antihistamine therapies 
• 
Fissuring lesions: Monsel’s solution, silver nitrate or zinc oxide cream 
• 
Desquamation: thick emollients and mild soap 
• 
Paronychia: antiseptic bath, local potent corticosteroids in addition to antibiotics; if no 
improvement, consult dermatologist or surgeon 
• 
Infected lesions: appropriate bacterial/fungal culture-driven systematic or topical 
antibiotics 
Dose modification and management guidance by rash adverse reaction grade is found in Table-5.  
 
Antitumor Effect – Solid Tumors 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) 
[Eur J Ca 45:228-247, 2009] (Appendix 1).  Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes 
are used in the RECIST criteria. 
 
Duration of Response 
 

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Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for CR until 
the first date that progressive disease is objectively documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements.  
 
Progression-Free Survival 
 
PFS is defined as the time from the date of first protocol therapy to the date of first documentation 
of disease progression or death due to any cause, whichever occurs first. For those subjects who are 
still alive and have not yet progressed, the subject’s data will be censored at the last disease 
assessment 
 
 
Overall Survival 
 
OS is measured from the date of first protocol treatment to the date of the subject’s death. If the 
subject is alive or the vital status is unknown, then the subject’s data will be censored at the date the 
subject was last known to be alive. 
5.7 Description of Study Procedures 
Medical history 
Findings from medical history (obtained at screening) and physical examination shall be given a baseline grade 
according to the procedure for AEs. Increases in severity of pre-existing conditions during the study will be 
considered AEs, with resolution occurring when the grade returns to the pre-study grade or below. 
 
Physical examination 
Physical examinations should be conducted according to the Schedule of Events.  Full physical examinations 
should be conducted at screening/baseline, Day 1 of cycle 2 and beyond, and EOT (evaluate all major organ 
systems, including the following categories:  general, head, eyes, ears, mouth/throat, neck, heart, lungs, 
abdomen, lymph nodes, joints, extremities, integumentary, neurologic, and psychiatric). Other examinations may 
be focused, at the discretion of the Investigator, to identify changes from baseline or evaluate changes based on 
the patient’s clinical symptoms.  Weight is to be recorded at each visit, height at screening/baseline visit only.   
 
Vital signs 
Vital signs (blood pressure [BP], pulse, temperature, and respiration rate) will be evaluated according to the 
assessment schedules.  Body weight is also recorded along with vital signs.   

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On infusion days, patients receiving treatment will be monitored during and after infusion of Nivolumab as 
presented in the bulleted list below.   
• 
Supine BP will be measured using a semi-automatic BP recording device with an appropriate cuff size, 
after the patient has rested for at least 5 minutes.  BP and pulse will be collected from patients receiving 
treatment before, during, and after each infusion at the following times (based on a 60-minute infusion):   
• 
Prior to the beginning of the infusion (measured once from approximately 30 minutes before up to 0 
minutes [i.e., the beginning of the infusion]).   
• 
Approximately 30 minutes during the infusion (halfway through infusion).   
• 
At the end of the infusion (approximately 60 minutes ±5 minutes).   
• 
A 1-hour observation period is required after the first infusion. If no clinically significant infusion reactions 
are observed during or after the first cycle, subsequent infusion observation periods can be at the 
Investigator’s discretion (suggested 30 minutes after each infusion).   
 
If the infusion takes longer than 60 minutes, then BP and pulse measurements should follow the principles as 
described above or be taken more frequently if clinically indicated.  The date and time of collection and 
measurement will be recorded on the appropriate eCRF.  Additional monitoring with assessment of vital signs is 
at the discretion of the Investigator per standard clinical practice or as clinically indicated. 
   
Electrocardiograms 
Resting 12-lead ECGs will be recorded at screening and as clinically indicated throughout the study.  ECGs should 
be obtained after the patient has been in a supine position for 5 minutes and recorded while the patient remains 
in that position. 
At Screening, a single ECG will be obtained on which QTcF must be <470 ms.   
In case of clinically significant ECG abnormalities, including a QTcF value >470 ms, 2 additional 12-lead ECGs 
should be obtained over a brief period (e.g., 30 minutes) to confirm the finding.  If 3 are taken, can use the 
average of the three for the qtc 
The Investigator or qualified Sub-Investigator will review all ECG interpretations and interval duration 
measurements for clinical significance.  Any ECG interpretation deemed to be clinically significant will be reported 
as an AE.   
 
Clinical laboratory tests 
The following clinical laboratory tests will be performed (see the Schedule of Assessments) 
• 
Hematology and Clinical Chemistry 
• 
CPK 
• 
Urinalysis 
• 
Tumor Biopsy 
• 
Coagulation parameters: Activated partial thromboplastin time and International normalized ratio to be 
assessed at baseline and as clinically indicated  
• 
Pregnancy test (female subjects of childbearing potential only) 
• 
Thyroid Stimulating Hormone 
o 
free T3 and free T4 only if TSH is abnormal 
• 
Other laboratory tests 
o 
Hepatitis A antibody, hepatitis B surface antigen, hepatitis C antibody 
o HIV antibody 
 
 
 
6. Statistical Considerations 

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6.1 Study Design/Endpoints 
The first 5 patients/cohort (total N=10) will be served 
as a safety run-in. If deemed to be safe, the trial will 
continue. Basically, it is a phase II clinical trial including 
two concurrent cohorts with the time-to-event (6-
months PFS) Bayesian optimal phase 2 (TOP) design for 
each. The TOP design is novel and allows for real-time 
go/no-go decision making when some patients’ 6-
month PFS status, the primary endpoint, are pending, 
thereby shortening the trial duration, and it also is 
efficient, allows any arbitrary number of interim looks, 
and maximizes statistical power with a well-controlled 
type I error rate. Based on the existing knowledge 
about salvage therapy in stage IV NSCLC (49) and a 
clinical meaningful expectation, we consider a 6-
month PFS rate < 25% as not interesting (null 
hypothesis H0) and > 50% as promising (alternative 
hypothesis H1). We will enroll a maximum of 25 patients with three futility interim looks after 10 and 20 
patients were treated with Go/No-Go rules illustrated in Table 6.  
 
Based on Table9, we perform the interim looks when the number of enrolled patients reaches 10 and 20. 
When the total number of patients reaches the maximum sample size of 25, we reject the null hypothesis 
and conclude that the treatment is promising if the number of responses >= 10; otherwise we conclude that 
the treatment is not promising. Here, ESS is the effective sample size, which is defined as 
ESS = Num. non −pending patients + sum of the follow −up time for pending patients
length of assessment window
 
 
Specifically, let 𝑛𝑛 denote the interim sample size and 𝑁𝑁 denote the maximum sample size. Let 𝑝𝑝𝑒𝑒𝑒𝑒𝑒𝑒 denote 
the probability of efficacy (response rate) and define the null hypothesis 𝐻𝐻0: 𝑝𝑝𝑒𝑒𝑒𝑒𝑒𝑒≤0.25, representing that 
the treatment is inefficacious. We will stop enrolling patients and claim that the treatment is not promising 
if 
𝑃𝑃𝑃𝑃(𝑝𝑝𝑒𝑒𝑒𝑒𝑒𝑒> 0.25|𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑) < 𝜆𝜆(𝑛𝑛
𝑁𝑁)𝛼𝛼, 
where 𝜆𝜆=0.875 and 𝛼𝛼=0.45 are design parameters optimized to maximize the power under the alternative 
hypothesis 𝐻𝐻1: 𝑝𝑝𝑒𝑒𝑒𝑒𝑒𝑒= 0.5, while controlling the type I error rate at 0.1 (i.e., the chance of incorrectly claiming 
that an inefficacious treatment is promising is no more than 10%). Assuming a Beta(0.25,0.75) prior 
distribution for 𝑝𝑝𝑒𝑒𝑒𝑒𝑒𝑒, the above decision rule corresponds to the following go/no-go rules and yields a 
maximum statistical power of 0.855 under 𝐻𝐻1. 
 
Table 10 shows the operating characteristics of the design based on 1000 simulations using the TOP web 
application. In the simulation, the assessment window is 1.5 months, and the patient arrival is uniformly 
distributed with an accrual rate of 3 patients per month. The time to response is simulated from a Uniform 
Table 9: Go/No-go Rules. 
Interim 
# 
treated 
# 6-mon 
progression 
free 
# 
pending  
Action 
1 
10 
<= 2 
>= 4 
Suspend 
10 
<= 2 
<= 3 
No go 
10 
>= 3 
<= 7 
Go 
2 
20 
3 
<= 15 
Go if ESS < 7.33 
20 
4 
<= 15 
Go if ESS < 
10.56 
20 
5 
<= 15 
Go if ESS < 
13.89 
20 
6 
<= 15 
Go if ESS < 
17.28 
20 
>= 7 
<= 13 
Go 
Final 
25 
<= 25 
>= 1 
Suspend 
25 
<= 9 
0 
No Go 
25 
>= 10 
0 
Go 
 

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distribution by controlling 50% of the responses occurring in the latter half of the response assessment 
window. 
 
Table 10: Operating characteristics 
Response 
rate 
Early stopping 
(%) 
Claim promising 
(%) 
Sample 
size 
Average 
trial 
duration 
(month) 
0.25 
89.1 
4.3 
14 
5.45 
0.5 
16.7 
79.5 
23 
9 
 
6.2 Analysis datasets 
Safety Population: The safety analysis dataset will include all eligible patients who begin treatment and 
receive at least one dose of protocol therapy. Patients will be analyzed in the cohort to which they were 
enrolled. 
 
Efficacy Evaluable Population: All evaluable patients will be included in the analysis of efficacy endpoints. 
The term evaluable is defined as any eligible patient who receives at least one dose of protocol therapy and 
does not withdraw consent until the patient’s first response assessment.  Patients who fail to have a response 
assessment due to early progression or death will be categorized as non-responders.  
 
6.3 Analysis of primary endpoint  
The primary endpoint is the 6m PFS rate. The rate will be calculated with an 95% confidence interval using 
Kaplan-Meier method based on the efficacy evaluable population. Patients who fail to have a response 
assessment for other reasons (e.g., refusal due to travel constraints) will be considered unevaluable and will 
not be included in the denominator when calculating the rate. 
 
6.4 Analysis of secondary endpoints 
For progression-free survival (PFS) and overall survival (OS), the Kaplan-Meier method will be used to 
estimate the median event-free time with 95% confidence interval. For the duration of overall response, 
summary statistics will be used to describe the mean and median duration of response. 
 
Analysis of Biomarker Correlative Study 
 
A total of 50 patients with LKB1-mutated lung cancer (half of them also with KRAS mutation) will enroll in the 
clinical trial with archived tissue samples available. We will obtain fresh tissue as possible, as biopsies are not 
mandatory for the study. 
 

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Overall, using available baseline biomarker information from the three projects, we will assess their 
prognostic effect on OS or PFS by calculating their prediction performance (e.g., Uno’s C-index33) for each 
biomarker individually or multiple biomarkers jointly through Cox proportional hazard model. A prognostic 
risk score may be generated based on the coefficients from the model.34 
 
Analysis of Safety Data 
 
All adverse events (including serious adverse events) will be summarized and described within each cohort. 
They will initially be reviewed regardless of attribution, but also whether they are possibly, probably, or 
definitely related to treatment. The incidence of severe adverse events or toxicities will be described. We 
will assess the proportion of patients who experience grade 3 or higher toxicity. To assess tolerability, we will 
also capture the proportion of patients who go off treatment due to adverse events. Will analyze SAEs as 
well, as well as laboratory data collected. 
 
Stopping rule for safety 
 
The first 5 patients in each cohort will be used as a safety run-in. The DLT is defined as above within the first 
cycle of treatment. We anticipate the DLT rate would not exceed 30%. Based on a Bayesian rule, if there are 
>=2 DLTs out of 5for a cohort, we would stop the enrollment for the cohort due to the safety concern, 
otherwise the trial will continue with the safety data being monitored by DSMB on a regular base. The 
potential stopping boundary for safety at the two interim looks would be >= 4 DLTs out of 10 and <= 8 DLTs 
out of 20. The safety stopping boundary is calculated based on the Bayesian Toxicity Monitoring (BTM) 
application (https://www.trialdesign.org) to control for the probability of excessive toxicity being less than 
70%. 
 
7. Sharing of Results with Participants 
In general, study staff will not provide any individual results to subjects (ex. outcome trial results or results from 
subject’s samples studies). If something of urgent medical importance to the participating subjects will be found, 
the PI (or co-Is) will inform the subject, although we expect that this will be a very rare occurrence. Samples and 
data will only be used for research. 
 
8. Study Timelines 
 
8.1 Duration of therapy 
In the absence of treatment delays due to adverse event(s), treatment may continue for until one of the following 
criteria applies: 
• 
Disease progression, 
• 
Intercurrent illness that prevents further administration of treatment, 
• 
Unacceptable adverse event(s), 
• 
Patient decides to withdraw from the study, or 
• 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 

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8.2 Duration of follow-up  
Subjects will be contacted every 3 months for up to 5 years upon leaving the study. 
 
Patient records may be reviewed until death to assess progression and survival.  Survival information may be 
collected by clinic visit, email, or telephone after ending protocol treatment and until the study is terminated, 
the patient dies, or the patient is lost to follow-up. 
 
A participant will be considered lost to follow-up if he fails to return for three scheduled visits and is unable to 
be contacted by the study site staff after three or more attempts at contact by phone. 
The following actions must be taken if a participant fails to return to the clinic for a required study visit: 
The site will attempt to contact the participant and reschedule the missed visit and counsel the participant on 
the importance of maintaining the assigned visit schedule and ascertain if the participant wishes to and/or should 
continue in the study. 
 
Patients removed from study for unacceptable adverse event(s) will be followed until resolution or stabilization 
of the adverse event. 
 
 
9. Inclusion and Exclusion Criteria 
 
Inclusion Criteria 
- 
Patients must have been histologically or cytologically diagnosed with non-small cell lung 
cancer, specifically lung adenocarcinoma 
 
- 
Patients must have advanced stage disease that is not amenable to combined modality 
therapy or surgical resection 
 
- 
Patients must have known LKB1 mutation 
 
- 
Patients must have known KRAS mutation (Cohort A only) 
 
- Patients must have progressed on immune checkpoint inhibitor alone and first line 
chemotherapy, either combined or sequentially, for advanced stage disease. There is no limit 
on prior lines of therapy.  
- 
Patients must have measurable disease, defined as at least one lesion that can be accurately 
measured in at least one dimension (longest diameter to be recorded for non-nodal lesions 
and short axis for nodal lesions) as >20 mm with conventional techniques or as >10 mm with 
spiral CT scan.   
 
- 
 Age >18 years.  
 
- 
 ECOG performance status 0 or 1  
 

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- 
Adequate recovery from toxicities related to prior treatments to at least Grade 1 by CTCAE 
v 5.0. Exceptions include alopecia and peripheral neuropathy grade ≤ 2. 
 
- 
 Patients must have normal organ and marrow function as defined below: 
− absolute neutrophil count 
>1,500/mcL 
− Hemoglobin  
 
 
 
 
>8.0 
− platelets  
 
 
 
 
 
>100,000/mcL 
− total bilirubin  
 
 
 
≤ 1.5 × upper limit of normal (ULN) for the  
institution; patients with Gilbert syndrome may enroll if 
total bilirubin < 3.0 mg/dL (51 μmole/L 
− AST(SGOT)/ALT(SGPT) 
 
alanine 
aminotransferase 
(ALT) 
and 
aspartate 
aminotransferase (AST) ≤ 2.5 × ULN (or < 5x ULN in 
patients with liver metastases) 
− creatinine clearance  
 
 
>50 mL/min/1.73 m2 for patients with creatinine levels 
above institutional normal. 
 
- 
 Patients must have the ability to ingest oral medications 
 
- 
 The effects of defactinib and avutometinib on the developing human fetus are unknown.  For 
this reason, women of child-bearing potential and men must agree to use adequate 
contraception (hormonal or barrier method of birth control; abstinence) prior to study 
entry,for the duration of study participation, for 3 months following the last dose of study 
therapy for male patients, and 1 month following the last dose of study therapy for female 
patients.  Should a woman become pregnant or suspect she is pregnant while she or her 
partner is participating in this study, she should inform her treating physician immediately. 
 
- 
 Patients must be able to understand and be willing to sign a written informed consent 
document. 
 
-Baseline QTc interval < 470 ms  using Fredericia’s QT correction formula. NOTE: This criterion 
does not apply to patients with a right or left bundle branch block. 
 
- 
Participants must receive prior authorization from their insurance companies to cover 
nivolumab prior to enrollment on study. 
 
Exclusion criteria 
 
An individual who meets any of the following criteria will be excluded from participation in this study: 
 
- 
Patients who have had systemic therapy within 3 weeks prior to entering the study or those 
who have not recovered from adverse events due to agents administered more than 4 weeks 
earlier. 
 
- 
Patients who are receiving any other investigational agents.  

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- 
 Patients with unstable or symptomatic brain metastasis or known leptomeningeal disease. 
Asymptomatic brain metastases are allowed if they meet the following criteria: a. Have been 
treated and have been stable for greater than or equal to 4 weeks as documented by 
radiologic imaging. b. Have not required increasing doses of corticosteroids within 2 weeks 
prior to study treatment. 
 
- 
 Patients with history of pre-existing auto-immune conditions that would pose a higher risk 
for toxicity with nivolumab will be excluded 
 
- 
 Patients who experienced serious auto-immune toxicity with prior immune checkpoint 
inhibitor therapy 
 
- 
 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to avutometinib or defactinib 
 
- 
 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements. 
 
- 
 Known hepatitis B, hepatitis C or human immunodeficiency virus (HIV) infection that is active 
and/or requires therapy. 
 
- 
Active skin disorder that has required systemic therapy within the past 1 year. Surgically 
removed early stage skin cancers are allowed. Topical creams are allowed as well. 
- 
History of rhabdomyolysis. 
- 
Concurrent ocular disorders: 
o Patients with history of glaucoma, history of retinal vein occlusion (RVO), 
predisposing factors for RVO, including uncontrolled hypertension, uncontrolled 
diabetes. 
o Patients with history of retinal pathology or evidence of visible retinal pathology 
that is considered a risk factor for RVO, intraocular pressure > 21 mm Hg as 
measured by tonometry, or other significant ocular pathology, such as anatomical 
abnormalities that increase the risk for RVO. 
o Patients with active or chronic, visually significant corneal disorders, other active 
ocular conditions requiring ongoing therapy or clinically significant corneal disease 
that prevents adequate monitoring of drug-induced keratopathy. Examples of 
visually significant corneal disorders include corneal degeneration, active or 
recurrent keratitis, and other forms of serious ocular surface inflammatory 
conditions. Visually significant corneal disorders do NOT include dry eyes, 
blepharitis, and uncomplicated corneal erosions. 

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- 
Patients with the inability to swallow oral medications or impaired gastrointestinal 
absorption due to gastrectomy or active inflammatory bowel disease. 
- 
Treatment with warfarin. Patients on warfarin for deep vein thrombosis/pulmonary 
embolism should be converted to low-molecular-weight heparin (LMWH) or direct oral 
anticoagulants (DOACs). Exposure to medications (with or without prescriptions), 
supplements, herbal remedies, or foods with potential for drug-drug interactions with 
defactinib within 14 days prior to the first dose of avutometinib or defactinib and during the 
course of therapy, including: 
o strong CYP3A4 inhibitors or inducers, strong CYP2C9 inhibitors or inducers, 
strong P-glycoprotein (P-gp) inhibitors or inducers. (See Concomitant therapy 
restrictions, Table-7 for more detail) 
- 
 Patients with a known ‘treatable driver mutation’ with FDA approved targeted therapy (such 
as EGFR, ALK, ROS1, NTRK, BRAF, RET, MET exon 14, HER2). The exception is KRAS as listed 
in the inclusion section. 
 
- 
 History of prior malignancy within past 2 years prior to study entry, with the exception of 
curatively treated malignancies or malignancies with very low potential for recurrence or 
progression. 
 
- 
 Female patients who are pregnant or breastfeeding. 
 
10.  Vulnerable Populations 
 
This study does not include the following special populations: 
- 
Adults unable to consent 
- 
Individuals who are not yet adults (infants, children, teenagers) 
- 
Pregnant women 
- 
Prisoners 
- 
Cognitively impaired or Individuals with Impaired Decision-Making Capacity 
 
11.  Local Number of Participants 
 
This study will enroll a maximum of 50 patients. 
 
12.  Recruitment Methods 
 
All subjects will be recruited from the lung cancer clinics at the Winship Cancer Institute. The study will be listed 
on the NIH clinical trials website and referring physicians will be notified by newsletters sent out by Winship. 
 

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13.  Withdrawal of Participants 
 
Participants are free to withdraw from participation in the study at any time upon request. An 
investigator may discontinue or withdraw a participant from the study for the following reasons:  
- 
Pregnancy  
- 
Significant study intervention non-compliance or if any clinical adverse event (AE), laboratory 
abnormality, or other medical condition or situation occurs such that continued participation 
in the study would not be in the best interest of the participant  
- 
If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation  
- 
Participant unable to receive study drug for a continuous duration beyond 4 weeks  
 
The reason for participant discontinuation or withdrawal from the study will be recorded on the Case Report 
Form (CRF). Subjects who sign the informed consent form, and receive the study intervention, and subsequently 
withdraw, or are withdrawn or discontinued from the study before the required period as listed in the statistics 
section, will be replaced. 
 
14.  Study Stopping Criteria 
In the event that one or more of the following stopping criteria are met, the study will be stopped due 
to risk of major safety concerns.  
I. 
Any death (other than disease progression) that is at least possibly related to the study agent. 
II. 
Occurrence of two or more Grade 4 events that are at least possibly related to the study agent. 
 
15. Risks to Participants 
The identified risks for avutometinib treatment are skin toxicity, eye toxicity, creatine phosphokinase 
(CPK) elevation, gastrointestinal tract toxicities, and edema. The potential risks are effects on the bone 
and cartilage, hematological toxicity, drug-drug interactions with strong inducers and inhibitors of 
CYP3A4, liver function abnormalities, renal toxicity, and tissue mineralization. The identified risk for 
defactinib treatment is hyperbilirubinemia/increased bilirubin. The important potential risks for 
defactinib treatment are gastrointestinal effects, interaction with warfarin, and drug-drug interactions; 
most specifically, drug-drug interactions with strong inhibitors or inducers of CYP3A4 or CYP2C9. Based 
on the monotherapy safety profiles there are no overlapping identified risks, while drug-drug 
interactions with inhibitors or inducers of CYP3A4 are overlapping potential risks. 
No apparent toxicities unique to the combination were observed in the preliminary data from 52 
patients treated with the combination as of 18 Mar 2020. The most common treatment-related 
adverse events (AEs) were rash (90%), CPK elevation (56%), hyperbilirubinaemia (42%), aspartate 
aminotransferase (AST) elevation (38%), fatigue (31%), glossitis/oral mucositis/mouth ulcers (31%), 
alanine aminotransferase (ALT) elevation (29%), diarrhoea (29%), visual disturbance (29%), nausea 
(25%) and peripheral oedema (21%), most of which were Grades 1 or 2 and reversible. 
The monotherapy and combination toxicities are managed using a combination of prophylaxis, 
supportive care, and dose modifications. Guidance on management of these AEs, including dose 
interruptions and modifications, is provided in Section 6.7. Detailed information about the known and 

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expected risks and reasonably expected AEs of avutometinib and defactinib and nivolumab may be 
found in the IB for each compound. 
Nivolumab risks may be reviewed in the Nivolumab Package Insert.  
16.  Potential Benefits to Participants 
 
There is no guarantee of benefit to subjects who enroll in this protocol. Patients may derive benefit due to 
improvements in symptoms, tumor shrinkage and delay in disease progression, as suggested by clinical activity 
seen with both monotherapies and the combination. 
 
17.  Data Management and Confidentiality 
All information will be collected on study-specific case report forms by the study staff.  The data submission 
schedule is as follows: 
 
At the time of registration: 
 
- 
Registration Form 
- 
Informed Consent Form (signed by the subject) 
- 
Eligibility Checklist 
- 
Source documents related to eligibility. 
 
Within 2 weeks after registration: 
 
- 
Baseline study case report forms 
- 
Pertinent source documents 
 
Within 2 weeks after 30-day follow-up: 
 
- 
On study case report forms 
- 
Pertinent source documents 
 
All study data will be reviewed for completeness and accuracy by the Protocol Chair. The Principal 
Investigator (or his/her designee) at each respective institution is responsible for review, and ensuring 
the completeness and accuracy, of the data generated by his/her institution. The study data will also be 
periodically reviewed by the Emory Winship Cancer Institute Clinical Research Office. 
 
The Data and Safety Monitoring Committee (DSMC) of the Winship Cancer Institute of Emory University will 
oversee the conduct of this study. This committee will review all pertinent aspects of study conduct including 
patient safety, compliance with protocol, data collection and efficacy.  
 
Adverse Events (AE’s), Serious Adverse Events (SAE’s) [including deaths, hospitalizations, and life-threatening 
events], and Unanticipated Problems (UP’s) will be managed and reported, as required to the IRB, the awarding 
IC, the NIH Office of Biotechnology Activities, and FDA as required. The trial will be monitored on an 
ongoing/continual basis to mitigate risks.  
 
The DSMC will review selected charts of patients entered to the study. Reviews will occur annually for studies 
that are low risk or moderate risk. High-risk studies will be reviewed every 6 months. The committee reserves 
the right to conduct additional audits, if necessary, at any time-point. The Principal Investigator is responsible for 
notifying the DSMC about the accrual of patients when the first subject has been entered to the study.  

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The charter for the Winship DSMC is available upon request to the investigator or other study-related personnel. 
Additionally, the study team [to include the PI] will present all data analyzed to date, record of accrual, and 
attributable toxicities at the Multidisciplinary Lung Oncology meeting which meets on a regular basis. 
 
As with our ongoing clinical trial, for the current proposal we will adhere strictly to Winship’s Data Safety 
Monitoring Plan which is provided in detail at the following link:  
 
https://winshipcancer.emory.edu/research/clinical-trials-office/data-and-safety-monitoring-
committee.html 
 
Any relevant findings or concerns will be shared with the Verastem team. 
17.1 Data: Objectives of correlative studies 
Correlative studies will be conducted in Projects 2 and 3 of the P01 program using samples from clinical trial 
participants. Studies will seek to address the following questions: 
 
Project 2: Determine the prognostic significance of STING expression in the response of LKB1-mutated 
patients underwent RAF/MEKi+FAKi+PD1 blockade clinical trial 
 
In order to evaluate the effect of FAK inhibitor + PD-1 blockade on the STING axis, we will analyze paired pre 
and post-treatment samples of PBMCs as well as paired tumor biopsies obtained in the context of clinical 
trial. These specimens will be analyzed for the expression of STING both by immunohistochemistry, as well 
as by single cell mass cytometry and transcriptomics. These studies will not only identify if this approach 
leads to changes in STING expression but also the cell type (e.g. tumor cells, or tumor-infiltrating immune 
cells such as myeloid cells), wherein this change is most evident. These changes will then be correlated with 
clinical endpoints such as overall or progression-free survival as well as with the changes in other immune 
cells (such as infiltrating T cells, or NK cells). In particular, as STING expression may be impacted by cytokines 
such as IFNg, we will particularly evaluate if there are changes in the expression of these cytokines or 
downstream pathways in immune cells during the course of this clinical trial. These studies obviously 
represent a collaboration involving not just project 3, but also the P01 Cores 2 and 3. 
 
Project 3: Determine how the combination of RAF/MEK inhibitor, FAK inhibitor and anti-PD-1 antibody 
treatment alters CD8 T cell recruitment and collective invasion through the microenvironment 
 
We hypothesize that hyperactive FAK due to LKB1-inactivation contributes to the resistance to immune 
response, and that FAK inhibition will enhance the efficacy of ICI.  To test this, we will leverage the Phase II 
clinical trial to determine if patients with mutant LKB1 have better efficacy with the novel combination, 
increased CD8+ T-cell recruitment, and if pY-FAK activation is associated with LKB1 inactivation and/or KRAS 
mutation among the different cohorts. Patients will be biopsied according to the clinical protocol. Tissues will 
be sectioned, paraffin embedded, and processed for IHC 35 for LKB1 (Abcam) and the biomarkers pY397-FAK 
(Invitrogen), pY861-FAK (Invitrogen), and total FAK (BD Transduction) performed in the lab with QC oversight 
and scoring by P01 Core 2. We can detect LKB1, pY397- and pY861-FAK by IHC in tissues 36, 37 and LKB1 mutation 
in the primary tumor 15. IHC scoring will be based upon percentage of tumor cells stained and intensity of 
stain, and performed independently in a blinded manner. The number, size, and morphology of CIPs and 
surrounding vim+, FSP1+ CAFs will be quantified by Core 2 37. Immune cell infiltration will be profiled using 
8-color immunophenotyping flow cytometry analysis and IHC staining using immune cell surface markers, 
such as CD8+ T cells and CD56+ NK cells by Core 2. We will also isolate immune cells from the lung to carry 

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out single-cell RNA (scRNA) sequencing with the 10X platform. This unbiased analysis will reveal changes in 
immune cells following defactinib treatment plus nivolumab, both at the level of cell types and changes in 
gene expression in individual cell types. We will use the biopsies to answer several questions: (1) Does LKB1 
loss, LKB1 mutation, pY-FAK activation, and/or KRAS mutation predict for efficacy with the combination 
regimen?; (2) Do NSCLC patients with LKB1 loss, LKB1 mutation, and/or KRAS mutation in the primary tumor 
show enhanced FAK activation? (3) Does defactinib treatment disrupt CAF:tumor cell interaction within the 
CIPs and collagen remodeling using IHC and SHG imaging as described in Aim 1-A and published in mice 
tissues 36, 37   
17.2 Specimens: 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, and the sponsor(s) 
and their agents. Therefore, the study protocol, documentation, data, and all other information generated will 
be held in strict confidence. No information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the Principal Investigator. The study participant’s contact 
information will be securely stored at each clinical site for internal use during the study. At the end of the study, 
all records will continue to be kept in a secure location for as long a period as dictated by local IRB and 
Institutional regulations. 
All stored samples will be maintained in the laboratory to which it was sent initially for analysis. Study 
participants who request destruction of samples will be notified of compliance with such request and all 
supporting details will be maintained for tracking. 
Tumor biopsies 
Archived tumor samples will be obtained from all the study participants as available. Pre-
treatment and on study repeat biopsy will be optional. 
Peripheral blood 
Peripheral blood samples will be obtained at baseline before initiation of study therapy 
and during weeks 1 of cycle1 2, 3, 5 and at time of progression. Approximately 20 ml of 
peripheral blood will be obtained in two vials. The mononuclear cells will be separated 
based on standard guidelines used in the Phase I Unit of the Winship Cancer Institute 
from one vial. The cells will be frozen at -80C until analysis. 
 
18.  Provisions to Monitor the Data to Ensure the Safety of Participants 
Plans to Monitor the Data to Ensure Safety of Participants and Data Integrity 
Check the box for the study’s risk level: 
☐ No more than minimal risk - Study not required to follow DSMP guidance, may delete the rest of this 
section. (Non-invasive sampling or imaging, blood draws, etc. are likely minimal risk if all procedures fall clearly 
within these categories. If all study procedures do not fall into these categories, and you still believe your study 
is minimal risk, consult with IRB staff.) 

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☒ More than minimal risk – Continue below. 
Review the Data and Safety Monitoring Questionnaire below and select the relevant monitoring table at the 
end of this section. You must complete only ONE of the tables.  
Mark the risk categorization, as determined by the Data and Safety Monitoring Questionnaire, that applies to 
your study below: 
Select one of the following (do not delete this table; review the guidance document for 
definitions): 
☐ Medium Complexity 
☒ High Complexity Category A 
☐ High Complexity Category B 
If choosing this category for a study under an IND or IDE because you believe the study 
intervention does not significantly impact morbidity or mortality, please provide your 
rationale: 
 
Monitoring Table  
Please address the specific details below. Please do not alter the table and leave all template text to assist in a 
quick review. If deemed not applicable, please provide rationale. 
 
DSMP Requirement 
How this Requirement is Met  
Frequency 
Responsible Party(ies) 
Real-time review of 
participant data during 
initial data collection. 
This requirement will be met per 
Winship’s NCI approved DSMP 
This will occur every 
time new 
information is 
obtained. 
Study team, DSMC 
Site Monitoring at pre-
determined intervals: The 
Principal Investigator has a 
responsibility to ensure 
that the study is following 
all aspects of the protocol.  
This requirement will be met per 
Winship’s NCI approved DSMP 
Annually 
DSMC 
 
100% review of regulatory 
files 
DSMC monitors will review the 
protocol, amendments, informed 
consent documents, IRB 
submissions and meet with the 
principal investigator for 
clarification of study objectives 
Reviewed at first and 
close-out visits 
DSMC 
100% review of consent 
forms 
QA check of 5-10 randomly 
selected consents to validate 
Central Subject Registration (CSR) 
and PRMS to conduct QA consent 
checks in real time as subjects are 
registered in OnCore vis CSR 
process 
Biannually 
PRMS, QM 

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Review of credentials, 
training records, the 
delegation of responsibility 
logs (if applicable) 
Clinical trials monitor will review 
the electronic regulatory binder 
and compare them against the 
staff listed on the DOA log. The 
monitor also reviews the site’s 
source documents to ensure that 
all study staff have been properly 
listed on the DOA and have 
corresponding documentation (CV, 
ML, GCP certs, training log) filed in 
the electronic regulatory study 
binder 
Biannually 
Study team, DSMC 
Comparison of case report 
forms (CRF) to source 
documentation for 
accuracy and completion 
The PI is responsible for ensuring 
that instances of egregious data 
insufficiencies that may impact the 
scientific integrity of the trial 
Biannually 
Study team, DSMC 
Review of documentation 
of all adverse events 
During the monitoring process, the 
DSMB reviews trial safety data for 
stopping rules, deviations, study 
amendments, accrual rates and 
monitoring reports for therapeutic 
investigator-initiated clinical trials 
and any other trial as deemed 
necessary 
Biannually 
Study team, DSMC 
Monitoring of critical data 
points (eligibility, study 
endpoints, etc.) 
The assigned monitor will 
randomly select subject(s) for 
review. Although the principal 
investigator and applicable study 
team members will receive 
notification of trial monitoring in 
advance, the subject selection will 
not be revealed in advance of the 
monitoring visit. 
Biannually 
Study team, DSMC 
Laboratory review of 
processing and storage of 
specimens 
The assigned monitor will 
randomly select subject(s) for 
review. 
Reviewed at first and 
close-out visits and 
at least biannually 
Study team, DSMC 
Assessment of laboratory 
specimens stored locally 
QM will monitor data entered into 
the study database against the site 
source documents, including 
laboratory reports. During visits to 
the laboratory, QM will ensure 
study specimens are being properly 
stored, handled and shipped 
according to the protocol and lab 
manual. 
Reviewed at first and 
close-out visits and 
at least annually 
Winship Quality 
Management 
Department 
Test article accountability 
review 
Protocol-designated pharmacy for 
clinical research  
Reviewed at first and 
close-out visits and 
at least biannually 
Research Pharmacist 

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Accountability logs, 
dispensing records, and 
other participant records  
QM will review accountability and 
dispensing log, including IP 
administration forms. 
Biannually 
Winship Quality 
Management 
Department 
For FDA regulated studies, 
the following requirements 
apply: 
Monitoring activities will meet the 
FDA's requirements as delineated 
in 21 CFR 50, 21 CFR 56, 21 CFR 812 
for studies conducted under an IDE 
and 21 CFR 312 for studies 
conducted under an IND. 
Annually 
DSMC 
Monitoring methods (may 
include centralized, on-site, 
and self-monitoring) 
On-site monitoring of protocol 
adherence and subject eligibility, 
comparison of source documents 
with CRFS for data integrity, review 
of adverse events, ensure IIP is 
stored properly and secure; remote 
monitoring of patient eligibility and 
consent as well as data quality and 
adverse events 
Annually                          DSMC 
*For international studies, you are required to engage a CRO that is working in the site country and/or to consult 
with Emory’s legal counsel regarding compliance with the country’s clinical research regulations. 
                                                                                                                       
The Data and Safety Monitoring Committee (DSMC) of the Winship Cancer Institute will provide oversight for 
the conduct of this study.  The DSMC functions independently within Winship Cancer Institute to conduct 
internal monitoring functions to ensure that research being conducted by Winship Cancer Institute 
Investigators produces high-quality scientific data in a manner consistent with good clinical practice (GCP) and 
appropriate regulations that govern clinical research.    Depending on the risk level of the protocol, the DSMC 
review may occur every 6 months or annually.  For studies deemed Moderate Risk, initial study monitoring will 
occur within 1 year from the date of the first subject accrued, with 2 of the first 5 subjects being reviewed.  
Subsequent monitoring will occur in routine intervals per the Winship Data and Safety Monitoring Plan (DSMP).  
 
The DSMC will render a recommendation and rating based on the overall trial conduct.  The PI is responsible for 
ensuring that instances of egregious data insufficiencies are reported to the IRB.  Continuing Review 
submissions will include the DSMC recommendation letter.  Should any revisions be made to the protocol-
specific monitoring plan after initial DSMC approval, the PI will be responsible for notifying the DSMC of such 
changes.  The Committee reserves the right to conduct additional audits if necessary.                                                                
Adverse Event Characteristics  
 
• 
CTCAE term (AE description) and grade:  The descriptions and grading scales found in the revised 
NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE 
reporting.  All appropriate treatment areas should have access to a copy of the CTCAE version 
5.0.  A copy of the CTCAE version 5.0 can be downloaded from the CTEP web site.   
 
• 
‘Expectedness’: AEs can be ‘Unexpected’ or ‘Expected’ (see Section 7.1 above) for expedited 
reporting purposes only.  ‘Expected’ AEs (the ASAEL) are bold and italicized in the CAEPR. 
 

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• 
Attribution of the AE: 
- 
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 treatment. 
 
SAE definition: Death, a life-threatening adverse event, inpatient hospitalization or prolongation of 
existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions, or a congenital anomaly/birth defect. Important medical events that 
may not result in death, be life-threatening, or require hospitalization may be considered serious 
when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may 
require medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Expedited Adverse Event Reporting  
 
All Adverse Events must be reported in routine study data submissions.  
The AE reporting period begins from the time that the patient signs the informed consent through and including 
30 calendar days after the last dose of study drug. All AEs/SAEs should be followed until resolution or 
stabilization. Any SAE occurring after the reporting period must be promptly reported if a causal relationship to 
the investigational drug is suspected. If the patient begins a new anticancer therapy, the safety reporting period 
ends at the time the new treatment is started, however, death must always be reported if it occurs during the 
AE reporting period irrespective of intervening treatment. 
 
Note:  All deaths on study require both routine and expedited reporting regardless of causality.  Attribution to 
treatment or other cause must be provided. 
  
Routine Adverse Event Reporting 
Overdose 
Overdoses will not be considered SAEs unless the outcome of the overdose meets seriousness criteria as defined 
in the protocol. In the event of an overdose that causes an SAE, Verastem Safety and Pharmacovigilance should 
be notified within 24 hours. The patient should be carefully monitored for potential adverse reactions and 
symptomatic treatment instituted as per institutional standard of care (SOC). The Investigator will determine if 
and when dosing should resume. 
 
Pregnancy and Contraception: 
The effects of defactinib on conception, pregnancy, and lactation are unknown. 
At Screening, all male and female patients of reproductive potential (i.e., not surgically sterile or female patients 
who are not postmenopausal) must agree to use highly effective methods of contraception for the duration of 
defactinib and for at least 3 months after the last dose of study drug(s) for male patients, and at least 1 month 
after the last dose of study drug(s) for female patients. Pregnancy testing should be conducted monthly during 
the trial. A positive urine test must be confirmed by a serum test. Male patients must also refrain from donating 

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sperm during their participation in the study and for at least 3 months after the last dose of study drug(s). Female 
patients should not breastfeed during the study and for at least 3 weeks after the last dose of study drug(s).  
 
A patient must immediately inform the Investigator if the patient or patient’s partner becomes pregnant from 
the time of consent to 30 days after the last dose of study drug(s). Any female patients receiving study drug(s) 
who become pregnant must immediately and permanently discontinue study drug(s). The pregnant woman 
should be referred to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation 
and counseling.  
 
Pregnancy per se is not considered as an AE unless there is cause to believe that the study drug(s) may have 
interfered with the effectiveness of contraceptive medication or if the outcome of pregnancy meets SAE criteria 
(miscarriage or congenital anomaly/birth defect, etc.), in which case it should be reported in the same manner 
and timelines as an SAE. 
 
Any SAEs associated with pregnancy (e.g. congenital abnormalities/birth defects/spontaneous miscarriage or any 
other serious events) must additionally be reported. In addition, any infant death or congenital anomaly 
occurring more than 30 days after the patient’s last dose of study drug(s) that the Investigator suspects is related 
to the in-utero exposure to the defactinib should also be reported as an SAE. Hospitalization for normal delivery 
of a healthy newborn is not an SAE. 
 
Consent to provide follow-up information regarding the outcome of the pregnancy and the health of the infant 
until 30 days old will be requested. Any pregnancy must be reported to Verastem, Inc. within 24 hours of the 
Investigator’s knowledge of the pregnancy using a site-specific SAE/Pregnancy or MedWatch/CIOMS-I Report 
Forms. The Investigator will observe the pregnant woman until completion of the pregnancy and must notify 
Verastem, Inc. of the outcome within 24 hours of the Investigator’s knowledge of the pregnancy outcome. This 
notification includes pregnancies resulting in live, normal births. 
Highly Effective Methods of Contraception: 
 
Methods that can achieve a failure rate of less than 1% per year when used consistently and 
correctly are considered as highly effective birth control methods. Such methods include: 
• 
combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation1: 
o oral 
o intravaginal 
o transdermal 
• 
progestogen-only hormonal contraception associated with inhibition of ovulation1: 
o oral 
o injectable 
o implantable2 
• 
intrauterine device (IUD)2 
• 
intrauterine hormone-releasing system (IUS)2 
• 
bilateral tubal occlusion2 
• 
vasectomized partner2,3 
• 
sexual abstinence4 

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1Hormonal contraception may be susceptible to interaction with the IMP, which may reduce the efficacy of the 
contraception method. 
2Contraception methods that are considered to have low user dependency 
3Vasectomized partner is a highly effective birth control method provided that partner is the sole sexual partner 
of the WCBP study participant and that the vasectomized partner has received medical assessment of the surgical 
success. 
4Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study treatments. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual 
lifestyle of the patient. 
 
Verastem, Inc. Safety and Pharmacovigilance Contact Information: 
Investigator to send SAE and Pregnancy Information to: 
Verastem, Inc. Safety and Pharmacovigilance  
Email: drugsafety@verastem.com 
Facsimile: + 1-781-465-7936 
 
19.  Provisions to Protect the Privacy Interests of Participants 
 
Data Collection and Management  
Data will be collected using an institutional electronic data recording system, Oncore. Electronic case report 
forms and study calendar will be generated prior to study activation. Investigator responsibilities are set 
out in the ICH guideline for Good Clinical Practice (GCP) and in the US Code of Federal Regulations. The 
Investigator will permit study-related audits by Verastem or its representatives, IRB/EC review, and 
regulatory inspection(s) (e.g., FDA, EMEA), providing direct access to the facilities where the study took 
place, to source documents, to CRFs, and to all other study documents. The Investigator, or a designated 
member of the Investigator’s staff, must be available at some time during audits to review data and resolve 
any queries and to allow direct access to the subject’s records (e.g., medical records, office charts, hospital 
charts, and study related charts) for source data verification. The data collection must be completed prior 
to each visit and be made available so that the accuracy and completeness may be checked.  
 
Disclosure and confidentiality  
The investigator will keep all information provided by Verastem in strict confidence and will request similar 
confidentiality from his/her staff and the IRB/IEC/REB. Study documents provided by Verastem 
(investigators' brochures and other material) will be stored appropriately to ensure their confidentiality. 
The information provided to the investigator may not be disclosed to others without direct written 
authorization from Verastem, except to the extent necessary to obtain informed consent from patients 
who wish to participate in the trial.  
 
Study records requirements  
The Investigator must ensure that the records and documents pertaining to the conduct of the study and 
the distribution of the protocol therapy, that is copies of CRFs and source documents (original documents, 
data, and records [e.g., hospital records; clinical and office charts; laboratory notes; memoranda; subject’s 

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diaries or evaluation checklists; SAE reports, pharmacy dispensing records; recorded data from automated 
instruments; copies or transcriptions certified after verification as being accurate copies; microfiches; 
photographic negatives, microfilm, or magnetic media; x-rays; subject files; and records kept at the 
pharmacy, at the laboratories, and at medico-technical departments involved in the clinical study; 
documents regarding subject treatment and drug accountability; original signed informed consents, etc.]) 
be retained by the Investigator for as long as needed to comply with national and international regulations 
(generally 2 years after discontinuing clinical development or after the last marketing approval).  
 
Source data and documents  
In accord with ICH-GCP as adopted by the FDA, all information in original records and certified copies of 
original records or clinical findings, observations, or other activities necessary for the reconstruction and 
evaluation of the trial is considered source data. Source data are contained in source documents, which can 
be original records or certified copies of hospital records, clinical and office charts, laboratory notes, 
memoranda, subjects' diaries of evaluation checklists, pharmacy dispensing records, recorded data from 
automated instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at 
the pharmacy, at the laboratories, and at medico-technical departments involved in the clinical trial. Case 
Report Forms (CRFs): Source data may be collected in the source documents or entered directly onto the 
case report forms.  
 
Training of study site personnel  
The study PI (sponsor-investigator) will provide training as appropriate to the delegated responsibility to all 
staffs involved in the conduct of the study. Before the first patient is enrolled in the study, study staff and 
co-investigators will review and discuss the requirements of the clinical study protocol and related 
documents including getting trained in any study-specific procedures and electronic data capture systems 
to be utilized. The Sponsor-Investigator will ensure that appropriate training relevant to the study is given 
to all of these staff and any new information relevant to the performance of this study is forwarded to the 
staff involved. The Principal Investigator will maintain a record of all individuals involved in the study 
(medical, nursing, and other staff). 
 
20.   Economic Burden to Participants 
 
The study-supporter will pay for certain items and services the subject may receive in this study. Subjects 
will have to pay for the items or services for which the study sponsor does not pay. The sponsor will not 
pay for regular medical care. 
 
21.  Consent Process 
 
The initial informed consent discussion will occur in Winship Cancer Institute or the Emory Clinic. At 
Winship Cancer Institute, the informed consent is an ongoing, interactive process rather than a one-time 
information session. The consent form document is designed to begin the informed consent process, which 
provides the patient with ongoing explanations that will help them make educational decisions about 

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whether to begin or continue participating in the trial. The research team knows that a written document 
alone may not ensure that the patient fully understands what participation means. Therefore, the research 
team will discuss with the patient the trial's purpose, procedures, risks and potential benefits, and their 
rights as a participant. The team will continue to update the patient on any new information that may 
affect their situation. Consent will be obtained prior to any research-driven procedures. The investigator 
will assess the patient’s capacity during his/her encounters with him or her. The investigator will give the 
person providing consent adequate opportunity to read the consent document before it is signed and 
dated. It will be explained to prospective participants that the study involves research, the purpose of the 
research, the expected duration of participation, as well as the approximate number of participants to be 
enrolled. The study procedures, and identification of research procedures v. non-research will also be 
thoroughly discussed. It will be explained to participants that participation is voluntary and that the subject 
may discontinue at any time. Refusal to participate or withdraw will not involve a penalty or loss of benefits 
to which the participant is otherwise entitled. Refusal will in no way affect the participant's future are. The 
participant will also be told of the possible consequences of the decision to withdraw from the research, 
and procedures for orderly termination of participation. Any significant new findings developed during the 
course of the research that may affect the participant's willingness to continue to participate will be 
provided. Also explained will be anticipated circumstances under which the subject's participation may be 
terminated by the investigator without the participant's consent. Prospective participants will be provided 
with a description of any reasonably foreseeable risks or discomforts as well as a description of any benefits 
to the participant or to others that might be reasons expected from the research. Alternative procedures or 
courses of treatment will also be thoroughly discussed. Prospective participants will also be given detailed 
information describing the extent to which confidentiality of records identifying the participant will be 
maintained and what records may be examined by the research staff, IRBs, sponsor, their representatives, 
and possibly the FDA or OHRP. Also communicated to the participant will be an explanation that 
emergency medical care will be arranged for a study-related illness or injury, and an explanation of 
whether funds are set aside to pay for this care and/or compensation, and if so by whom (e.g., sponsor, 
subject, insurer). The participant is told the source of the study's funding. All participants will be told of any 
additional costs that may result from participation in the research. 
 
Non-English-Speaking Participants   
A certified translator/interpreter will be present during the consenting process and all questions and concerns 
will be answered by the treating physician. A Short Form in that specific language will be used. A certified 
translator/interpreter will be present during the consenting process and this will be documented. We will use 
what's available on Emory IRB website. For the languages that are not available, we will have the short form 
translated to that language and submit the IRB for review and approval prior to use. Process to Document 
Consent in Writing: Winship SOP 2.1:”Obtaining Informed consent for Interventional clinical trial” will be 
followed. 
 
 

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22.   Setting 
 
The research will be conducted at Emory University, and at Emory Saint Joseph’s. Potential participants will be 
identified in medical oncology clinics, multidisciplinary cancer clinic, surgical oncology clinics, and 
multidisciplinary tumor board at Emory University. 
 
23.  Resources Available 
 
Emory University was founded in 1836 and is a national center for teaching, research, and service. Emory 
University has been named as one of the nation’s top 25 universities for more than a decade by the U.S. News 
and World Report. Emory University research partners include the Georgia Institute of Technology, the University 
of Georgia, Morehouse School of Medicine, the US Centers for Disease Control and Prevention, Children's 
Healthcare of Atlanta, and the Georgia Clinical and Translational Science Alliance (GACTSA). Emory University 
researchers received $734 million from external funding agencies in fiscal year 2018, including approximately 
$441 million in funding from federal agencies, $359 million of this from the National Institutes of Health (NIH).  
 
Winship Cancer Institute (Winship) is Georgia's first and only National Cancer Institute (NCI)-designated 
Comprehensive Cancer Center (P30CA138292) and is dedicated to the integration of innovative clinical and basic 
science research with outstanding patient care for the prevention, treatment and control of cancer. First 
designated in 2009, Winship’s NCI designation was renewed in 2012 and 2016, achieving an “outstanding” rating. 
Winship earned the prestigious Comprehensive Cancer Center designation from the NCI in 2016, after 
demonstrating that its outstanding programs are reducing the cancer burden on the state of Georgia through 
research conducted in its laboratories, its clinical trial program, and its population-based science. The 
institutional support for Winship was rated as ‘exceptional’ by the review panel.  
 
The Winship Clinic Building C houses the primary offices and clinical space for cancer services including the 
medical oncology, hematology, and surgical oncology clinics, the radiation oncology program, and the Winship 
Ambulatory Infusion Center. In summer 2017, Emory Healthcare completed the expansion of Emory University 
Hospital Tower on Clifton Road. This nine-floor facility adds 144 inpatient beds to the hospital, of which more 
than 80% are dedicated to cancer care. The hospital expansion also accommodates cancer patient-specific 
intensive care units, an expanded BMT Unit with peri-transplant clinics to facilitate continuity of care, and a 24-
hour cancer urgent care center, which serves as both a triage facility and short stay treatment center for patients 
with cancer-related medical concerns.  
 
The Winship Phase I Unit, on the fourth floor of the Emory University Hospital Tower, is the largest unit in Georgia 
dedicated to the earliest and most critical phase of new cancer therapy evaluation. There is space for 15 private 
treatment bays, four clinic rooms, its own lab for doing patient blood work, a dedicated secure medication room, 
computer workspace for research and other support staff, and a "fast track" bay with three chairs for rapid use 
in patients who, for example, might need only a research lab test done. 
 
 

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24. References 
 
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8. Epub 2005/09/02. doi: 6602744 [pii] 10.1038/sj.bjc.6602744. PubMed PMID: 16136050. 
23. 
Sood AK, Coffin JE, Schneider GB, Fletcher MS, DeYoung BR, Gruman LM, Gershenson DM, Schaller MD, 
Hendrix MJ. Biological significance of focal adhesion kinase in ovarian cancer: role in migration and 
invasion. Am J Pathol. 2004;165(4):1087-95. Epub 2004/10/07. doi: 165/4/1087 [pii]. PubMed PMID: 
15466376; PMCID: 1618649. 
24. 
Gabarra-Niecko V, Schaller MD, Dunty JM. FAK regulates biological processes important for the 
pathogenesis of cancer. Cancer Metastasis Rev. 2003;22(4):359-74. Epub 2003/07/30. PubMed PMID: 
12884911. 
25. 
Owens LV, Xu L, Craven RJ, Dent GA, Weiner TM, Kornberg L, Liu ET, Cance WG. Overexpression of the 
focal adhesion kinase (p125FAK) in invasive human tumors. Cancer research. 1995;55(13):2752-5. Epub 
1995/07/01. PubMed PMID: 7796399. 
26. 
Weiner TM, Liu ET, Craven RJ, Cance WG. Expression of focal adhesion kinase gene and invasive cancer. 
Lancet. 1993;342(8878):1024-5. Epub 1993/10/23. PubMed PMID: 8105266. 
27. 
Wang C, Yang R, Yue D, Zhang Z. Expression of FAK and PTEN in bronchioloalveolar carcinoma and lung 
adenocarcinoma. Lung. 2009;187(2):104-9. Epub 2009/02/27. doi: 10.1007/s00408-008-9130-6. 
PubMed PMID: 19242756. 
28. 
Bagi CM, Roberts GW, Andresen CJ. Dual focal adhesion kinase/Pyk2 inhibitor has positive effects on 
bone tumors: implications for bone metastases. Cancer. 2008;112(10):2313-21. Epub 2008/03/19. doi: 
10.1002/cncr.23429. PubMed PMID: 18348298. 
29. 
Halder J, Lin YG, Merritt WM, Spannuth WA, Nick AM, Honda T, Kamat AA, Han LY, Kim TJ, Lu C, Tari AM, 
Bornmann W, Fernandez A, Lopez-Berestein G, Sood AK. Therapeutic efficacy of a novel focal adhesion 
kinase inhibitor TAE226 in ovarian carcinoma. Cancer research. 2007;67(22):10976-83. Epub 2007/11/17. 
doi: 67/22/10976 [pii] 10.1158/0008-5472.CAN-07-2667. PubMed PMID: 18006843. 
30. 
Schwock J, Dhani N, Hedley DW. Targeting focal adhesion kinase signaling in tumor growth and 
metastasis. 
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2010;14(1):77-94. 
Epub 
2009/12/17. 
doi: 
10.1517/14728220903460340. PubMed PMID: 20001212. 
31. 
van Nimwegen MJ, van de Water B. Focal adhesion kinase: a potential target in cancer therapy. Biochem 
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2007;73(5):597-609. 
Epub 
2006/09/26. 
doi: 
S0006-2952(06)00505-3 
[pii] 
10.1016/j.bcp.2006.08.011. PubMed PMID: 16997283. 
32. 
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33. 
Uno H, Cai T, Pencina MJ, D'Agostino RB, Wei LJ. On the C-statistics for evaluating overall adequacy of 
risk prediction procedures with censored survival data. Statistics in medicine. 2011;30(10):1105-17. Epub 
2011/01/13. doi: 10.1002/sim.4154. PubMed PMID: 21484848. 
34. 
Mehta HB, Mehta V, Girman CJ, Adhikari D, Johnson ML. Regression coefficient-based scoring system 
should be used to assign weights to the risk index. Journal of clinical epidemiology. 2016;79:22-8. Epub 
2016/05/18. doi: 10.1016/j.jclinepi.2016.03.031. PubMed PMID: 27181564. 
35. 
Kline ER, Shupe J, Gilbert MM, Zhou W, Marcus AI. LKB1 represses focal adhesion kinase (FAK) signaling 
via a FAK-LKB1 complex to regulate FAK site maturation and directional persistence. J Biol Chem. 2013. 
Epub 2013/05/03. doi: M112.444620 [pii] 10.1074/jbc.M112.444620. PubMed PMID: 23637231. 
36. 
Gilbert-Ross M, Konen J, Koo J, Shupe J, Robinson BS, Wiles WGt, Huang C, Martin WD, Behera M, Smith 
GH, Hill CE, Rossi MR, Sica GL, Rupji M, Chen Z, Kowalski J, Kasinski AL, Ramalingam SS, Fu H, Khuri FR, 
Zhou W, Marcus AI. Targeting adhesion signaling in KRAS, LKB1 mutant lung adenocarcinoma. JCI Insight. 
2017;2(5):e90487. Epub 2017/03/16. doi: 10.1172/jci.insight.90487. PubMed PMID: 28289710; PMCID: 
PMC5333956 exists. 

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Richardson AM, Havel LS, Koyen AE, Konen JM, Shupe J, Wiles WGt, Martin WD, Grossniklaus HE, Sica G, 
Gilbert-Ross M, Marcus AI. Vimentin Is Required for Lung Adenocarcinoma Metastasis via Heterotypic 
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: an official journal of the American Association for Cancer Research. 2018;24(2):420-32. Epub 
2017/12/07. doi: 10.1158/1078-0432.CCR-17-1776. PubMed PMID: 29208669; PMCID: PMC5771825. 
 
 
 
 
 

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APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
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. 
 
As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., 
Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 
1982. The Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair 
 
 

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APPENDIX B  
Drug Diary 
 
See attached 
 
 
APPENDIX C   Abbreviations and definition of terms 
 
The following abbreviations and special terms are used in this study Clinical Study Protocol. 
 
Abbreviation or special term 
Explanation 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALK 
Anaplastic lymphoma kinase 
ALT 
Alanine aminotransferase 
APF12 
Proportion of patients alive and progression free at 12 months from randomization 
AST 
Aspartate aminotransferase 
BoR 
Best objective response 
BP 
Blood pressure 
C 
Cycle 
CD 
Cluster of differentiation 
CI 
Confidence interval 
CL 
Clearance 
Cmax 
Maximum plasma concentration 
Cmax,ss 
Maximum plasma concentration at steady state 
CR 
Complete response 
CSA 
Clinical study agreement 
CSR 
Clinical study report 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Event 
CTLA-4 
Cytotoxic T–lymphocyte-associated antigen 4 
Ctrough,ss 
Trough concentration at steady state 
CXCL 
Chemokine (C-X-C motif) ligand 
DoR 
Duration of response 

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Abbreviation or special term 
Explanation 
EC 
Ethics Committee, synonymous to Institutional Review Board and Independent 
Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDoR 
Expected duration of response 
EGFR 
Epidermal growth factor receptor 
EU 
European Union 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
GMP 
Good Manufacturing Practice 
hCG 
Human chorionic gonadotropin 
HIV 
Human immunodeficiency virus 
HR 
Hazard ratio 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IFN 
Interferon 
IgE 
Immunoglobulin E 
IgG 
Immunoglobulin G 
IHC 
Immunohistochemistry 
IL 
Interleukin 
ILS 
Interstitial lung disease 
IM 
Intramuscular 
IMT 
Immunomodulatory therapy 
IP 
Investigational product  
irAE 
Immune-related adverse event 
IRB 
Institutional Review Board 

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Abbreviation or special term 
Explanation 
irRECIST 
Immune-related Response Evaluation Criteria in Solid Tumors 
ITT 
Intent-to-Treat 
IV 
Intravenous 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System 
mAb 
Monoclonal antibody 
MDSC 
Myeloid-derived suppressor cell 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHLW 
Minister of Health, Labor, and Welfare 
miRNA 
Micro-ribonucleic acid 
MRI 
Magnetic resonance imaging 
NCI 
National Cancer Institute 
NE 
Not evaluable 
NSCLC 
Non–small-cell lung cancer 
OAE 
Other significant adverse event 
ORR 
Objective response rate 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cell 
PD 
Progressive disease 
PDx 
Pharmacodynamic(s) 
PFS 
Progression-free survival 
PFS2 
Time to second progression 
PGx 
Pharmacogenetic research 
PK 
Pharmacokinetic(s) 
PR 
Partial response 
q2w 
Every 2 weeks 
q3w 
Every 3 weeks 
q4w 
Every 4 weeks 
q6w 
Every 6 weeks 
q8w 
Every 8 weeks 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 

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Abbreviation or special term 
Explanation 
RECIST 1.1 
Response Evaluation Criteria in Solid Tumors, version 1.1 
RNA 
Ribonucleic acid 
RR 
Response rate 
RT-QPCR 
Reverse transcription quantitative polymerase chain reaction 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS 
Safety analysis set 
SCLC 
Small cell lung cancer 
SD 
Stable disease 
SNP 
Single nucleotide polymorphism 
SoC 
Standard of Care 
T3 
Triiodothyronine 
T4 
Thyroxine 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
US 
United States 
WBDC 
Web-Based Data Capture 
WHO 
World Health Organization 
 

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APPENDIX D. GUIDANCE ON INHIBITORS, INDUCERS, AND SUBSTRATES 
Examples of CYP2C9 and CYP3A4 inhibitors, inducers and substrates are provided below. Examples 
of P-gp and BCRP inhibitors and inducers are provided below. Examples of P-gp and 
OATP1B1/1B3 substrates are provided below. Additional information can be found at: 
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-
substrates-inhibitors-and-inducers and https://www.drugbank.ca/categories/DBCAT002635 
(CYP2C9 inhibitors). 
CYP2C9 or CYP3A4 Inhibitors 
Patients receiving avutometinib or defactinib are prohibited from concomitant use of medications (with 
or without prescriptions), supplements, herbal products or foods that are known to be strong inhibitors 
of CYP3A4. Patients receiving defactinib are also prohibited from concomitant use of agents that are 
known to be strong inhibitors of CYP2C9.  
The table below provides examples of agents known to inhibit CYP2C9 or CYP3A4 activity. Note that 
this is not a comprehensive list of all agents which may inhibit CYP2C9 or CYP3A4 activity.  
Classification of In Vivo Inhibitors of CYP2C9 and CYP3A4 
CYP 
Strong Inhibitorsa 
Moderate Inhibitorsb 
Weak Inhibitorsc 
CYP2C9 
Nicardipine, Gemfibrozil, 
Floxuridine, Turmeric, 
Sulphaphenazole, 
Clotrimazole 
Amiodarone, Fluconazole, 
Miconazole 
Disulfiram, Fluvastatin, 
Fluvoxamine, Voriconazole 
CYP3A4 
Boceprevir, Clarithromycin, 
Conivaptan, Grapefruit 
Juiced, Indinavir, 
Itraconazole, Ketoconazole, 
Lopinavir/Ritonavir, 
Mibefradile, Nefazodone, 
Nelfinavir, Posaconazole, 
Ritonavir, Saquinavir, 
Telaprevir, Telithromycin, 
Voriconazole 
Amprenavir, Aprepitant, 
Atazanavir, Ciprofloxacin, 
Darunavir/Ritonavir, 
Diltiazem, Erythromycin, 
Fluconazole, Fluvoxamin, 
Grapefruit Juiced, Verapamil 
Alprazolam, Amiodarone, 
Amlodipine, Atorvastatin, 
Cilostazol, Cimetidine, 
Cyclosporine, Fluoxetine, 
Fluvoxamine, Ginkgof, 
Goldensealf, Isoniazid, Oral 
Contraceptives, Ranitidine, 
Ranolazine, Tipranavir/ 
Ritonavir, Zileuton 
Abbreviations: AUC: area under the curve; CL: clearance; CYP: Cytochrome P450; 
a A strong inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a substrate for that CYP by ≥ 5-
fold or > 80% decrease in CL. 
b A moderate inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a sensitive substrate for that 
CYP by < 5-fold but ≥ 2-fold or 50 to 80% decrease in CL. 
c A weak inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a sensitive substrate for that CYP 
by < 2-fold but ≥ 5-fold or 20 to 50% decrease in CL. 
d The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation-dependent. Studies 
have shown that it can be classified as a “strong CYP3A4 inhibitor” when a certain preparation was used (eg, high dose, 
double strength) or as a “moderate CYP3A4 inhibitor” when another preparation was used (eg, low dose, single strength). 
e Withdrawn from the US market because of safety reasons. 
f Herbal product. 

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CYP2C9 or CYP3A4 Inducers 
Patients receiving avutometinib and defactinib are prohibited from concomitant use of medications 
(with or without prescriptions), supplements, herbal products, or foods that are known to be strong 
inducers of CYP3A4. Patients receiving defactinib are also prohibited from concomitant use of agents 
that are known to be strong inducers of CYP2C9.  
The table below provides examples of agents known to induce CYP2C9 or CYP3A4 activity. Note that 
this is not a comprehensive list of all agents which may induce CYP2C9 or CYP3A4 activity. 
 
 
CYP2C9 or CYP3A4 Inducers 
CYP 
Strong Inducers 
 ≥ 80% decrease in AUC 
Moderate Inducers 
50-80% decrease in 
AUC 
Weak Inducers 
20-50% decrease in AUC 
CYP2C9 
- 
Rifampin 
Aprepitant, Carbamazepine, 
Ritonavir 
CYP3A4 
Carbamazepine, Mitotane, 
Phenytoin, Rifampin,  
St. John’s Wort a,b  
Bosentan, Efavirenz, 
Etravirine, Modafinil, 
Nafcillin 
Amprenavir, Aprepitant, 
Armodafinil, Echinacea b, 
Pioglitazone, Prednisone, 
Rufinamide 
Abbreviations: AUC: area under the curve; CYP: cytochrome P450 
a The effect of St. John’s Wort varies widely and is preparation dependent. 
b Herbal product 
CYP2C9 or CYP3A4 Substrates 
Substrates of CYP2C9 or CYP3A4 should be used with caution. Co-administration of a CYP3A4 or 
CYP2C9 substrate with defactinib may increase treatment-related toxicities of these drugs. Known 
sensitive substrates and moderate sensitive substrates are listed in the table below Consider finding an 
alternative drug that is not a substrate of CYP2C9 or CYP3A4. 
CYP2C9 and CYP3A4 Substrates 
CYP 
Sensitive Substratesa 
Moderate Sensitive Substratesb 
CYP2C9 
Celecoxib 
Glimepiride, Phenytoin, Tolbutamide, 
Warfarin 
CYP3A4 
Alfentanil, Buspirone, Conivaptan, Darifenacin, 
Darunavir, Ebastine, Lomitapide, Lovastatin, 
Midazolam, Naloxegol, Nisoldipine, Saquinavir, 
Simvastatin, Tacrolimus, Tipranavir, Triazolam 
Alprazolam, Aprepitant, Atorvastatin, 
Colchicine, Eliglustat, Pimozide, Rilpivirine, 
Rivaroxaban 
Abbreviations: AUC: area under the curve; CYP: Cytochrome P450; DDI: drug-drug interaction 
a Sensitive substrates are drugs that demonstrate an increase in AUC of ≥ 5-fold with strong index inhibitors of a given 
metabolic pathway in clinical DDI studies. 
b Moderate sensitive substrates are drugs that demonstrate an increase in AUC of ≥ 2 to <5-fold with strong index inhibitors 
of a given metabolic pathway in clinical DDI studies. 

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Medications Known to be P-gp Inhibitors or Inducers 
Patients receiving avutometinib or defactinib are prohibited from concomitant use of medications (with 
or without prescriptions), supplements, herbal products, or foods that are known to be strong inhibitors 
or inducers of P-gp. Known P-gp inhibitors and inducers are listed in the table below. Consider finding 
an alternative drug that is not an inhibitor and inducer of P-gp. 
P-gp Inhibitors and Inducers 
P-gp Inhibitors 
P-gp Inducers 
Amiodarone, Azithromycin 
(systemic), Carvedilol, 
Clarithromycin, Cobicistat and 
cobicistat-containing 
coformulations, Cyclosporine 
(systemic), Daclatasvir, 
Dronedarone, Elagolix, 
Eliglustat, Erythromycin 
(systemic), Flibanserin, 
Fostamatinib, Glecaprevir-
pibrentasvir, Itraconazole, 
Ivacaftor, Ketoconazole 
(systemic)  
Lopinavir-ritonavir, 
Propafenone, Quinidine, 
Quinine, Ranolazine, Ritonavir 
and ritonavir-containing 
coformulations, Rolapitant, 
Tacrolimus (systemic), 
Telaprevir, Ticagrelor, 
Verapamil 
Carbamazepine, Fosphenytoin, 
Phenobarbital, Phenytoin, 
Rifampin (rifampicin), St. John's 
Wort 
Abbreviation: P-gp: P-glycoprotein.  
Reproduced from: 
https://www.uptodate.com/contents/image/print?imageKey=EM%2F73326&topicKey=HEME%2F1370&source=outlineli
nk 
Medications Known to BCRP inhibitors 
Patients receiving avutometinib are prohibited from concomitant use of medications (with or without 
prescriptions), supplements, herbal products, or foods that are known to be strong inhibitors or inducers 
of BCRP. Known BCRP inhibitors are listed in the table below. Consider finding an alternative drug 
that is not an inhibitor and inducer of BCRP.  
BCRP inhibitors 
BCRP Inhibitors 
Curcumin, cyclosporine A, darolutamide, eltrombopag, febuxostat, fostamatinib, 
rolapitant, teriflunomide  
Medications known to be P-gp and OATP1B1/1B3 Substrates  
Substrates of P-gp and OATP1B1/1B3 should be used with caution. The table below lists substances 
that are known to be substrates of P-gp and OATP1B1/1B3 and should be used with caution in patients 
exposed to defactinib.  
Note that this is not a comprehensive list of all agents which may be substrates of P-gp and 
OATP1B1/1B3.  
P-gp and OATP1B1/1B3 Substrates 

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P-gp Substrates  
OATP1B1 and OATP1B3 Substrates  
Digoxin, Dabigatran etexilate, Fexofenadine, 
Loperamide, Quinidine, Talinolol,  
atorvastatin, bosentan, danoprevir, Telmisartan, 
fexofenadine, glyburide, pitavastatin, pravastatin, 
repaglinide, rosuvastatin