Clinical trial NCT04925986
Conditions: Carcinoma, Non-Small-Cell Lung Lung Diseases Lung Neoplasms Metastatic Lung Non-Small Cell Carcinoma Stage IV Lung Non-Small Cell Cancer AJCC v7 PD-L1 Gene Mutation Advanced Treatment-Naïve PD-L1 Sitravatinib Pembrolizumab
Sponsor: Sarah Goldberg
Start date: 2022-02-10; Completion date: 2023-10-30
Enrollment: 9 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multicohort phase 2 study to evaluate the efficacy of pembrolizumab combined with the investigational drug sitravatinib in the frontline treatment of advanced, non-squamous PD-L1 positive NSCLC.

Detailed description:
This is a multicohort phase 2 study to evaluate the efficacy of pembrolizumab combined with the investigational drug sitravatinib in the frontline treatment of advanced, non-squamous PD-L1 positive NSCLC. For clinical analysis, there will be two patient cohorts defined by PD-L1 status: Cohort 1 for patients with PD-L1 Tumor Proportion Score (TPS) 1-49% and Cohort 2 for patients with TPS≥50%. The investigators will implement a Simon's two-stage design to evaluate the efficacy of sitravatinib in combination with pembrolizumab for each cohort separately.

There will be two groups within each cohort of this study: the "main study population" (Group A) in which patients will receive pembrolizumab plus sitravatinib beginning on Cycle 1 Day 1 (C1D1), and a "pembrolizumab run-in population" (Group B) in which patients will receive pembrolizumab alone for 1 dose followed by pembrolizumab plus sitravatinib beginning C2D1.

The primary endpoint of the trial is the ORR for patients treated with pembrolizumab plus sitravatinib in the main study population. The purpose of the pembrolizumab run-in population is to obtain tissue and blood samples from these patients to be used as controls for correlative studies and to determine the preliminary efficacy of pembrolizumab alone followed by the combination.

Primary Objective

(1) The primary objective of this study is to evaluate the efficacy of sitravatinib in combination with pembrolizumab in the front-line treatment of patients with advanced non-squamous PD-L1 positive NSCLC by measuring Objective Response Rate (ORR).

Secondary Objectives

1. To evaluate other measures of efficacy including Overall Survival (OS), Progression Free Survival (PFS), Duration of Response (DOR) and Clinical Benefit Rate (CBR) in the first-line setting for patients with advanced, non-squamous, PD-L1 positive NSCLC treated with the combination of sitravatinib and pembrolizumab.
2. To evaluate the toxicity profile and tolerability of sitravatinib/pembrolizumab in advanced, treatment naïve, non-squamous, PD-L1 positive NSCLC.

Exploratory Objectives:

1. To evaluate ORR, OS, PFS, DOR, and CBR in patients with advanced, non-squamous, treatment naïve, PD-L1 positive NSCLC who receive pembrolizumab run-in followed by pembrolizumab/sitravatinib combination therapy.
2. To evaluate the CNS activity of sitravatinib/pembrolizumab in patients with advanced, treatment naïve, PD-L1 positive NSCLC by measuring Intracranial Objective Response Rate (iORR) and Intracranial Duration of Response(iDOR) in patients with baseline CNS disease, and Intercranial Progression-Free Survival (iPFS) in all patients.
3. To study correlates of the adaptive and innate immune responses induced by sitravatinib and pembrolizumab treatment in both tumor tissue and peripheral blood.
4. To explore the association between tumor immune contexture and clinical benefit to sitravatinib and pembrolizumab.

Arms: arm 1: Participants with PD-L1 Tumor Proportion Score (TPS) 1-49% receive Pembrolizumab 200mg intravenous (IV) every 3 weeks (Q3w) and Sitravatinib 100mg PO (by mouth) daily, beginning on cycle 1 day 1 (C1D1). arm 2: Participants with PD-L1 Tumor Proportion Score (TPS) 1-49% receive Pembrolizumab 200mg intravenous (IV) for one dose alone, beginning on cycle 1 day 1 (C1D1). On Cycle 2 Day 1 (C2D1), participants receive Pembrolizumab 200mg intravenous (IV) once every 3 weeks (Q3w) and Sitravatinib 100mg PO (by mouth) daily. arm 3: Participants with PD-L1 Tumor Proportion Score (TPS) ≥ 50% receive Pembrolizumab 200mg intravenous (IV) every 3 weeks (Q3w) and Sitravatinib 100mg PO (by mouth) daily, beginning on cycle 1 day 1 (C1D1). arm 4: Participants with PD-L1 Tumor Proportion Score (TPS) ≥ 50% receive Pembrolizumab 200mg intravenous (IV) for one dose alone, beginning on cycle 1 day 1 (C1D1). On Cycle 2 Day 1 (C2D1), participants receive Pembrolizumab 200mg intravenous (IV) once every 3 weeks (Q3w) and Sitravatinib 100mg PO (by mouth) daily.
Interventions: intervention 1: Sitravatinib intervention 2: Pembrolizumab
Intervention descriptions: intervention 1: Groups 1A and 2A receive Sitravatinib 100mg orally (PO) daily starting on cycle 1 day 1 (C1D1). Groups 1B and 2B) receive Sitravatinib 100mg orally (PO) daily starting on Cycle 2 Day 1 (C2D1). intervention 2: All groups (1A, 1B, 2A, 2B) receive Pembrolizumab 200mg intravenous every three weeks (IV Q3w) on cycle 1 day 1 (C1D1).

Protocol documents:
Prot_SAP_000.pdf: 
ClinicalTrials.gov ID: NCT04925986 
Brief Title: Sitravatinib Plus Pembrolizumab in Patients With Advanced Treatment-Naïve PD-L1+ 
Non-Squamous NSCLC 
Document Date: 10/6/2022 
Document: Protocol w SAP 


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
 
Phase 2 Trial of Sitravatinib plus 
Pembrolizumab in Patients with Advanced 
Treatment-Naïve PD-L1+ Non-Squamous 
Non-Small Cell Lung Cancer
Protocol Number
2000030093
Protocol Version
07/15/22
Version 5.0
PRINCIPAL INVESTIGATOR:
Sarah Goldberg, M.D., M.P.H. 
Section of Medical Oncology Yale Cancer Center 
333 Cedar St., FMP130 
New Haven, CT 06520 Tel: (203) 785‐7564 
Fax: (203) 785‐3788 
Sarah.Goldberg@yale.edu
IND Number: 155305
IND Holder: Sarah Goldberg, M.D., M.P.H.
NCT Number: 04925986
Study Phase: 2
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
2
Confidentiality Statement:
I, the undersigned, have read and approve this protocol and agree on its contents. It is confirmed that 
the information and guidance given in this protocol complies with scientific principles, the guideline of 
Good Clinical Practice, the Declaration of Helsinki in the latest relevant version, and the applicable 
legal and regulatory requirements. I agree to conduct the study in compliance with all applicable 
regulations including International Ethical Guidelines for Biomedical Research Involving Human 
Patients (Council for International Organizations of Medical Sciences 2002), Guidelines for Good 
Clinical Practice (GCP) (International Council for Harmonisation [ICH] 1996), ICH E6 (R2) and 
concepts that have their origin in the Declaration of Helsinki (World Medical Association 1996, 2008 & 
2013). 
Printed Name of Principal Investigator: _________________________________________________
Signature of Principal Investigator
Date
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
3
REVISION HISTORY:
Revision #
Version Date
1.0
2/7/21
2.0
4/20/21
3.0
6/25/21
4.0
10/26/21
5.0
07/15/22
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
4
Synopsis
Primary Objective
(1) The primary objective of this study is to evaluate the efficacy of sitravatinib in combination 
with pembrolizumab in the front-line treatment of patients with advanced non-squamous 
PD-L1 positive NSCLC by measuring Objective Response Rate (ORR).
Secondary Objectives 
(1) To evaluate other measures of efficacy including Overall Survival (OS), Progression Free 
Survival (PFS), Duration of Response (DOR) and Clinical Benefit Rate (CBR) in the first-
line setting for patients with advanced, non-squamous, PD-L1 positive NSCLC treated 
with the combination of sitravatinib and pembrolizumab.
(2) To evaluate the toxicity profile and tolerability of sitravatinib/pembrolizumab in advanced, 
treatment naïve, non-squamous, PD-L1 positive NSCLC.
Exploratory Objectives: 
(1) To evaluate ORR, OS, PFS, DOR, and CBR in patients with advanced, non-squamous, 
treatment naïve, PD-L1 positive NSCLC who receive pembrolizumab run-in followed by 
pembrolizumab/sitravatinib combination therapy.  
(2) To evaluate the CNS activity of sitravatinib/pembrolizumab in patients with advanced, 
treatment naïve, PD-L1 positive NSCLC by measuring Intracranial Objective Response 
Rate (iORR) and Intracranial Duration of Response(iDOR) in patients with baseline CNS 
disease, and Intercranial Progression-Free Survival (iPFS) in all patients.  
(3) To study correlates of the adaptive and innate immune responses induced by sitravatinib 
and pembrolizumab treatment in both tumor tissue and peripheral blood.
(4) To explore the association between tumor immune contexture and clinical benefit to 
sitravatinib and pembrolizumab.
Study Duration
4 Years 
Summary of Study Design 
This is a multicohort phase 2 study to evaluate the efficacy of pembrolizumab combined with 
the investigational drug sitravatinib in the frontline treatment of advanced, non-squamous PD-
L1 positive NSCLC.  For clinical analysis, there will be two patient cohorts defined by PD-L1 
status: Cohort 1 for patients with PD-L1 Tumor Proportion Score (TPS) 1-49% and Cohort 2 
for patients with TPS≥50% using the FDA approved 22c3 PD-L1 IHC assay or a local assay 
performed in a CLIA facility.  We will implement a Simon’s two-stage design to evaluate the 
efficacy of sitravatinib in combination with pembrolizumab for each cohort separately.  
There will be two groups within each cohort of this study: the “main study population” (Group 
A) in which patients will receive pembrolizumab plus sitravatinib beginning on Cycle 1 Day 1 
(C1D1), and a “pembrolizumab run-in population” (Group B) in which patients will receive 
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
5
pembrolizumab alone for 1 dose followed by pembrolizumab plus sitravatinib beginning 
C2D1. 
The primary endpoint of the trial is the ORR for patients treated with pembrolizumab plus 
sitravatinib in the main study population.  The purpose of the pembrolizumab run-in 
population is to obtain tissue and blood samples from these patients to be used as controls 
for correlative studies and to determine the preliminary efficacy of pembrolizumab alone 
followed by the combination.
Number of Study Sites
Up to 2 sites 
Study Population
A total of 70 evaluable patients will be enrolled in the trial, 35 to cohort 1 and 35 to cohort 2.  
30 patients from each cohort will be enrolled to Group A (main study population) and 5 
patients from each cohort will be enrolled to Group B (pembrolizumab run-in population).  
Patients will be eligible if they have previously untreated, non-squamous, PD-L1 positive 
NSCLC with no known mutations/alterations in EGFR, ROS1, ALK, or BRAF.
Number of Participants 
70
Primary Endpoints
(1) The primary endpoint for this study is ORR as defined by Response Evaluation Criteria in 
Solid Tumors version 1.1 (RECIST 1.1) in the main study population.
Secondary and Exploratory Endpoints 
(1) Overall Survival (OS) in main study group
(2) Progression Free Survival (PFS) in main study group
(3) Duration of Response (DOR) in main study group
(4) Clinical Benefit Rate (CBR) in main study group
(5) Adverse events as per CTCAE v.5
(6) ORR, DOR, CBR, PFS, OS in the run-in population 
(7) iORR, iDOR, and iPFS
(8) Percentage of activated myeloid cells, effector T cells, and AXL+/MERTK+ macrophages 
in the TME
(9) Immune cell population changes in the TME as defined by changes in population 
heterogeneity detected by single cell RNA sequencing
(10)
Gene expression changes in peripheral blood mononuclear cells  
(11)
Correlation of clinical response to immune populations present in baseline samples 
and immune cell population changes induced by therapy 
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
6
Abbreviations 
AE
Adverse Event
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
AUC
Area Under the Curve
BCRP
Breast Cancer Resistance Protein
CBR
Clinical Benefit Rate
CI
Confidence Interval
CIT
Checkpoint Inhibitor Therapy
Cmax
Maximum Plasma Concentration
CNS
Central Nervous System 
CR
Complete Response
CRF
Case Report Form
CRO
Contract Research Organization
CT
Computed Tomography Scan
CTCAE
Common Terminology Criteria for Adverse Events
Ctrough
Trough Concentration
ctDNA
Circulating Tumor Deoxyribonucleic Acid
DKA
Diabetic Ketoacidosis
DLT
Dose Limiting Toxicity
DOR
Duration of Response
DSMC
Data and Safety Monitoring Committee
EKG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
7
EIU
Exposure In-Utero
FDA
Food and Drug Administration
GFR
Glomerular Filtration Rate
HDPE
High-Density Polyethylene
hERG
human Ether-a-go-go Related Gene
HGF
Hepatocyte Growth Factor
hr
Hour
HR
Hazard Ratio
IB
Investigator’s Brochure
IC50
Half Maximal Inhibitory Concentration
ICF
Informed Consent Form
ICH
International Council for Harmonization
IDMC
Independent Data Monitoring Committee
iDOR
Intracranial Duration of Response 
IgG4
Immunoglobulin G4
IND
Investigational New Drug
iORR
Intracranial Objective Response Rate 
iPFS
Intracranial PFS
irAE
Immune-related Adverse Event
IRB
Institutional Review Board
ITT
Intent-to-Treat
IUD
Intrauterine Device
kg
Kilogram
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
8
LVEF
Left Ventricular Ejection Fraction
mAb
Monoclonal Antibody
MDSC
Myeloid-Derived Suppressor Cell
mg
Milligram
mins
Minutes
mL
Milliliter
MRI
Magnetic Resonance Imaging
mRNA
Messenger Ribonucleic Acid
NCI
National Cancer Institute
NE
Not Evaluable
NGS
Next Generation Sequencing
NK
Natural Killer
NPCB
No Prior Clinical Benefit
NSAIDS
Non-Steroidal Anti-Inflammatory Drugs 
NSCLC
Non-Small Cell Lung Cancer
ORR
Objective Response Rate
OS
Overall Survival
PBMC
Peripheral Blood Mononuclear Cells
PCB
Prior Clinical Benefit
PD
Objective Progression of Disease
PD-1
Programmed Cell Death 1
PD-L1
Programmed Cell Death Ligand 1
PET
Positron Emission Tomography
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
9
PFS
Progression-Free Survival
P-gp
P-glycoprotein
PPE
Palmer Plantar Erythrodysesthesia 
PPI
Proton Pump Inhibitor
PR
Partial Response
Q3W
Every 3 Weeks
QD
Once Daily
QTc
Corrected QT Interval
RANO-BM
Response Assessment in Neuro-Oncology-Brain Metastases 
RECIST
Response Evaluation Criteria in Solid Tumors
RTKs
Receptor Tyrosine Kinases
SAE
Serious Adverse Event
scRNAseq
Single-cell RNA sequencing 
 
SD
Stable Disease
T1DM
Type  1 Diabetes Mellitus 
TAM
Tyro3, Axl and MERTK
TGI
Tumor Growth Inhibition 
TKIs
Tyrosine Kinase Inhibitors
TMB
Tumor Mutation Burden
TME
Tumor Microenvironment
Tregs
T Regulatory Cells
ULN
Upper Limit of Normal
WHO
World Health Organization
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
10
WOCBP
Women of Child Bearing Potential
μg
Microgram
μM
Micromolar
USA
United States of America
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
11
Table of Contents
1
INTRODUCTION AND BACKGROUND ..........................................................15
1.1
Introductory Statement...............................................................................................................15
1.2
Disease and Current Therapeutics Background ........................................................................15
1.2.1
Non-Small Cell Lung Cancer ............................................................................................15
1.2.2
PD-1/PD-L1 Immune Checkpoint Pathway.......................................................................15
1.2.3
PD-L1/PD-1 Inhibitors in Treatment of NSCLC.................................................................16
1.2.4
Pembrolizumab.................................................................................................................16
1.3
Sitravatinib..................................................................................................................................17
1.3.1
Sitravatinib Mechanism of Action......................................................................................17
1.3.2
Sitravatinib Pharmacology ................................................................................................17
1.3.3
Sitravatinib Pharmacokinetics...........................................................................................19
1.3.4
Sitravatinib Preclinical Studies..........................................................................................19
1.3.4.1
Sitravatinib ................................................................................................................19
1.3.4.2
Sitravatinib plus Immunotherapy...............................................................................20
1.3.5
Clinical Experience with Sitravatinib .................................................................................21
1.3.5.1
Sitravatinib Clinical Safety Experience .....................................................................21
1.3.5.2
Sitravatinib Clinical Efficacy in NSCLC Patients.......................................................22
2
STUDY RATIONALE/SIGNIFICANCE .............................................................23
2.1
Problem Statement.....................................................................................................................23
2.2
Study Rationale..........................................................................................................................23
2.2.1
Rationale for Combination of Sitravatinib/Pembrolizumab................................................23
2.2.2
Rationale for Selected Study Population ..........................................................................24
2.2.3
Rationale for Regimen Dosing/Schedule..........................................................................24
2.3
Potential Risks............................................................................................................................24
2.4
Potential Benefits .......................................................................................................................25
3
STUDY OBJECTIVES AND HYPOTHESES....................................................26
3.1
Primary Objective and Hypothesis .............................................................................................26
3.2
Secondary Objectives and Hypotheses .....................................................................................26
3.3
Exploratory Objectives and Hypotheses ....................................................................................26
4
TRIAL DESIGN.................................................................................................29
4.1
Trial Schema ..............................................................................................................................29
4.2
General Design Description .......................................................................................................30
4.3
Study Date Range and Duration ................................................................................................31
4.4
Endpoints ...................................................................................................................................31
4.4.1
Primary Endpoint ..............................................................................................................31
4.4.2
Secondary Endpoints........................................................................................................31
4.4.3
Exploratory Endpoints.......................................................................................................31
4.4.4
Rationale for Endpoints.....................................................................................................32
4.4.4.1
Rationale for Clinical Endpoints................................................................................32
4.4.4.2
Rationale for Exploratory Endpoints/Correlative Studies..........................................33
4.5
Study Population ........................................................................................................................33
4.5.1
Number of Participants .....................................................................................................33
4.5.2
Inclusion Criteria: ..............................................................................................................33
4.5.3
Exclusion Criteria:.............................................................................................................34
4.5.4
Life Style Guidelines .........................................................................................................36
4.6
Method of Assignment/Randomization.......................................................................................38
5
STUDY TREATMENTS ....................................................................................38
5.1
Sitravatinib..................................................................................................................................38
5.1.1
Sitravatinib Formulation, Packing and Storage.................................................................38
5.1.2
Sitravatinib Schedule and Administration .........................................................................39
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
12
5.1.3
Sitravatinib Dose Modification or Discontinuation.............................................................39
5.1.4
Sitravatinib Dispensing and Accountability .......................................................................40
5.2
Pembrolizumab ..........................................................................................................................41
5.2.1
Pembrolizumab Formulation, Packing and Storage..........................................................41
5.2.2
Pembrolizumab Schedule and Administration ..................................................................41
5.2.3
Pembrolizumab Dose Modification or Discontinuation......................................................41
5.3
Management of Adverse Events ................................................................................................43
5.3.1
Sitravatinib-Related Adverse Events ................................................................................43
5.3.1.1
General Management of Sitravatinib Related Non-Hematologic Toxicities ..............43
5.3.1.2
General Management of Sitravatinib Related Hematological Toxicities ...................44
5.3.2
Management of Selected Sitravatinib Adverse Events.....................................................45
5.3.3
Pembrolizumab-Related Adverse Events .........................................................................48
5.3.3.1
General Management of Pembrolizumab-Related Adverse Events .........................48
5.3.3.2
Management of Selected Pembrolizumab-Related Adverse Events ........................49
5.4
Concomitant Therapies ..............................................................................................................52
5.4.1
Concomitant Medications..................................................................................................52
5.4.2
Other Concomitant Treatments.........................................................................................54
5.4.2.1
Surgery .....................................................................................................................54
5.4.2.2
Radiation...................................................................................................................54
5.4.2.3
Transfusions .............................................................................................................54
5.4.2.4
Other Anticancer or Experimental Therapy...............................................................54
6
STUDY PROCEDURES ...................................................................................55
6.1
Study Calendars.........................................................................................................................55
6.1.1
Study Calendar for Group A..............................................................................................55
6.1.2
Study Calendar for Group B..............................................................................................57
6.2
Informed Consent.......................................................................................................................58
6.3
Screening ...................................................................................................................................59
6.4
Enrollment ..................................................................................................................................59
6.5
Research Blood and Tissue Collection ......................................................................................60
6.5.1
Biopsy Collection for Correlative Studies..........................................................................60
6.5.2
Research Blood Sample Collection for Correlative Studies..............................................60
6.6
On Study Visits...........................................................................................................................60
6.6.1
Laboratory Testing............................................................................................................60
6.6.2
Toxicity Assessment/Adverse Event Monitoring...............................................................61
6.6.3
Vital Signs.........................................................................................................................61
6.6.4
Physical Exam ..................................................................................................................61
6.6.5
ECOG performance status................................................................................................61
6.6.6
Tumor Imaging/Disease Assessment ...............................................................................61
6.7
End of Treatment Visit................................................................................................................62
6.8
Treatment Beyond Progression..................................................................................................62
6.9
Study Follow up..........................................................................................................................63
6.9.1
Initial Follow Up.................................................................................................................63
6.9.2
Long Term Follow Up........................................................................................................63
6.10
Removal of Subjects/Patient Discontinuation/Withdrawal ........................................................63
7
STUDY ASSESSMENTS..................................................................................64
7.1
Efficacy Assessments ................................................................................................................64
7.1.1
Radiographic Disease Assessment ..................................................................................64
7.1.2
Survival Assessments.......................................................................................................65
7.1.3
CNS Disease Assessment................................................................................................65
7.2
Safety Assessments...................................................................................................................66
7.2.1
Medical History .................................................................................................................66
7.2.2
Physical Exam and Vital Signs .........................................................................................66
7.2.3
Laboratory Safety Assessments .......................................................................................66
7.2.4
Electrocardiograms...........................................................................................................67
7.2.5
Echocardiogram................................................................................................................67
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
13
8
ADVERSE EVENT REPORTING .....................................................................68
8.1
Evaluating Adverse Events ........................................................................................................68
8.1.1
Definitions .........................................................................................................................68
8.1.2
Recording AEs..................................................................................................................68
8.1.3
Severity Assessment ........................................................................................................69
8.1.4
Causality ...........................................................................................................................69
8.1.5
Expectedness ...................................................................................................................69
8.2
Serious Adverse Events.............................................................................................................69
8.3
Reporting of AEs and SAEs .......................................................................................................70
8.3.1
Reporting Period...............................................................................................................70
8.3.2
Reporting Requirements...................................................................................................71
8.3.3
SAE reporting to Mirati Therapeutics Inc. .........................................................................71
8.3.4
Reporting of SUSARs to Yale Cancer Center...................................................................72
8.3.5
Reporting to the FDA ........................................................................................................73
8.4
Reporting of Pregnancy and Lactation.......................................................................................74
8.5
Safety Reporting and Monitoring (DSMP)..................................................................................74
8.5.1
Data and Safety Monitoring Committee............................................................................74
8.5.2
Study Site Monitoring........................................................................................................75
9
STATISTICS .....................................................................................................76
9.1
Statistical Methods .....................................................................................................................76
9.1.1
Statistical Design ..............................................................................................................76
9.1.2
General Analysis Plan.......................................................................................................77
9.1.3
Sample Size Considerations.............................................................................................77
9.2
Efficacy Endpoints Definition and Analyses ...............................................................................78
9.2.1
Analysis Population...........................................................................................................78
9.2.2
Objective Response Rate (ORR)......................................................................................78
9.2.3
Overall Survival and Progression Free Survival Analysis.................................................79
9.2.4
Duration of Response .......................................................................................................79
9.2.5
Clinical Benefit Rate..........................................................................................................80
9.2.6
Intracranial Objective Response Rate ..............................................................................80
9.2.7
Intracranial Duration of Response ....................................................................................80
9.2.8
Intracranial Progression Free Survival..............................................................................80
9.3
Safety Analysis...........................................................................................................................81
9.4
Correlative Analyses Plan ..........................................................................................................81
9.5
Handling of Missing Data ...........................................................................................................81
10
TRIAL ADMINISTRATION ...............................................................................81
10.1
Ethical Considerations: Informed Consent/Assent and HIPAA Authorization...........................81
10.2
Institutional Review Board (IRB) Review ..................................................................................82
10.3
Subject Confidentiality ..............................................................................................................82
10.4
Data Collection .........................................................................................................................83
10.5
Study Records ..........................................................................................................................83
10.6
Data or Specimen Storage/Security .........................................................................................83
10.7
Retention of Records ................................................................................................................84
10.8
Study Modification ....................................................................................................................84
10.9
Study Discontinuation ...............................................................................................................84
10.10
Study Completion..................................................................................................................84
10.11
Conflict of Interest Policy ......................................................................................................85
10.12
Funding Source.....................................................................................................................85
10.13
Publication Plan ....................................................................................................................85
11
CORRELATIVE STUDIES................................................................................85
11.1
Introduction/Summary...............................................................................................................85
11.2
Sample Collection.....................................................................................................................86
11.2.1
Tissue Collection...............................................................................................................86
11.2.2
Blood Collection................................................................................................................86
11.3
Tumor Tissue Analysis .............................................................................................................87
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
14
11.3.1
Tissue Samples ................................................................................................................87
11.3.2
Multiplex Quantitative Immunofluorescence .....................................................................87
11.3.3
Isolation of CD45+ cells and Single-cell RNA Sequencing...............................................88
11.4
Peripheral Blood Analysis.........................................................................................................88
11.5
Other Analyses .........................................................................................................................88
12
APPENDICES...................................................................................................89
12.1
Appendix 1: NCI Common Terminology Criteria for Adverse Events (CTCAE)........................89
12.2
Appendix 2: Eastern Cooperative Oncology Group (ECOG) Performance Status...................89
12.3
Appendix 3 Abbreviated Presentation of RECIST Version 1.1 Guidelines (21) ..........................90
12.4
Appendix 4  Abbreviated Presentation of RANO-Brain Metastases Criteria(22) ........................93
12.5
Appendix 5: Medications or Substances to be Avoided or Used with Caution During Treatment 
with Sitravatinib.....................................................................................................................................95
12.6
Appendix 6 – Pill Diary............................................................................................................100
13
REFERENCES ...............................................................................................101
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
15
1 Introduction and Background 
1.1
Introductory Statement
This document is a protocol for a human research study. The purpose of this protocol is to 
ensure that this study is to be conducted according to ICH GCP guidelines, and according to 
CFR 21 Part 312, other applicable government regulations and Institutional research policies 
and procedures
1.2
Disease and Current Therapeutics Background 
1.2.1
Non-Small Cell Lung Cancer
Lung cancer remains the leading cause of cancer-related death worldwide, with 
approximately 2.1 million new cases diagnosed in 2018 and approximately 1.76 million 
deaths attributed to lung cancer(1). Non-small cell lung cancer (NSCLC) accounts for 
approximately 83% of lung cancer cases, of which approximately half are classified as 
adenocarcinoma of the lung(2).  Increased understanding of cancer biology, and specifically 
the role of the immune system in tumor development and growth, has led to the 
development of new therapeutic strategies over the past 10 years.  Immune-modulating 
drugs, in particular those targeting the “immune checkpoint” pathways, have emerged as 
paradigm shifting therapies in the treatment of many cancers, including NSCLC.
1.2.2
PD-1/PD-L1 Immune Checkpoint Pathway
The PD-1/PD-L1 interaction has been the main immune checkpoint pathway to be studied 
and used as a target for cancer therapeutics.  The PD-1 receptor along with the ligands PD-
L1 and PD-L2 constitute an important regulatory pathway for the immune system, inhibiting 
T-cell activation when engaged(3, 4).  Under normal physiologic circumstances, PD-L1 
functions to limit collateral damage in tissues where an immune response has been 
triggered.  PD-1 is expressed on T-cells whereas PD-L1 and PD-L2 are expressed on other 
types of immune cells as well as some cancer cells.  Upregulation of PD-1 ligands is utilized 
by tumors to help evade detection and elimination by the host immune system tumor 
response.  PD-L1 expression in tumor, including in lung cancer, has been associated with 
poor survival motivating the development of PD-1 pathway inhibitors(5).
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
16
1.2.3
PD-L1/PD-1 Inhibitors in Treatment of NSCLC 
Two PD-1/PD-L1 inhibitors have been shown in clinical trials to be effective as monotherapy 
treatment in the front-line setting for advanced NSCLC: pembrolizumab (PD-1 inhibitor) and 
atezolizumab (PD-L1 inhibitor)(6-8).  Of these two, only pembrolizumab has been approved 
as a single agent in the front-line setting for all PD-L1 positive patients (PD-L1>1%)(6). 
1.2.4
Pembrolizumab 
Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between 
PD-1 and its ligands, PD-L1 and PD-L2. Details regarding pharmacokinetics and safety 
studies for pembrolizumab are described in current KEYTRUDA product label.  
Initial clinical trials for pembrolizumab in NSCLC patients demonstrated good tolerability and 
safety, as well as marked improvements in efficacy compared with standard of care 
chemotherapy(9, 10).   Pembrolizumab was initially granted accelerated approval for use in 
metastatic NSCLC as second line treatment on the basis of the Phase I trial KEYNOTE-001;  
pembrolizumab demonstrated an acceptable safety and tolerability profile as well as 
significant anti-tumor activity(9).  The Phase 2/3 study KEYNOTE-010 examined 
pembrolizumab versus standard second line chemotherapy in patients with pre-treated PD-
L1 positive advanced or metastatic NSCLC (10).  Patients were randomized to high or low 
dose pembrolizumab versus docetaxel, with significant improvements seen in objective 
response rate, duration of response and overall survival in the pembrolizumab group.  In 
addition, pembrolizumab was better tolerated than docetaxel.  Subsequently, a Phase 3 trial 
of first-line pembrolizumab versus standard chemotherapy in patients with PD-L1 high 
(TPS>50%) advanced NSCLC demonstrated the superiority of pembrolizumab in the first 
line setting(7). Improvement was reported across multiple efficacy endpoints including 
overall survival, along with a favorable safety profile, leading to US approval for 
pembrolizumab in the first-line treatment setting in this patient population.  Pembrolizumab 
has now also been approved as first-line monotherapy for patients with PD-L1>1% on the 
basis of the Phase 3 KEYNOTE-042(6).  More recently, the combination of pembrolizumab 
with a platinum-based doublet chemotherapy regimen demonstrated an OS advantage as 
compared to chemotherapy plus placebo in the first-line, advanced disease treatment 
setting(11). 
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
17
1.3
Sitravatinib 
1.3.1
Sitravatinib Mechanism of Action 
Sitravatinib is a spectrum-selective receptor tyrosine kinase (RTK) inhibitor that acts on 
several closely related RTKs including the TAM family (Tyro3/Axl/MERTK), VEGFR2, KIT, 
and MET(12). These receptor tyrosine kinases are key regulators of multiple signaling 
pathways leading to cell growth, survival, and migration(13). RTKs are dysregulated in many 
cancers through overexpression, genetic alteration or co-expression with high affinity ligands 
(13). The family of RTKs inhibited by sitravatinib are genetically altered in a variety of 
cancers and act as oncogenic drivers, promoting cancer development and progression(14). 
In addition to the immunostimulatory effects of Axl and MET inhibition, sitravatinib may also 
condition the TME in favor of antitumor activity via immunomodulatory effects of VEGFR and 
KIT inhibition. Preclinical data with sitravatinib indicate that it can increase expression of PD-
L1 on tumor cells in vitro and in vivo. Pilot studies in syngeneic mouse tumor models also 
suggest that sitravatinib increases the proliferation and fraction of systemic/spleen CD4+ and 
CD8+ T lymphocytes and reduces the number of systemic MDSCs.  Reduction of 
intratumoral MDSCs as well as a shift in macrophage physiology was also observed 
clinically in patients with oral squamous cell carcinomas who were treated with sitravatinib 
(15).
1.3.2
Sitravatinib Pharmacology 
Sitravatinib demonstrated potent, concentration-dependent inhibition of the kinase activity of 
MET, Axl, MERTK, VEGFR family, PDGFR family, KIT, FLT3, Trk family, RET, DDR2, and 
selected Eph family members in biochemical assays and inhibited phosphorylation and 
kinase dependent function in cell-based assays. Sitravatinib also inhibited oncogenic 
functions associated with target RTKs including MET-dependent cell viability and migration 
and endothelial tube formation and angiogenesis. Consistent with this anti-tumor and anti-
angiogenic mechanism of action, sitravatinib demonstrated anti-tumor efficacy over a broad 
spectrum of human tumor xenograft models including robust cytoreductive anti-tumor activity 
in a subset of models exhibiting genetic alterations in RTK targets including MET, RET, 
FLT3 and others.
In a bidirectional permeability study with Caco-2 cell lines, sitravatinib was classified as a 
highly permeable compound and not a substrate of P-glycoprotein (P-gp) and breast cancer 
resistance protein (BCRP).  Sitravatinib is an inhibitor of BCRP and P-gp transporters based 
on in vitro studies. 
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
18
To assess CYP-mediated metabolism of sitravatinib, phenotyping of sitravatinib in human 
liver microsome CYPs and recombinant human CYP enzymes was performed. Results 
suggested that multiple enzymes, including CYP1A2, CYP2A6, CYP2B6, CYP2C8, 
CYP2C9, CYP2D6, CYP2E1, and CYP3A4, are involved in the metabolism of sitravatinib, 
with a low risk of any single CYP demonstrating a disproportionate contribution to sitravatinib 
metabolism.
The potential for sitravatinib to induce expression or activity of selected CYPs was 
investigated in primary cultures of cryopreserved human hepatocytes (PK-MGCD516-014) 
and in human liver microsomes (PK-MGCD516-013).  For full details, please see the most 
current version of the Investigator’s Brochure.  The data overall suggest that sitravatinib is 
not expected to act as a CYP enzyme inducer at the concentration levels observed clinically.  
There was little or no evidence of direct inhibition of CYP1A2, CYP2A6, or CYP2E1 by 
sitravatinib. There was little or no evidence of time- or metabolism-dependent inhibition by 
sitravatinib of any of the CYP enzymes evaluated. Under the experimental conditions 
examined, sitravatinib demonstrated direct inhibition of CYP2C8, CYP2C9, CYP2C19, 
CYP2D6, and CYP3A4/5. 
Based on the FDA Guidance for Industry on In Vitro Drug Interaction Studies — Cytochrome 
P450 Enzyme- and Transporter-Mediated Drug Interactions (Jan 2020), the calculated ratio 
of intrinsic clearance values of a probe substrate for an enzymatic pathway in the absence 
and in the presence of the interacting drug (R1) for reversible inhibition for CYPs 2C8, 2C9, 
2C19, 2D6, and 3A4 were equal to or greater than the 1.02 threshold, suggesting a potential 
for clinical drug interactions.
Preclinical studies suggest elimination of sitravatinib is mainly fecal, with very small (<1%) 
contribution of urinary excretion. 
Using an ultra-centrifugation technique sitravatinib was 98.6% bound to human plasma 
proteins.
For additional information on sitravatinib pharmacology refer to the most current version of 
the Investigator’s Brochure.  
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
19
1.3.3
Sitravatinib Pharmacokinetics
Full details on sitravatinib pharmacokinetics are available in the most current version of the 
Investigator’s Brochure.  
After single dose administration of sitravatinib free base capsules, sitravatinib reaches peak 
concentration in a median time of approximately 3 to 9 hours. Exposure parameters 
(maximum concentration [Cmax] and area under the curve [AUC]) were approximately dose 
proportional with single doses up to 200 mg. Median elimination half-life varies between 
approximately 43 and 58 hours after oral administration.
Mirati study 516-006 evaluated the relative bioavailability and PK of sitravatinib in plasma 
following single doses of sitravatinib free base and sitravatinib malate capsule formulations 
in healthy subjects in a 2-part, open-label, crossover study.  Part 1 enrolled 16 healthy 
subjects and assessed the relative bioavailability and PK of a single oral dose of 80 mg 
sitravatinib free base capsule formulation and single oral dose of 80 mg sitravatinib malate 
capsule formulation. Bioavailability (as measured by Cmax, AUC0-∞ and AUC0-t) was 
approximately 30% higher for the malate capsule formulation than the free base capsule 
formulation.  Part 2 enrolled 26 healthy subjects and assessed the relative bioavailability and 
PK of a single dose of 120 mg sitravatinib free base capsule formulation and single oral 
dose of 100 mg sitravatinib malate capsule formulation.  The geometric least squares (LS) 
means ratios (90% CI) of sitravatinib AUC0-∞, AUC0-t, and Cmax for the 100 mg malate capsule 
formulation and the 120 mg free base formulation were 98.9% (91.8%, 106.6%), 98.8% 
(91.6%, 106.5%), and 102.4% (92.9%, 112.7%), respectively, demonstrating 
bioequivalence.   
1.3.4
Sitravatinib Preclinical Studies 
1.3.4.1
Sitravatinib
The anti-tumor efficacy of sitravatinib was evaluated in a variety of human tumor xenograft 
models (total of 17) representative of cancer indications in which dysregulation of target 
RTKs is implicated. Sitravatinib demonstrated significant anti-tumor efficacy (tumor 
regression or tumor growth inhibition vs. vehicle control) across all models evaluated at dose 
levels ranging from 1.25 to 20 mg/kg/day depending on the model. Anti-tumor efficacy was 
generally dose- dependent for models for which multiple dose levels were evaluated. 
Sitravatinib was generally well tolerated with minimal overt toxicity or body weight loss at 
dose levels up to 20 mg/kg/day for up to 18 days of administration. The 20 mg/kg/day dose 
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
20
level was utilized as the maximum dose for comparative purposes across models utilized for 
efficacy studies. At this dose, anti-tumor efficacy ranged from partial growth inhibition to 
robust cytoreductive anti-tumor activity/tumor regression, with the minimum tumor growth 
inhibition observed being 77% (DU145 prostate and HCT-116 colon), which was statistically 
significant. Sitravatinib demonstrated near complete tumor growth inhibition (>90% 
inhibition) in the majority of models evaluated at the 20 mg/kg/day dose with multiple models 
exhibiting frank tumor regressions at this dose level. 
Sitravatinib also demonstrated significant and robust anti-tumor efficacy at lower dose levels 
including the observation of tumor regression of the MKN45 and CTG-0838 models at 10 
mg/kg/day and COLO205 model at 5 mg/kg/day indicating cytoreductive anti-tumor activity 
can be elicited at lower dose levels.  Even at dose levels as low as 5 mg/kg/day sitravatinib 
demonstrated significant and robust TGI ranging from 47-101% in several models. 
1.3.4.2
Sitravatinib plus Immunotherapy 
Sitravatinib was evaluated in combination with a mouse surrogate anti PD-1 antibody in the 
CT26 syngeneic mouse tumor model. Treatment with sitravatinib or an anti-mouse PD-1 
antibody resulted in limited growth delay effects whereas the combination led to dramatic 
and statistically significant reduction in tumor volume and sustained growth suppression 
compared to single agent and vehicle controls. Sitravatinib was evaluated in additional 
preclinical models in vitro and in vivo(16).  Sitravatinib reduced immunosuppressive cell 
populations in vivo, including monocytic MDSCs and M2-polarized macrophages, increased 
intra-tumoral and circulating CD4+ and CD8+ populations, and augmented the effect of anti-
PD-1 therapy. A subset of combination-treated mice had a complete remission and when 
these animals were re-implanted with tumor cell inoculum, no tumors formed, in contrast to 
tumor implantation in treatment naïve mice.  
A similar approach was taken to evaluate the efficacy of sitravatinib alone or in combination 
with anti-PD-1 or anti-PD-L1 in the inhibition of MC38 colon cancer tumor growth (Rothlin-
Ghosh lab, unpublished results). Sitravatinib (10mg/kg/day) potently suppressed tumor 
growth. While all control, vehicle treated-mice reached the end point (defined as tumors 
reaching a size of 1000mm3) before day 40, 100% of mice treated with sitravatinib alone 
survived beyond 80 days and tumors were significantly reduced in size.  Furthermore, 
sitravatinib (10mg/kg/day) was administered in combination with anti-PD-1 (5mg/kg/twice a 
week) or anti-PD-L1 (10mg/kg/twice a week) in the MC38 model. It should be noted that the 
doses chosen for anti-PD1 and anti-PD-L1 were below their IC50. Anti-PD-1 alone or anti-
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
21
PD-L1 alone, at these doses, did not show statistically significant differences from vehicle 
alone in tumor growth or survival. Sub-therapeutic doses were chosen to allow for the testing 
of any potential synergism upon combination with sitravatinib. When sitravatinib 
(10mg/kg/day) was administered in combination with anti-PD-1 (5mg/kg/twice a week) or 
anti-PD-L1 (10mg/kg/twice a week), tumor sizes were significantly smaller than when mice 
were treated with sitravatinib (10mg/kg/day) alone.  Finally, depletion of CD8+ T cells partially 
reversed the effect of sitravatinib (10mg/kg/day) on tumor growth. Sitravatinib treatment 
(10mg/kg/day) in CD8+ T cell-depleted mice were less effective than immunocompetent mice 
(isotype treated), indicating that CD8+ T cells, at least in part, mediate the beneficial effects 
of sitravatinib.
Collectively, these data illustrate broad anti-tumor activity of sitravatinib across a diverse set 
of human tumor xenograft models over an extensive dose range.  In addition, these data 
suggest that concurrent treatment with sitravatinib may enhance the activity of anti-PD-1 
therapy. 
Additional details of preclinical sitravatinib studies can be found in the most current version 
of the Investigator’s Brochure.
1.3.5
Clinical Experience with Sitravatinib 
1.3.5.1
Sitravatinib Clinical Safety Experience 
Sitravatinib has been administered to cancer patients in multiple clinical studies, including 
Phase 1 and 2 studies as a single-agent and in combination with other anticancer 
therapies in non-squamous non-small cell lung cancer (NSCLC), urothelial cancer (UC), 
renal cell carcinoma (RCC), and hepatocellular carcinoma (HCC), among other 
malignancies. In addition, sitravatinib in combination with nivolumab is being evaluated 
in a Phase 3 study in non-squamous NSCLC.  
As of 26 Jun 2021, safety data are available for a total of 1106 subjects with advanced 
solid malignancies treated with sitravatinib, either as a single agent (n = 220 ), in 
combination with the PD-1 inhibitor nivolumab (n = 565), combination with 
ipilimumab/nivolumab (n=10), combination with pembrolizumab/EV (n=13) or in 
combination with tislelizumab (n = 300). 
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
22
Among the 1106 subjects with solid malignancies who were treated with sitravatinib, 
1012 (92%) experienced at least one sitravatinib-related AE.  Among the 1106 subjects, 
sitravatinib-related Grade 3 events were reported in 485 subjects (44%) overall. 
Sitravatinib-related Grade 3 events reported in ≥5% of subjects were hypertension 
(16%), diarrhea (7%), and fatigue (5%). Sitravatinib-related Grade 4 AEs were reported 
in 26 subjects (2%). The only Grade 4 sitravatinib-related events occurring in more than 
1 subject by Preferred Term was lipase increased in 5 subjects (0.5%). Sitravatinib-
related Grade 5 AEs were reported in12 subjects, including death in 6 subjects, cardiac 
arrest in 2 subjects, and cardiac failure, hepatic encephalopathy, ischemic stroke, and 
respiratory failure in 1 subject each.
For full details and most up to date information regarding safety data please see the 
most current version of the Investigator’s Brochure.  
1.3.5.2
Sitravatinib Clinical Efficacy in NSCLC Patients 
Study MRTX-500 is a Phase 2 randomized trial which evaluated the efficacy and safety of 
the combination of sitravatinib and nivolumab versus docetaxel in patients who had 
progressed on or after checkpoint inhibitor treatment (CIT). Enrollment was stratified by prior 
outcome of treatment with a checkpoint inhibitor: those with prior clinical benefit (PCB) or no 
prior clinical benefit (NPCB) to prior CIT.  Patients who were CIT-naïve were stratified 
according to their PD-L1 status: no/low PD-L1 expression or high PD-L1 expression. There 
was no limit to the number of prior therapies.  Patients in the PCB stratum experienced 
clinical benefit (RECIST confirmed CR or PR or stable disease for at least 12 weeks) on their 
prior CIT. Data as of September 2019 included 79 patients enrolled into the PCB stratum of 
MRTX-500. The preliminary median overall survival for this stratum was 15.6 months. Fifty-
four patients were evaluable for response; 8 patients had a confirmed response (2 CR, 6 
PR). The median duration of response was 170 days (range: 64, NA).  As of 26 Jun 2020, a 
total of 204 subjects have been enrolled, and 200 have received at least one dose of 
sitravatinib plus nivolumab.
A Phase 3 randomized trial was initiated in 2019 comparing the sitravatinib and nivolumab 
combination against docetaxel in checkpoint inhibitor-refractory NSCLC patients. This Phase 
3 trial is currently enrolling and as of 26 Jun 2020, a total of 65 subjects have been 
randomized in the study, and 60 have received at least one dose of study treatment.  
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
23
2 Study Rationale/Significance
2.1
Problem Statement 
PD1/PD-L1 axis inhibitors have revolutionized the treatment of lung cancer by offering many 
patients significantly prolonged responses and improved overall survival.  However, a 
significant subset of patients do not respond to first line treatment with immune checkpoint 
agents, either alone or in combination with chemotherapy.  Additional approaches, such as 
combination with other drugs that target immune pathways, are needed to improve and 
prolong initial responses to checkpoint therapy. 
2.2
Study Rationale 
2.2.1
Rationale for Combination of Sitravatinib/Pembrolizumab 
A logical step towards improving outcomes of immune therapy treatment is the use of 
combinations of agents that have both immune modulatory and anti-tumor properties and 
that target the molecular and cellular mechanisms seen in checkpoint inhibitor resistance.  
Sitravatinib is a novel spectrum selective oral tyrosine kinase inhibitor, which targets the 
TAM family of RTKs as well as VEGFR2, KIT, RET and MET.  Based on pre-clinical 
research at Yale and elsewhere, the TAM family of receptor tyrosine kinases (RTKs), 
including TYRO3, AXL and MERTK are one target that has emerged as a key modulator of 
the innate immune response(12).  They are overexpressed in multiple types of cancer, 
including lung (overexpression tends to portend a worse prognosis(14)), and are also 
expressed on many cells of the innate immune system including macrophages, dendritic 
cells and NK cells (17). TAM RTKs are thought to serve as “innate immune checkpoints”, 
playing an important role in maintaining the immunosuppressive tumor microenvironment 
(TME) (12).   This immune checkpoint function of TAM RTKs is achieved through several 
mechanisms, including suppression of dendritic cell function (18) and downstream regulation 
of cytokine release to favor an “anti-inflammatory” TME.  The latter leads to a shift in 
macrophage phenotype (19, 20), further suppressing the release of pro-inflammatory 
cytokines (IL-12, IL-6, TNF) and enhancing the production of others (IL-10, IL-4, TGF-beta) 
to create a more pro-tumor environment (12).  The inhibition of the TAM family RTKs would 
thus be expected to shift production towards a more pro-inflammatory cytokine milieu, which 
in turn supports response of cytotoxic T lymphocytes.
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
24
The addition of a TAM inhibitor would therefore be expected to augment the effects of PD-1 
axis inhibitors by altering the TME in favor of anti-tumor activity, as well as promoting the 
anti-tumoral T-cell response which is unleashed through inhibition of the PD-1/PD-L1 
pathway.
2.2.2
Rationale for Selected Study Population
The purpose of this study is to evaluate the combination of sitravatinib and pembrolizumab 
in the first-line treatment of NSCLC.  Pembrolizumab is currently FDA-approved for first-line 
treatment of previously-untreated patients with stage IV NSCLC with PD-L1 expression ≥ 1% 
based on an improvement in overall survival compared to chemotherapy, however the 
response rate with pembrolizumab in this trial was only 27%.  While the combination 
sitravatinib and a PD-L1 inhibitor has been studied in the second-line treatment of metastatic 
NSCLC, this regimen has not been evaluated in treatment naïve patients.  Patients with 
NSCLC who are treatment naïve may have a higher response rate with the combination of 
sitravatinib and pembrolizumab compared to treatment with immunotherapy alone.   In 
addition, correlative studies performed on treatment naive patients will allow for better 
understanding of sitravatinib’s mechanism of action and help to characterize any molecular 
signatures associated with sitravatinib treatment and perhaps identify predictive biomarkers 
as well.
2.2.3
Rationale for Regimen Dosing/Schedule 
Pharmacology and pharmacokinetics of sitravatinib has been discussed separately in 
Sections 1.3.2 and 1.3.3.  Current recommended dosing of sitravatinib is 100mg daily of the 
sitravatinib malate capsule formulation based on results of Study 516-006, which showed 
equivalence of this dose to the previously used dose of 120mg sitravatinib free base capsule 
formulation. 
100mg oral dose of sitravatinib malate capsule formulation will be administered as a 
continuous regimen expressed in 21-day cycles (based on the standard pembrolizumab 
schedule of q3 week administration).  Pembrolizumab dosing will be a standard dose of 
200mg IV every 3 weeks.  
2.3
Potential Risks
Risks associated with this trial are those posed by use of the drugs sitravatinib and 
pembrolizumab, both alone and in combination.  For details of pembrolizumab associated 
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
25
risks, please see updated US Package Insert.  Sitravatinib is a non-FDA approved novel 
therapy and details of potential risks associated with this drug can be found in the most 
current version of the Sitravatinib Investigator’s Brochure.  The potential exists for toxicity to 
be observed with increased severity or frequency during use of the combined agents.  Data 
outlining the adverse events observed in combination studies with sitravatinib and PD-L1 
inhibitors can be found in the most current version of the Investigator’s Brochure.  Close 
monitoring for safety and adverse events will be performed as described in Section 7.2.  
There is additionally some risk associated with study-mandated procedures, including tissue 
biopsy.  
2.4
Potential Benefits
Patients enrolled in this study may clinically benefit from the novel combination of sitravatinib 
and pembrolizumab.  However, no individual patient can be guaranteed to derive benefit 
from participation in this trial.  
Multiple correlative studies have been planned to help better understand the molecular and 
cellular actions of sitravatinib in vivo, and to evaluate for a potential molecular signature 
which may help predict response to this combination.  Increased knowledge of cancer 
biology and mechanisms of treatment is a benefit to society at large.  
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
26
3 Study Objectives and Hypotheses
3.1
Primary Objective and Hypothesis
(1) Primary Objective: To evaluate the efficacy of sitravatinib in combination with 
pembrolizumab in the front-line treatment of patients with advanced non-squamous PD-
L1 positive NSCLC by measuring Objective Response Rate (ORR).
Hypothesis: Treatment with the novel combination of sitravatinib and pembrolizumab 
will improve ORR in this population.   
3.2
Secondary Objectives and Hypotheses 
(1) Objective: To evaluate other measures of efficacy including Overall Survival (OS), 
Progression Free Survival (PFS), Duration of Response (DOR) and Clinical Benefit Rate 
(CBR) of sitravatinib/pembrolizumab in the first-line setting for patients with PD-L1 
positive non-squamous NSCLC.
Hypothesis: The combination of sitravatinib and pembrolizumab will improve OS, PFS, 
DOR, and CBR for patients with metastatic PD-L1 positive non-squamous NSCLC.
(2) Objective: To evaluate the toxicity profile and tolerability of sitravatinib/pembrolizumab 
combination in treatment-naïve patients with advanced PD-L1 positive non-squamous 
NSCLC.
Hypothesis: The combination of sitravatinib and pembrolizumab will be safe and 
tolerable in treatment-naïve patients with PD-L1 positive non-squamous metastatic 
NSCLC. 
3.3
Exploratory Objectives and Hypotheses 
(1) Objective: To evaluate ORR, OS, PFS, DOR, CBR in patients with treatment naïve 
advanced PD-L1 positive NSCLC who receive a 3 week pembrolizumab run-in followed 
by treatment with pembrolizumab/sitravatinib combination therapy.
Hypothesis: The combination of pembrolizumab/sitravatinib with a pembrolizumab run-
in will improve clinical outcomes in patients with treatment naïve, metastatic PD-L1 
positive non-squamous NSCLC.
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
27
(2) Objective: To evaluate CNS activity of the combination of sitravatinib and 
pembrolizumab by measuring intracranial ORR (iORR) and intracranial duration of 
response (iDOR) in patients with baseline CNS disease in the main study population,  
and intracranial progression-free survival (iPFS) in all patients. 
Hypothesis: The combination of pembrolizumab/sitravatinib will result in improved 
iORR, iDOR, and iPFS.
(3) Objective: To study correlates of the adaptive and innate immune responses induced by 
sitravatinib and pembrolizumab treatment in both tumor tissue and peripheral blood.
Hypothesis:  The combination of pembrolizumab with sitravatinib will increase the 
percentage of CD68+HLA-DR+CD163- myeloid cells as well as the percentage of 
effector CD3+GranzymeB+Ki67+ T cells in the tumor microenvironment (TME). The 
percentage change upon treatment with pembrolizumab + sitravatinib will be greater in 
patients receiving the combination than in patients treated with pembrolizumab alone.
The above-mentioned changes will be observed in samples with >50% AXL+ and 
MERTK+ CD68+ myeloid cells before treatment and AXL and MERTK expression will 
inversely correlate with percentage of effector CD8+ T cells and positively with FOXP3+ T 
regulatory cells. Upon treatment, the percentage of effector CD8+ T cells are expected to 
increase with a concomitant reduction in FOXP3+ T regulatory cells.
There will be gene expression changes in myeloid and T cell populations following 
pembrolizumab + sitravatinib treatment as detected by single- cell RNA sequencing in 
CD45+ cells in the tumor microenvironment (TME). Similar gene expression changes are 
expected to occur in myeloid and T cell populations with pembrolizumab + sitravatinib 
treatment versus pembrolizumab alone. Single-cell RNA sequencing, being an unbiased 
genome-wide transcriptome analyses, may reveal novel population-level complexities 
and unique gene expression markers associated with sitravatinib + pembrolizumab 
treatment compared with baseline or pembrolizumab alone. 
Corresponding mRNA changes are also expected in PBMCs in the peripheral blood as 
evaluated by bulk single cell and bulk RNA sequencing. These experiments may reveal 
surrogate peripheral blood predictive biomarkers of sitravatinib + pembrolizumab 
treatment. 
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
28
(4) Objective: To explore the association between tumor immune contexture and clinical 
benefit to sitravatinib and pembrolizumab
Hypothesis: Changes observed in innate and adaptive immune responses with  
pembrolizumab/sitravatinib treatment will positively correlate with improved clinical 
outcomes.  
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
29
4 Trial Design
4.1
Trial Schema 
• Advanced/metastatic non-
squamous NSCLC
• No prior systemic therapy for 
advanced disease
• PD-L1>1%
Cohort 1: 
PD-L1 1-49%
Cohort 2: 
PD-L1 >50%
Group 1A
n=30
Group 2B 
n=5
Group 1B 
n=5
Group 2A
n=30
Pembrolizumab
200mg IV x1
+ 
Sitravatinib
100mg PO
daily
3-week 
on-treatment
biopsy
Pembrolizumab
200mg IV Q3w
+ 
Sitravatinib
100mg PO daily
Pembrolizumab
200mg IV x 1
Pembrolizumab
200mg IV x 1
Group A: 
Main Study Population
Group B: 
Pembrolizumab Run-in
Population
Pembrolizumab
200mg IV x1
+ 
Sitravatinib
100mg PO
daily
Randomization
Randomization
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
30
4.2
General Design Description
This is an open-label multicohort Phase 2 study to evaluate the efficacy and safety of 
pembrolizumab combined with the investigational drug sitravatinib in the first-line treatment 
of advanced, non-squamous, PD-L1 positive NSCLC.  For clinical analysis, there will be two 
patient cohorts defined by PD-L1 status: Cohort 1 for patients with PD-L1 Tumor Proportion 
Score (TPS) 1-49% and Cohort 2 for patients with (TPS)>50%, using the FDA approved 
22c3 PD-L1 IHC assay or a local assay performed in a CLIA facility.  A Simon’s two-stage 
design will be used to evaluate the efficacy of sitravatinib in combination with pembrolizumab 
for each cohort separately.  There will be two treatment groups within each cohort: the “main 
study population” (Group A) in which patients will receive pembrolizumab plus sitravatinib 
beginning on cycle 1 day 1 (C1D1), and a “pembrolizumab run-in population” (Group B) in 
which patients will receive pembrolizumab alone for one dose followed by treatment with 
pembrolizumab plus sitravatinib beginning C2D1.
Potentially eligible patients will undergo screening after informed consent.  If they do not 
have archival tissue or PD-L1 status available, they will need to undergo pre-treatment 
biopsy.  If patients require pre-treatment biopsy for other clinical reasons after enrollment, 
this tissue will also be collected for research purposes.  Patients will then be stratified into 
cohorts by PD-L1 status (as above), before being randomized to either Group A (main study 
population) or Group B (pembrolizumab run-in population).  The randomized portion of the 
study will be performed exclusively at Yale.  Once 5 patients in each cohort have been 
randomized to Group B, all subsequent patients will be enrolled to Group A.  Patients in 
Groups 1A and 2A will begin treatment with pembrolizumab IV 200mg every 3 weeks plus 
sitravatinib PO 100mg daily on C1D1 of the study.  Patients in Groups 1B and 2B will begin 
pembrolizumab 200mg IV on study C1D1 and sitravatinib PO 100mg daily will be added on 
C2D1.  All patients will undergo an on-treatment study biopsy within 7 days prior to C2D1 of 
the study.  Research bloods will be drawn on a subset of patients prior to treatment and at 
intervals as specified in Study Calendars (Section 6.1).
Efficacy evaluations will be performed at 6 week intervals for the first 3 months, then 9 week 
intervals for the next 9 months and 12 week intervals thereafter.  Efficacy evaluations will 
include CT scans of the chest/abdomen (and pelvis if indicated) and MRI brain if indicated 
(see Section 7.1.1) as well as survival assessments (see Section 7.1.2).  Toxicity grading will 
occur as per CTCAE v5.0, with treatment interruptions or discontinuation of trial drugs as 
detailed in Sections 5.1.3 and 5.2.3.  Treatment will continue for two years or until 
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
31
progression of disease, unacceptable toxicity, patient refusal or death.   Patients 
experiencing clinical benefit in the judgment of the Treating Investigator may continue study 
treatment beyond disease progression as detailed in Section 6.8.   Post-treatment disease 
assessment will continue until objective disease progression or start of subsequent anti-
cancer therapy, whichever is sooner.
4.3
Study Date Range and Duration
This study is expected to last for 48 months including 24 months of recruitment and 24 
months of follow up.  
4.4
Endpoints
4.4.1
Primary Endpoint 
(1) Objective Response Rate (ORR): The primary endpoint for this study will be ORR as 
defined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) in the 
main study population.  
4.4.2
Secondary Endpoints 
(1) Overall Survival (OS) in the main study population (Section 9.2.3).  
(2) Progression Free Survival (PFS) in the main study population (Section 9.2.3).  
(3) Duration of Response (DOR) in the main study population (Section 9.2.4)
(4) Clinical Benefit Rate (CBR) in the main study population (Section 9.2.5)
(5) Adverse events in all groups.  Toxicity will be evaluated as detailed in Section 7.2 at 
regular intervals according to the Study Calendars (Section 6.1).   Severity will be graded 
as per CTCAE v.5.0.  
4.4.3
Exploratory Endpoints  
(1) ORR, PFS, OS, DOR in the pembrolizumab run-in population.  These results will not be 
included in the analysis of the main study population, but will be used to generate a 
preliminary assessment of benefit with this strategy.  
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
32
(2) Intracranial Objective Response (iORR) and intracranial Duration of Response 
(iDOR) in patients with baseline CNS disease (Sections 9.2.6 and 9.2.7).  
 
(3) Intracranial Progression Free Survival (iPFS) in all patients (Section 9.2.8).
(4) Correlative Endpoints: 
a.
Percentage of activated myeloid cells, effector T cells, and AXL+/MERTK+ 
macrophages in the TME as assessed by multiplex qualitative 
immunofluorescence in pre- and post-treatment tissue samples in both the main 
study population and pembrolizumab run-in population. 
b.
Clinical response as correlated to immune populations present in baseline 
samples and immune cell population changes induced by therapy 
c.
Immune cell population changes in the TME as defined by changes in population 
heterogeneity detected by single cell RNA in pre- and post-treatment tissue 
samples in both the main study population and pembrolizumab run-in population
d.
Gene expression changes in peripheral blood mononuclear cells in pre- and post-
treatment tissue samples in both the main study population and pembrolizumab 
run-in population.
e.
Percentage of CD8+ T cells and FOXP3+ T regulatory cells in pre- and post-
treatment tissue samples in both the main study population and pembrolizumab 
run-in population.
f.
The percentage of CD8+ T cells and FOXP3+ T regulatory cells correlated with the 
percentage of activated myeloid cells and AXL+/MERTK+ macrophages in the 
TME in pre- and post-treatment tissue samples in both the main study population 
and pembrolizumab run-in population.
4.4.4
Rationale for Endpoints
4.4.4.1
Rationale for Clinical Endpoints
The primary purpose of this trial is to evaluate the clinical efficacy of sitravatinib and 
pembrolizumab in the first line setting for patients with metastatic PD-L1 positive non-
squamous NSCLC.   There is no standard of care comparator arm in this study, however 
there are well established historical ORR for patients treated with pembrolizumab 
monotherapy.  Our study is powered to detect a 25% increase in ORR for the combination of 
sitravatinib/pembrolizumab in Groups 1A and 2A (main study population) compared with 
historical ORR seen with pembrolizumab monotherapy.  OS and PFS in Groups 1A and 2A 
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
33
will also be determined as secondary endpoints.  Safety and toxicity of this combination have 
been evaluated in the second line setting for NSCLC but have not been evaluated in the 
first-line setting.  As such, adverse events will also a secondary endpoint in this trial.
Clinical outcomes in Groups 1B and 2B will not be included in analysis of the main study 
(given limited sample size) but will be assessed as an exploratory endpoint.  Outcomes for 
these patients will be used to descriptively summarize clinical benefit with a pembrolizumab 
run-in followed by combination therapy, as well as to correlate outcomes with any observed 
immunologic and molecular changes found in tissue and blood. 
4.4.4.2
Rationale for Exploratory Endpoints/Correlative Studies 
Planned assessments of blood and tumor tissue including quantitative immunofluorescence 
and gene expression analysis will be performed with the aim of better understanding the 
underlying mechanisms of this drug combination.  Analysis is also hoped to reveal predictive 
biomarkers which may help assess the patients that are most likely to achieve clinical benefit 
from this drug combination.  
 
4.5
Study Population
4.5.1
Number of Participants
This study will plan to enroll a maximum of 35 evaluable patients to each cohort for a total of 
70 study participants.  30 patients from each cohort will be enrolled to Group A and 5 
patients from each cohort will be enrolled to Group B (see Trial Schema Section 4.1).  In 
order to accrue 70 evaluable patients, we expect to screen 80 patients (~10% ineligibility 
rate).  The randomized portion of the study will be performed exclusively at Yale, after which 
time we expect a roughly equal enrollment between the 2 sites.
4.5.2
Inclusion Criteria:
In order to be to be eligible to participate in this study, an individual must meet all of the 
following criteria:
1.
Histologically or cytologically confirmed non-squamous NSCLC that is metastatic (Stage 
IV), recurrent, or unresectable locally advanced (Stage IIIB/IIIC) disease, not amenable 
to treatment with curative intent.
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
34
2.
No prior systemic therapy for advanced disease.  Prior chemotherapy for local or locally 
advanced disease is allowed if completed >6 months prior to trial enrollment.  Prior 
immunotherapy is not allowed. 
3.
PD-L1 ≥ 1% using the 22c3 PD-L1 IHC assay or a local assay performed in a CLIA 
facility
4.
Age ≥ 18 years.
5.
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
6.
Life expectancy of at least 3 months.
7.
Measurable disease as per RECIST v1.1 
8.
Adequate bone marrow and organ function demonstrated by:
a.
Absolute neutrophil count >1,500/mm3 (1.5 × 109/L).
b.
Hemoglobin ≥ 8.0 g/dL not dependent on transfusion support.
c.
Platelet count ≥ 75 × 109/L (≥ 75,000 per mm3).
d.
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 1.5 × 
ULN without liver metastases; < 5.0 x ULN if documented liver metastases
e.
Serum total bilirubin ≤ ULN, or for patients with potential Gilbert’s, direct bilirubin 
≤ ULN 
f.
Calculated creatinine clearance ≥ 40 mL/min, using the Cockcroft-Gault formula.
9.
Women of child-bearing potential (WOCBP) or men whose partner is a WOCBP agrees 
to use contraception while participating in this study, and for a period of 6 months 
following termination of study treatment.
10. Completed informed consent process, including signing IRB approved informed consent 
form.
11. Willing to comply with clinical trial instructions and requirements.
12. Willing to undergo an on-treatment biopsy with an appropriate biopsy site identified prior 
to treatment initiation (see 6.5.1).
4.5.3
Exclusion Criteria:
An individual who meets any of the following criteria will be excluded from participation in 
this study: 
1. Symptomatic or untreated brain metastases ≥ 2cm in diameter.  Patients with brain 
lesions that are adequately treated with local therapy (i.e. radiation therapy) and 
neurologically stable without the need for corticosteroids for at least 2 weeks prior to 
enrollment are allowed. Patients with brain lesions that are asymptomatic, smaller than 
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
35
2cm, in non-critical regions of the brain and not requiring corticosteroids for at least 2 
weeks prior to enrollment may be eligible after review with the Sponsor Investigator. 
2. Leptomeningeal disease
3. Known mutations/alterations in EGFR, ROS1, ALK, or BRAF
4. Any prior treatment with checkpoint inhibitor therapy or other immunotherapy agents
5. Any prior treatment with therapy having the same mechanism of action as sitravatinib 
(e.g., tyrosine kinase inhibitor with a similar target profile or bevacizumab/ramucirumab)
6. Active or prior documented autoimmune disease within the past 2 years (note: patients 
with type 1 diabetes, vitiligo, Graves’ disease, hypothyroidism due to an autoimmune 
condition only requiring hormone replacement, or psoriasis not requiring systemic 
treatment (within the past 2 years) are not excluded).
7. Active or prior immunocompromising conditions, including use of immunosuppressive 
medication within 2 weeks of enrollment.  This does not include topical, intranasal or 
inhaled steroids with minimal systemic absorption or systemic corticosteroids at 
physiologic doses not to exceed 10mg/day of prednisone or equivalent.  Use of higher 
dose corticosteroids for short/defined course (ie prophylaxis in patients with contrast dye 
allergy) is also allowed if indicated.  
8. Uncontrolled HIV.  Patients with HIV may be eligible if they meet the following criteria: 
a.
CD4+ T cell count>350 cell/uL
b.
No history of AIDS-defining opportunistic infection within the past 12 months
c.
Currently tolerating treatment with ART for at least 4 weeks prior to enrollment, 
with HIV viral load <400 copies/mL 
d.
Patients on specific ART drugs with possibility for drug-drug interaction with 
sitravatinib may be excluded (see appendix 5).
9. Active hepatitis C (HCV) infection.  Patients with a history of HCV may be eligible if they 
have completed curative antiviral treatment with undetectable HCV viral load and liver 
function tests are otherwise within acceptable limits (as described in Section 4.5.2).  
Patients with chronic Hepatitis B (HBV) infection are not excluded if liver function is 
within acceptable limits, but should be evaluated for reactivation risk and started on 
suppressive antiviral therapy prior to enrollment if appropriate.  
10.History of stroke or transient ischemic attack within the previous 6 months.
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
36
11.History of life threatening venous thromboembolic event (such as hemodynamically 
significant pulmonary embolism) or any arterial thrombotic event within the previous 6 
months.  Patients with non-life threatening venous thromboembolic events are not 
excluded and should be managed with anti-coagulation as per standard institutional 
practice.  
12.Any of the following cardiac abnormalities:
a.
Unstable angina pectoris within the past 6 months.
b.
Congestive heart failure ≥ NYHA Class 3 within the past 6 months.
c.
Prolonged QTc on electrocardiogram >500 milliseconds.
d.
Left ventricular ejection fraction (LVEF) < 40%.
13.Uncontrolled hypertension (>150mm Hg or >100mm Hg diastolic) on multiple 
observations despite standard of care treatment 
14.Major surgery within 4 weeks of the date of randomization.
15.History of significant hemoptysis or hemorrhage within 4 weeks of the date of 
randomization.
16.Known or suspected presence of another malignancy that could be mistaken for the 
malignancy under study during disease assessments.
17.Has received a live vaccine within 30 days prior to the first dose of trial treatment. 
18.Pregnancy. WOCBP must have a negative serum or urine pregnancy test documented 
within the screening period prior to the date of randomization.  
19.Breast-feeding or planning to breast-feed during the study or within 30 days following the 
last dose of sitravatinib and within 5 months following the last dose of pembrolizumab.
20.Any serious illness, uncontrolled inter-current illness, psychiatric illness, active or 
uncontrolled infection, or other medical history, including laboratory results, which, in the 
Investigator’s opinion, would be likely to interfere with the patient’s participation in the 
study, or with the interpretation of the results.
4.5.4
Life Style Guidelines
Patients who are biologically capable of having children and sexually active must agree to 
use at least 2 acceptable methods of birth control, one of which must be highly effective for 
the duration of the treatment period and for at least 6 months after the last dose of study 
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
37
treatment. The Investigator will counsel the patient on selection of contraception method and 
instruct the patient in its consistent and correct use. 
Examples of acceptable birth control methods considered highly effective are the following:
1. Oral, inserted, injected or implanted hormonal methods of contraception, provided it has 
been used for an adequate period of time to ensure effectiveness.
2. Correctly placed copper containing intrauterine device (IUD).
3. Male sterilization with confirmed absence of sperm in the post-vasectomy ejaculate.
4. Bilateral tubal ligation or bilateral salpingectomy.
5. Sexual abstinence (in the context of this protocol, sexual abstinence is considered a 
highly effective method of birth control only if refraining completely from heterosexual 
intercourse during the entire period of risk (i.e., during study treatment, including during 
temporary breaks from treatment, and for at least 6 months after stopping study treatment)). 
Acceptable birth control methods not considered highly effective include the following:
1. Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mode of action
2. Male or female condom with spermicide
3. Cap, diaphragm, or sponge with spermicide
The Investigator will instruct the patient to call immediately if the selected birth control 
method is discontinued or if pregnancy is known or suspected.
Note: Women are considered post-menopausal and/or not of child bearing potential if they 
have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g., age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy) or tubal ligation at least 6 months ago. In case 
of any ambiguity, the reproductive status of the woman should be confirmed by hormone 
level assessment.
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
38
4.6
Method of Assignment/Randomization 
Following review of all screening procedures, patient eligibility will be confirmed by 
appropriately qualified staff at the investigational site.  Patients will be enrolled to 1 of the 2 
cohorts based on PD-L1 status, TPS ≥ 50% and TPS 1-49%.  Within each cohort, patients 
will initially be randomized 1:1 to either the Group A (“main study population”) or Group B 
(“pembrolizumab run-in population”).  Randomization in each cohort will continue until 5 
patients have been enrolled to Group 1B and 5 patients have been enrolled to Group 2B.  
The randomized portion of the study will be performed exclusively at Yale.  All subsequent 
patients will be assigned (not randomized) to Group A.  This study will not be blinded. 
5 Study Treatments  
The investigational treatments to be used in this trial are the novel drug sitravatinib and FDA 
approved therapy pembrolizumab.  
5.1
Sitravatinib 
Sitravatinib is a spectrum-selective RTK inhibitor that acts on several closely related RTKs 
including the TAM family (Tyro3/Axl/MERTK), VEGFR2, KIT, and MET.  This drug is 
currently experimental and is not FDA approved. It is administered as a daily oral 
medication.  
5.1.1
Sitravatinib Formulation, Packing and Storage 
The sitravatinib formulation used in this protocol is the malate salt capsule product which 
consists of a blend of sitravatinib malate salt drug substance, microcrystalline cellulose, 
mannitol, colloidal silicon dioxide, croscarmellose sodium, colloidal silicon dioxide and 
magnesium stearate. The blend is filled into hard gelatin capsules.  
Sitravatinib drug product is packaged in high-density polyethylene (HDPE), white opaque, 
round 60 cc bottles. A tamper-proof heat induction seal and a child-resistant closure are 
used. The provided bottles may be labeled for specific patient use and given to the patient. 
Sitravatinib medication labels comply with the legal requirements of the US.
Investigational clinical trial material must be stored in an area that is secure, with limited 
access and monitored for temperature using a calibrated thermostat or thermometer. Only 
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
39
qualified personnel who are familiar with procedures that minimize undue exposure 
to them and to the environment should undertake the preparation, handling, and safe 
disposal of small molecule therapeutic agents. Sitravatinib capsules should be stored 
under the conditions stated on the container labels and the Pharmacy Study Manual.
Please Refer to the Pharmacy Study Manual for further details. 
5.1.2
Sitravatinib Schedule and Administration
Sitravatinib capsules will be administered orally, once per day (QD), as a continuous 
regimen expressed in 21-day cycles.  The starting dose of the sitravatinib malate capsule 
formulation is 100 mg QD.   For patients in Groups 1A and 2A (main study population), 
sitravatinib dosing will begin on C1D1.  For patients in Groups 1B and 2B (pembrolizumab 
run-in population) dosing of sitravatinib will begin on C2D1 of the study.
The following guidelines should be followed for sitravatinib administration:

Dosing in the morning is preferred.

Capsules should be taken on an empty stomach (at least 2-hour fast before each dose 
and no food for a minimum of 1 hour after each dose) until notified otherwise by the 
Sponsor. 

Capsules should be taken with at least 240 mL (approximately 1 cup) of water.

Patients should swallow the capsules whole and not chew them.

If vomiting occurs after dosing, sitravatinib doses should not be replaced.

Missed doses should be taken within 12 hours of the scheduled time and the next dose 
should be taken at its scheduled time.
Additional details are provided in the Pharmacy Study Manual.  
5.1.3
Sitravatinib Dose Modification or Discontinuation 
Depending on safety observations, the sitravatinib dose during subsequent cycles of 
treatment may be reduced as per Table 1.  Indications for dose modification and treatment 
delay are discussed in Section 5.3.1 (Management of Sitravatinib Adverse Events).  Once 
the dose has been reduced, re-escalation is generally not recommended but may be 
considered on a case-by-case basis after discussion with the Sponsor Investigator. If the 
administration of sitravatinib is interrupted for reasons other than toxicity then treatment with 
the study drug may be resumed at the same dose.  
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
40
Although sitravatinib has not been associated with irAEs, it may potentiate the effect of 
pembrolizumab and contribute to irAEs.  Therefore, for any AE that requires interruption of 
pembrolizumab, sitravatinib should also be interrupted until the event improves to Grade ≤1. 
Please see section 5.3.1 for management of sitravatinib in the case of irAEs.  
In the case of an AE that can clearly be attributed to sitravatinib and is not immune-mediated 
(ie hypertension), dose reduction with continuous treatment is preferred over repeated dose 
interruption. If treatment with sitravatinib is delayed for ≥ 14 days due to AEs, then 
resumption will be at a reduced dose. If treatment with sitravatinib is withheld for ≥ 28 
consecutive days due to AEs, then sitravatinib will be permanently discontinued unless 
reviewed and approved by the Sponsor Investigator.  In the case of interruption or 
discontinuation of sitravatinib, pembrolizumab may be continued at the discretion of the 
Treating Investigator if the AE is attributed to sitravatinib alone.  If pembrolizumab is 
discontinued due to toxicity, the continuation of sitravatinib as monotherapy may be 
considered once the AE improves to Grade ≤1 and following discussion with the Sponsor-
Investigator. 
Table 1:
Sitravatinib Sequential Dose Reductions for Individual Patients on 
Malate Capsule Formulation
100 mg once daily
70 mg once daily
50 mg once daily
35 mg once daily
5.1.4
Sitravatinib Dispensing and Accountability
Dispensing of sitravatinib will be performed as per the Pharmacy Study Manual.  Receipt 
and dispensing of study drug must be recorded by an authorized person at the study site. 
Study drug may not be used for any purpose other than that stated in the Protocol. 
Patients will be asked to record their daily dosing in a pill dairy (Appendix 6). and report any 
missed doses or lost doses at the next clinic visit.  Patients should be told to bring study 
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
41
treatment bottle(s) (empty or not) and completed dosing diaries with them to the clinic visit 
for a compliance check and capsule count. 
At the end of the study, all unused sitravatinib drug supplies must be destroyed in 
accordance with local Standard Operating Procedure, or returned to the manufacturer. 
5.2
Pembrolizumab 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of 
the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its 
ligands, PD-L1 and PD-L2.  KeytrudaTM (pembrolizumab) is approved in the United Stated as 
monotherapy for the treatment of patients with unresectable or metastatic NSCLC and PD-
L1 expression >1%.  
5.2.1
Pembrolizumab Formulation, Packing and Storage
Pembrolizumab will be provided commercially for patients as an FDA approved therapy for 
treatment naïve patients with PD-L1 positive NSCLC. 
Refer to the current pembrolizumab approved product insert for further details on 
formulation, packing and storage information.  
5.2.2
Pembrolizumab Schedule and Administration
All patients will receive pembrolizumab 200mg administered as a 30 minute IV infusion every 
3 weeks starting on study Day 1.  Treatment will be continued for 35 cycles or until 
progression, unacceptable toxicity, withdrawal of consent or study end, whichever occurs 
first.  Patients with progression of disease by RECIST v1.1 may be allowed to continue trial 
therapy as per Section 6.8 at the discretion of Sponsor Investigator.  
 Further administration details as per current pembrolizumab product label.  
5.2.3
Pembrolizumab Dose Modification or Discontinuation 
Interruption or discontinuation of pembrolizumab may be required for some toxicities as 
summarized in Table 2.  Treatment of suspected pembrolizumab related adverse events is 
discussed in Section 5.3.3.  Dose reductions of pembrolizumab are not allowed.  Dosing 
interruptions are permitted in the case of medical / surgical events or logistical reasons not 
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
42
related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, 
and/or holidays). Subjects should be placed back on study therapy within 3 weeks of the 
scheduled interruption, unless otherwise discussed with the Sponsor Investigator.  The 
reason for interruption should be documented in the patient's study record.
Table 2: 
Dose Modification Guidelines for Drug-Related Adverse Events for 
Pembrolizumab 
Toxicity
Hold 
Treatment 
For Grade
Timing for Restarting Treatment
Discontinue Subject
2-3
Toxicity resolves to Grade 0-1.
Toxicity does not resolve within 12 weeks of last dose 
or inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks.
Diarrhea/Colitis
4
Permanently discontinue
Permanently discontinue
2
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 12 weeks of last dose.
AST, ALT, or 
Increased 
Bilirubin
3-4
Permanently discontinue
(see exception below)1
Permanently discontinue
Type 1 diabetes 
mellitus (if new 
onset) or 
Hyperglycemia
T1DM or
3-4
Hold pembrolizumab for new onset 
Type 1 diabetes mellitus or Grade 
3-4 hyperglycemia associated with 
evidence of beta cell failure. 
Resume pembrolizumab when patients are clinically 
and metabolically stable.
2
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 12 weeks of last dose 
or inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks.
Hypophysitis
3-4
Withhold until clinically stable or 
permanently discontinue depending 
on severity 
Permanently discontinue depending on severity.
Hyperthyroidism 
3-4
Withhold until clinically stable or 
permanently discontinue depending 
on severity
Toxicity does not resolve within 12 weeks of last dose 
or inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks.
Hypothyroidism
2-4
Therapy with pembrolizumab can 
be continued while treatment for the 
thyroid disorder is instituted
Therapy with pembrolizumab can be continued while 
treatment for the thyroid disorder is instituted.
Infusion 
Reaction
3-4
Permanently discontinue
Permanently discontinue
2
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 12 weeks of last dose 
or inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks.
Pneumonitis
3-4
Permanently discontinue
Permanently discontinue
2
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 12 weeks of last dose 
or inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks.
Renal Failure or 
Nephritis
3-4
Permanently discontinue
Permanently discontinue
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
43
Toxicity
Hold 
Treatment 
For Grade
Timing for Restarting Treatment
Discontinue Subject
3 or Severe
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 12 weeks of last dose 
or inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks.
All Other Drug-
Related Toxicity2
4
Permanently discontinue
Permanently discontinue
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening event.
1 For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or 
equal to 50% relative to baseline and lasts for at least 1 week then patients should be discontinued.
2 Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion.  Permanently 
discontinue study drug for persistent Grade 2 adverse reactions for which treatment with study drug has been held, that do not 
recover to Grade 0-1 within 12 weeks of the last dose.  
5.3
Management of Adverse Events
A complete review of adverse events should be conducted at each clinic visit with laboratory 
assessment as per Study Calendars (Section 6.1). 
5.3.1
Sitravatinib-Related Adverse Events 
5.3.1.1
General Management of Sitravatinib Related Non-Hematologic Toxicities 
General management of non-hematologic sitravatinib related toxicities are summarized in 
Table 3.  Symptomatic Grade 2 sitravatinib-related non-hematological adverse events 
occurring any time on study, particularly early in treatment, are managed using dose 
reduction to the next lower dose level, per the reduction schedule outlined in Table 1, rather 
than continued dosing until interruption becomes necessary. 
Non-hematological toxicities ≥ Grade 3 and considered to be related to sitravatinib treatment 
will be managed with sitravatinib interruption, with or without dose reduction, until resolution 
of toxicity to ≤ Grade 1 or to baseline value. If the toxicity is adequately managed by routine 
supportive care (such as electrolyte supplementation), treatment may be resumed at the 
same dose; otherwise, treatment may be resumed at one or more levels below the dose 
level where toxicity was observed as outlined in Table 1.  Recurrence of a toxicity may be 
managed similarly. If treatment is interrupted for ≥ 28 days, sitravatinib will be permanently 
discontinued unless reviewed and approved by the Sponsor Investigator. 
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
44
5.3.1.2
General Management of Sitravatinib Related Hematological Toxicities 
Hematological toxicities are not a frequent cause of treatment interruption or discontinuation 
of sitravatinib treatment. Observed ≥ Grade 3 hematological events that are considered to be 
causally related to sitravatinib should initially be managed using treatment interruption until 
resolution of toxicity to ≤ Grade 2. In addition, dose reduction of sitravatinib will be 
implemented in the following cases:

Grade 3 or 4 febrile neutropenia;

Grade 4 neutropenia persisting for ≥ 8 days; or

Grade 4 thrombocytopenia of any duration or Grade 3 thrombocytopenia with bleeding.
Table 3:  
Dose Modifications for Sitravatinib Toxicity
1 Management of selected sitravatinib toxicities as per Section 5.3.2 
2 Patients may resume at the same dose in the following cases:
a.
Grade 3 or 4 electrolyte abnormality that is not clinically complicated and resolves spontaneously or with conventional 
medical treatment within 72 hours;
Toxicity
Grade
Treatment Delay  
Dose Modification  
1
Not required 
None 
Asymptomatic: None required 
2
Not required 
Symptomatic: None required.  Early dose reduction 
to the next lower dose level is recommended over 
treatment interruption.  
General non-
hematologic 
toxicity1
3-4
Hold until < grade 1 or return to 
baseline
Resume at reduced dose.  Exceptions presented in 
footnotes2 
1-2
Not required 
None 
3
Hold until < grade 2
Reduce dose for grade 3 febrile neutropenia or 
grade 3 thrombocytopenia with bleeding
Hematologic 
toxicities 
4
Hold until < grade 2
Reduce for grade 4 febrile neutropenia, grade 4 
neutropenia lasting >8 days or grade 4 
thrombocytopenia  
1-2
Not required 
None required
Not clinically significant3: Not 
required 
Decrease dose if unresponsive to anti-hypertensive 
treatment
3
Clinically significant3:  Hold until < 
grade 2 or return to baseline 
Resume at decreased dose level 
Hypertension
4
Discontinue
Discontinue 
1
Not required 
None required
2
Not required 
Decrease by one dose level 
Transaminitis
3-4
Hold until < grade 1 or return to 
baseline 
If resolution occurs within 29 days, decrease by 1 
dose level.  If no resolution within 29 days, 
discontinue sitravatinib
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
45
b.
Grade 3 amylase or lipase elevation that is not associated with symptoms or other clinical (e.g., electrolyte abnormalities, 
radiographic changes) manifestations of pancreatitis.
3 Clinical significance is defined as either an increase of ≥ 30 mmHg in systolic BP to ≥ 180 mmHg or increase of ≥ 20 mmHg in 
diastolic BP to ≥ 110 mmHg, confirmed with repeated testing after at least 5 minutes
5.3.2
Management of Selected Sitravatinib Adverse Events 
Hypertension
Hypertension, including Grade 4 events, has been reported with sitravatinib. Anti-
hypertensive therapy should be considered for patients with Grade 3 hypertension without 
clinically significant increases in blood pressure (BP). In cases of Grade 3 hypertension with 
clinically significant increases in blood pressure (defined as either an increase of ≥ 30 mmHg 
in systolic BP to ≥ 180 mmHg or increase of ≥ 20 mmHg in diastolic BP to ≥ 110 mmHg, 
confirmed with repeated testing after at least 5 minutes), sitravatinib dosing will be 
temporarily suspended until blood pressure is controlled. Treatment with sitravatinib may 
then resume at the lower dose level (Table 3). If significant hypertension recurs, options 
include change in medical management of the patient, reduction of sitravatinib dose, or 
discontinuation of study treatment, at the discretion of the Treating Investigator. In the event 
of Grade 4 hypertension, sitravatinib will be permanently discontinued (Table 3)
Palmar-Plantar Erythrodysesthesia
Palmar plantar erythrodysesthesia (PPE) has been reported as a dose limiting toxicity in the 
Phase 1 study of sitravatinib. Measures that can be taken to manage PPE include avoidance 
of exposure of hands and feet to hot water when washing dishes or bathing, or to other 
sources of heat, avoidance of activities that cause unnecessary force or friction (rubbing) on 
the hands or feet, avoiding contact with harsh chemicals such as cleaning products, use of 
tools or household items that result in pressure on the hands, such as garden tools, knives, 
and screwdrivers, and wearing of loose fitting, well-ventilated shoes and clothes.
Treatment may include use of topical moisturizing agents, topical anesthetics, or topical anti-
inflammatory medications such as corticosteroid creams. In more severe cases, dose 
interruption and reduction may be warranted.
Diarrhea
Diarrhea should be evaluated to determine whether it may be immune-mediated colitis due 
to pembrolizumab, related to sitravatinib, or due to another cause.  Diarrhea has been 
reported with sitravatinib treatment, though the mechanism remains unclear.  Patients 
should be counseled that diarrhea is a possible side effect and advised to take loperamide 
or a similar medication as needed if diarrhea due to sitravatinib develops. Any patients 
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
46
developing dehydration or clinically significant electrolyte abnormalities due to sitravatinib 
should interrupt sitravatinib treatment, but treatment may be restarted once diarrhea is 
controlled.  The diarrhea observed with sitravatinib generally improves within several days of 
interrupting study medication so discontinuation with close observation may help establish 
causality.  If any features of the clinical presentation, including timing of presentation, failure 
to improve with dose interruption, laboratory or radiologic tests suggests the presence of 
immune-related colitis, all study medications should be withheld and treatment with 
immunosuppressive therapy considered as per Section 5.3.3.2.  
Hemorrhagic Events
The risk of hemorrhagic events with sitravatinib has not been fully characterized, however, 
such events have been reported with inhibitors of VEGFR. Patients with active hemoptysis 
or gastrointestinal bleeding should not take sitravatinib and suspension of treatment is 
recommended for patients developing clinically significant bleeding.
Thrombotic Events
Arterial and venous thrombotic events have been observed with sitravatinib and described 
with other inhibitors of the VEGFR pathway. The majority of thrombotic events observed with 
sitravatinib have been venous thrombotic events. The occurrence of thrombotic events with 
sitravatinib is being monitored for further characterization. Patients with a history of VTE 
should be anticoagulated as per local standard of care.  Treatment should be discontinued in 
subjects who develop clinically significant thromboembolic complications.
Thyroid Dysfunction Other than Immune-Related
Hypothyroidism and increases in thyroid-stimulating hormone (TSH) have been reported in 
patients taking sitravatinib. Patients diagnosed with hypothyroidism should be treated with 
thyroid replacement therapy and may continue treatment with sitravatinib.
Decreased Left Ventricular Ejection Fraction
Decreased LVEF has been reported with sitravatinib. In addition, decreases of LVEF to 
<50% on-study were observed in patients undergoing scheduled echocardiograms (ECHO) 
or multigated acquisition (MUGA) scans. The dose of sitravatinib should be interrupted 
and/or reduced in patients with an ejection fraction that has dropped >20% below baseline 
and is <50%.. Discontinuation should be considered for patients requiring acute 
hospitalization for treatment of congestive heart failure (CHF).
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
47
Proteinuria
Proteinuria has been observed with sitravatinib and described with other inhibitors of the 
VEGFR pathway. Urinalysis for urine protein should be performed prior to each cycle 
following the start of sitravatinib and as clinically warranted during treatment with sitravatinib. 
Subjects who develop ≥2+ proteinuria should undergo 24-hour urine collection for 
assessment of urine protein; treatment with sitravatinib should be discontinued in the 
presence of ≥2 grams of proteinuria/24 hours and may be restarted when protein levels 
decrease to less than 2 grams/24 hours. Subjects who develop nephrotic syndrome should 
be withdrawn from treatment with sitravatinib.
Increased Transaminases
The management of increases in AST and ALT should be guided by the clinical judgment of 
the Treating Investigator, including an assessment of the most likely causative etiology, with 
special consideration given to the potential for immune-related hepatitis. Increased 
transaminases should be evaluated to determine whether confounding factors exist, such as 
viral infection, metastatic lesions or biliary obstruction.  Increased transaminases have been 
observed in subjects treated with sitravatinib. Most cases were asymptomatic elevations in 
ALT or AST, while some were associated with liver metastases or cholestasis. No cases of 
drug-induced liver injury meeting Hy’s Law have been identified.
For cases where transaminase increases are not likely to be immune-related, treatment 
management decisions should be made using the Treating Investigator’s discretion in 
consideration of clinical factors. Recommended treatment modifications for sitravatinib are 
provided in Table 3 .  However, if any features of the clinical presentation, including timing of 
presentation, failure to improve with dose interruption, laboratory or radiologic tests suggests 
the presence of immune-related hepatitis, all study medications will be withheld and 
treatment with immunosuppressive therapy considered as detailed in management of 
pembrolizumab related adverse events (Section 5.3.3)
Increased Amylase and Lipase
Increased amylase and lipase have been observed in subjects treated with sitravatinib and 
have been reported with other inhibitors of the VEGF pathway. Most sitravatinib-related 
treatment-emergent events of increased amylase and lipase were asymptomatic while some 
were associated with signs and/or symptoms of pancreatitis. Treatment with sitravatinib may 
continue without dose modification (eg, interruption or reduction) in cases of asymptomatic 
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
48
amylase and/or lipase increases in the absence of other clinical evidence of pancreatitis (eg, 
symptoms, electrolyte abnormalities, radiographic changes) at the Treating Investigator’s 
discretion. Sitravatinib should be interrupted for any grade pancreatitis and the subject 
managed according to standard-of-care. After resolution of pancreatitis, sitravatinib 
resumption is at the discretion of the Treating Investigator; if pancreatitis is assessed as 
sitravatinib treatment-related and treatment is resumed, a dose reduction is recommended. 
Immune-Related Adverse Events (irAEs)
Single agent sitravatinib has not been associated with irAEs. However, the potential exists 
for irAEs associated with sitravatinib to contribute to irAEs associated with pembrolizumab 
treatment. In the event of a Grade 2 irAE during study treatment, administration of 
sitravatinib and pembrolizumab will be interrupted until the event stabilizes to Grade ≤1 (see 
Section 5.3.3 on pembrolizumab associated adverse event treatment). At the time of 
resumption of sitravatinib dosing, a dose reduction may be implemented at the discretion of 
the Treating Investigator.
Management of Grade 3 and 4 irAEs should be performed as in section on pembrolizumab 
related adverse events management (Section 5.3.3).  Recurrent Grade 3, or any Grade 4, 
irAEs should generally be managed with permanent discontinuation of pembrolizumab, and 
temporary or permanent interruption of sitravatinib. Sitravatinib may be resumed at the same 
or lower dose at the discretion of the Treating Investigator once the event stabilizes to Grade 
≤ 1.
5.3.3
Pembrolizumab-Related Adverse Events 
5.3.3.1
General Management of Pembrolizumab-Related Adverse Events 
Pembrolizumab related AE management is as per institutional standard of care, with the 
following recommended guidelines.  Pembrolizumab must be withheld for certain drug-
related toxicities and severe or life-threatening AEs as per Table 2.  Subjects should receive 
appropriate supportive care measures as deemed necessary by the Treating Investigator.  
Suggested supportive care measures for the management of adverse events with potential 
immunologic etiology are outlined below. Where appropriate, these guidelines include the 
use of oral or intravenous treatment with corticosteroids as well as additional anti-
inflammatory agents if symptoms do not improve with administration of corticosteroids.   
Note that several courses of steroid tapering may be necessary as symptoms may worsen 
when the steroid dose is decreased. These are guidelines and local standard of 
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
49
care/institutional standards may be followed at the discretion of the Treating Investigator.  
For each disorder, attempts should be made to rule out other causes such as metastatic 
disease or bacterial or viral infection, which might require additional supportive care. The 
treatment guidelines are intended to be applied when the investigator determines the events 
to be irAEs.  For guidelines regarding restarting pembrolizumab, please see Table 2.  
5.3.3.2
Management of Selected Pembrolizumab-Related Adverse Events 
Pneumonitis: 
For Grade 2 events pembrolizumab should be held and treatment with corticosteroids 
initiated.  When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.  For Grade 3-4 events, immediately treat with 
intravenous steroids.  Administer additional anti-inflammatory measures, as needed.  Add 
prophylactic antibiotics for opportunistic infections in the case of prolonged steroid 
administration.
Diarrhea/Colitis: 
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus).  All subjects who experience diarrhea/colitis 
should be advised to drink liberal quantities of clear fluids.  If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be substituted via IV infusion.  GI consultation should 
be considered for Grade 2 or higher diarrhea/colitis.  For Grade 2 diarrhea/colitis that 
persists greater than 3 days despite supportive treatment and anti-diarrheals, 
pembrolizumab should be held and oral steroids should be administered. For Grade 3 or 4 
diarrhea/colitis, pembrolizumab should be held and IV or oral corticosteroids should be 
administered.  For grade 3-4 diarrhea that persists > 4 days despite oral steroids, treat with 
intravenous steroids followed by high dose oral steroids.  If not improving despite IV steroid 
administration, may also consider additional anti-inflammatory treatments.  When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over no less than 
4 weeks.
New Onset Type 1 diabetes mellitus (including diabetic ketoacidosis [DKA]) or ≥ Grade 3 
Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis (DKA):
For T1DM or Grade 3-4 Hyperglycemia associated with metabolic acidosis or ketonuria, 
initiation of insulin is recommended. Pembrolizumab may be held while glucose control is 
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
50
obtained.  Evaluate patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide. 
Hypophysitis:
For Grade 2 events, hold pembrolizumab, treat with corticosteroids and provide hormonal 
supplementation as appropriate. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks.  For Grade 3-4 events, treat 
with an initial dose of IV corticosteroids followed by oral corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over no less than 
4 weeks. Replacement of appropriate hormones may be required as the steroid dose is 
tapered.
Hyperthyroidism or Hypothyroidism: 
Thyroid disorders can occur at any time during treatment. Monitor patients for changes in 
thyroid function (at the start of treatment, during treatment, and as indicated based on 
clinical evaluation) and for clinical signs and symptoms of thyroid disorders. For grade 2-4 
hypothyroidism, thyroid hormone replacement therapy is indicated per standard of care.  
Pembrolizumab may be held if patients are severely symptomatic or show signs of 
myxedema   For Grade 2 hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy.  For Grade 3-4 hyperthyroidism, hold pembrolizumab and 
consider treatment with corticosteroids in addition to treatment with non-selective beta-
blockers. When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. Replacement of appropriate hormones may be 
required as the steroid dose is tapered.
Hepatitis:
For Grade 2 events, hold pembrolizumab and monitor liver function tests more frequently.  
Consider treatment with IV or oral corticosteroids if elevation persists for 3-5 days or if there 
are accompanying clinical symptoms.  For Grade 3-4 events, hold pembrolizumab and treat 
with intravenous corticosteroids for 24 to 48 hours followed by high dose oral steroids. When 
symptoms improve to Grade 1 or less, a steroid taper should be started and continued over 
no less than 4 weeks.
Renal Failure or Nephritis:
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
51
For Grade 2 events, hold pembrolizumab and administer IV or oral corticosteroids.  Consider 
nephrology consultation.  For Grade 3-4 events, treat with IV corticosteroids.  When 
symptoms improve to Grade 1 or less, steroid taper should be started and continued over no 
less than 4 weeks. 
Management of Infusion Reactions: 
Signs and symptoms usually develop during or shortly after drug infusion and generally 
resolve completely within 24 hours of completion of infusion.  See Table 6 below for treatment 
guidelines for patients who experience a transfusion reaction. 
Table 6: Infusion Reaction Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at 
subsequent dosing
Grade 1
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated
Increase monitoring of vital signs as medically indicated 
until the subject is deemed medically stable in the opinion 
of the investigator.
None
Grade 2
Requires infusion interruption 
but responds promptly to 
symptomatic treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); prophylactic 
medications indicated for < =24 
hrs
Stop Infusion and monitor symptoms.
Additional appropriate medical therapy may include but is 
not limited to:

IV fluids

Antihistamines

NSAIDS

Acetaminophen

Narcotics
Increase monitoring of vital signs as medically indicated 
until the subject is deemed medically stable in the opinion 
of the investigator.
If symptoms resolve within one hour of stopping drug 
infusion, the infusion may be restarted at 50% of the original 
infusion rate (e.g., from 100 mL/hr to 50 mL/hr).  Otherwise 
dosing will be held until symptoms resolve and the subject 
should be premedicated for the next scheduled dose.
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further trial treatment 
administration.
Subject may be premedicated 1.5h 
(± 30 minutes) prior to infusion of 
pembrolizumab with:
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine).
Acetaminophen 500-1000 mg po 
(or equivalent dose of antipyretic).
Grades 3 or 4
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
Stop Infusion.
Additional appropriate medical therapy may include but is 
not limited to:

IV fluids

Antihistamines
No subsequent dosing
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
52
NCI CTCAE Grade
Treatment
Premedication at 
subsequent dosing
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae (e.g., 
renal impairment, pulmonary 
infiltrates)
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated

NSAIDS

Acetaminophen

Narcotics

Oxygen

Pressors

Corticosteroids

Epinephrine
Increase monitoring of vital signs as medically indicated until 
the subject is deemed medically stable in the opinion of the 
investigator.
Hospitalization may be indicated.
Subject is permanently discontinued from further trial 
treatment administration.
5.4
Concomitant Therapies 
5.4.1
Concomitant Medications  
Prior medications (including chronically administered medication) used in the 28 days prior 
to signing consent will be reviewed and recorded.  Patients may continue to use any ongoing 
medications not prohibited by the inclusion/exclusion criteria or treatment plan. 
Comprehensive list of medications to be used with caution or avoided are listed for 
sitravatinib in Appendix 5.  
Anti-diarrheals: In general, patients should be counseled that diarrhea is a possible side 
effect of the study treatments and advised to take loperamide or a similar medication as 
needed if diarrhea develops.
Anti-Emetics: Patients may be premedicated for nausea and vomiting. 
Medications with QTc Prolonging Activity: The risk of QTc prolongation in patients receiving 
sitravatinib has not been characterized. Use of medications known to prolong QTc and pose 
risk of Torsades de Pointes (listed in Appendix 5) should be used with caution.  
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
53
P-gp and BCRP transporters with Sitravatinib: Sitravatinib is a strong inhibitor of P-gp and 
BCRP transporters. Concomitant medications that are sensitive substrates or substrates with 
narrow therapeutic index for these transporters (listed in the Appendix 5) should be used 
with caution during sitravatinib treatment.
Cytochrome p450 Substrates with Sitravatinib: In vitro experiments in microsomes and 
recombinant human P450 enzymes suggest that sitravatinib is metabolized by several 
cytochromes, including CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2D6, 
CYP2E1, and CYP3A4, with a low risk of any one CYP demonstrating a disproportionate 
contribution to its metabolism. Caution should therefore be used when administering 
sitravatinib to subjects taking medications that are strong inhibitors or inducers of the 
cytochrome P450 system (Appendix 5).
Herbal Medications/Preparations: Herbal medications and preparations should be avoided 
throughout the study. Herbal medications include but are not limited to the following: St. 
John’s wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), 
yohimbe (yohimbine), saw palmetto, and ginseng.
Immunosuppressive Medications: Use of immunosuppressive mediations should be limited 
to the extent possible to allow testing of the immune-stimulatory mechanisms proposed in 
this clinical trial. Immunosuppressive medications should be used as needed to manage 
irAEs and the extent required to manage comorbidities and symptoms of disease.
Anticancer treatments: Use of approved or investigational anticancer treatment is not 
permitted during the study treatment period, including chemotherapy, 
bevacizumab/ramucirumab, biological response modifiers, hormone therapy or 
immunotherapy. No other investigational drug may be used during treatment on this 
protocol. Concurrent participation in another therapeutic clinical trials is not allowed.  Certain 
ongoing hormonal therapies taken to prevent recurrence of a malignancy not under study 
(e.g., tamoxifen/aromatase inhibitor for breast cancer) may be permitted after discussion 
with and agreement of the Sponsor Investigator.
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
54
5.4.2
Other Concomitant Treatments 
5.4.2.1
Surgery
The use of surgery to manage cancer lesions during study treatment is discouraged. The 
impact of sitravatinib on wound healing has not yet been characterized. In the event that 
major surgery is needed during study treatment, the patient should, if possible, interrupt 
dosing with sitravatinib 2 weeks in advance of the surgery and resume dosing 2 weeks after 
the surgery.
5.4.2.2
Radiation
Any foreseeable need for palliative radiotherapy should be addressed before study entry if 
possible and clinically appropriate (e.g., bone lesions at risk for spontaneous fractures or 
painful lesions). However, these treatments may be used in cases where it is medically 
necessary or in select cases of oligoprogression at the Sponsor Investigators discretion (see 
Section 6.8). If radiotherapy is required, sitravatinib should be held the day prior to radiation 
and resume the day after.    
5.4.2.3
Transfusions
Patients may receive transfusions as necessary.
5.4.2.4
 Other Anticancer or Experimental Therapy
Use of approved or investigational anticancer treatment will not be permitted during the 
study treatment period as discussed in Section 5.4.1.  No other investigational drug may be 
used during treatment on this protocol. Concurrent participation in another therapeutic 
clinical trial is not allowed.
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
55
6 Study Procedures
6.1
Study Calendars
6.1.1
Study Calendar for Group A
Screening
Visit1
On Study Visits3
Follow-
Up2
C1D13
C1D8
C2D1
C3D1 and
subsequent
End of Treatment4
Informed Consent5
x
Biopsy
X6
X7
If clinically
indictated8
Complete medical history,
disease history
x
Tissue analysis (PDL-1
staining, mutation testing)
x
Vital signs, weight
x
x
x
x
x
x
Height
x
Toxicity Assessment/
AE Monitoring
x
x
x
x
x
x
X9
ECOG performance status
x
x
x
x
x
x
Physical Exam10
x
x
x
x
x
x
ECHO11
x
Required cycle 3
only, then as clinically
indicated12
x
Urinalysis
x
x
x
x
Pregnancy Test13
x
As clinically indicated
CBC, CMP
x
x
x
x
x
x
TSH with reflex free T4
x
Cycle 3 and then
every other cycle
x
Triplicate 12- lead EKGs
x
x
x
As clinically indicated
MRI Brain (or CT head
with contrast if MRI is
contraindicated)11
x
As per protocol14
CT C/A/P11
x
q6 weeks x 3 months, q9 weeks x 9 months, q12 weeks thereafter
X15
Survival Status
x
x
x
x
x
x
Pembrolizumab
Administration
x
x
x
Sitra Dispensing and
Reconciliation
x
x
x
Blood work for correlative
studies
x
x
Cycle 3 only, not
subsequent
x
1All screening procedures must be completed within 28 days of start of trial 
2 Survival status and subsequent therapies will be collected during long term follow-up every 3 months (±14 days) from the End 
of Treatment Visit until death or lost to follow-up. Long-term follow-up may be performed by telephone contact or email.
3 Study treatment is administered in 21 day cycles; all study visits have a window of +/- 3 days 
4 To occur 28-35 days after last dose of study treatment 
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
56
5 Must be completed prior to any initiation of any study specific assessments
6 Archival tissue from within 3 months of screening may be substituted for pre-treatment biopsy if available
7 To be performed within 7 days prior to C2D1
8 If biopsy is required for clinical purposes, research tissues samples may also be collected and stored at that time for future 
analysis 
9 Subjects with an AE of Grade > 1 will be followed for at least 28 days after the last dose of study drug or until the resolution of 
the AE to Grade 0-1 or progression to chronic condition, or until the beginning of a new anti-neoplastic therapy, whichever 
occurs first.  SAEs that occur within 28 days of the end of treatment or before initiation of a new anti-cancer treatment should 
also be followed and recorded
10 Full physical exam should be performed at screening, C1D1 and End of Treatment visit.  At other visits, symptom directed 
exam is permissible 
11 Window for echocardiogram and radiologic assessments is -7 days;screening imaging and ECHO should be completed no 
more than 28 days prior to starting trial drug; first on study imaging to occur 6 weeks (+/-7 days) after C1D1
12 Following mandatory ECHO with C3, further ECHOs only need to be performed if there are clinical concerns for cardiac 
disease (eg signs or symptoms concerning for heart failure, pericarditis, tamponade, pulmonary hypertension) 
13Pregnancy Test: If the patient is a woman of childbearing potential, negative serum or urine pregnancy test performed by the 
local laboratory at screening will be required. The informed consent process must include discussion of the risks associated 
with pregnancy and adequate contraception methods. Additional pregnancy testing may be necessary if required by local 
practices or regulations, or if potential pregnancy is suspected.
14MRI brain (or CT head with contrast if MRI is contraindicated) should be performed on schedule with other radiologic disease 
evaluations if there is known CNS disease.  If no known CNS metastases, MRI brain/CT head with contrast should be 
performed as clinically indicated  
15 If study treatment is discontinued prior to disease progression, disease assessments should continue as per study protocol 
until the time of disease progression or start of new therapy
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
57
6.1.2
Study Calendar for Group B
Screening
Visit1
On Study Visits3
Follow-
Up2
C1D1
C2D1
C2D8
C3D1 and
subsequent
End of
Treatment4
Informed Consent5
x
Biopsy
X6
X7
If clinically
indictated8
Complete medical
history, disease history
x
Tissue analysis (PDL-1
staining, mutation
testing)
x
Vital signs, weight
x
x
x
x
x
x
Height
x
Toxicity Assessment/
AE Monitoring
x
x
x
x
x
x
X9
ECOG performance
status
x
x
x
x
x
x
Physical Exam10
x
x
x
x
x
x
ECHO11
x
Required cycle 3
only, then as
clinically indicated12
x
Urinalysis
x
x
x
Pregnancy Test13
x
As clinically indicated
CBC, CMP
x
x
x
x
x
x
TSH with reflex T4
x
Cycle 3 then every
other cycle
x
Triplicate 12- lead
EKGs
x
x
Required cycle 3
only, then as
clinically indicated
MRI Brain (or CT head
with contrast if MRI is
contraindicated)11
x
As per protocol14
CT C/A/P11
x
q6 weeks x 3 months, q9 weeks x 9 months, q12 weeks thereafter
X15
Survival Status
x
x
x
x
x
x
Pembrolizumab
Administration
x
x
x
Sitra Dispensing and
Reconciliation
x
x
Blood work for
correlative studies
x
x
Cycle 3 only, not
subsequent
x
1All screening procedures must be completed within 28 days of start of trial 
2 Survival status and subsequent therapies will be collected during long term follow-up every 3 months (±14 days) from the End 
of Treatment Visit until death or lost to follow-up. Long-term follow-up may be performed by telephone contact or email.
3 Study treatment is administered in 21 day cycles ;all study visits have a window of +/- 3 days 
4 To occur 28-35 days after last dose of study treatment 
5 Must be completed prior to any initiation of any study specific assessments
6 Archival tissue from within 3 months of screening may be substituted for pre-treatment biopsy if available
7 To be performed within 7 days prior to C2D1
8 If biopsy is required for clinical purposes, research tissues samples may also be collected and stored at that time for future 
analysis 
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
58
9 Subjects with an AE of Grade > 1 will be followed for at least 28 days after the last dose of study drug or until the resolution of 
the AE to Grade 0-1 or progression to chronic condition, or until the beginning of a new anti-neoplastic therapy, whichever 
occurs first.  SAEs that occur within 28 days of the end of treatment or before initiation of a new anti-cancer treatment should 
also be followed and recorded
10 Full physical exam should be performed at screening, C1D1 and End of Treatment visit.  At other visits, symptom directed 
exam is permissible 
11 Window for echocardiogram and radiologic assessments is -7 days; screening imaging and ECHO should be completed no 
more than 28 days prior to starting trial drug; first on study imaging to occur 6 weeks (+/-7 days) after C1D1
12 Following mandatory ECHO with C3, further ECHOs only need to be performed if there are clinical concerns for cardiac 
disease (eg signs or symptoms concerning for heart failure, pericarditis, tamponade, pulmonary hypertension) 
13Pregnancy Test: If the patient is a woman of childbearing potential, negative serum or urine pregnancy test performed by the 
local laboratory at screening will be required. The informed consent process must include discussion of the risks associated 
with pregnancy and adequate contraception methods. Additional pregnancy testing may be necessary if required by local 
practices or regulations, or if potential pregnancy is suspected.
14 MRI brain (or CT head with contrast if MRI is contraindicated) should be performed on schedule with other radiologic disease 
evaluations if there is known CNS disease.  If no known CNS metastases, MRI brain/CT head with contrast should be 
performed as clinically indicated  
15 If study treatment is discontinued prior to disease progression, disease assessments should continue as per study protocol 
until the time of disease progression or start of new therapy
6.2
Informed Consent 
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial. Consent must be documented by the subject’s dated signature 
or by the subject’s legally acceptable representative’s dated signature on a consent form 
along with the dated signature of the person conducting the consent discussion.  A copy of 
the signed and dated consent form should be given to the subject before participation in the 
trial.
The initial informed consent form, any subsequent revised written informed consent form and 
any written information provided to the subject must receive the IRB approval/favorable 
opinion in advance of use.  The subject or his/her legally acceptable representative should 
be informed in a timely manner if new information becomes available that may be relevant to 
the subject’s willingness to continue participation in the trial.  The communication of this 
information will be provided and documented via a revised consent form or addendum to the 
original consent form that captures the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature.
The informed consent will adhere to IRB requirements, applicable laws and regulations and 
Sponsor requirements.
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
59
6.3
Screening 
• Voluntary, written, dated, and signed informed consent must be obtained before any study 
specific procedures are performed. Patients who completed the informed consent process 
but were not randomized into the study will be considered as screen failures. Limited 
information will be recorded in the CRF for these patients.
• All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial. 
• A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
is considered to be clinically significant by the Investigator.  Details regarding the disease 
for which the subject has enrolled in this study will be recorded separately and not listed as 
medical history.  
• The investigator or qualified designee will obtain prior and current details regarding 
disease status. 
• The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject in 
the 28 days prior to signing consent.  Treatment for the disease for which the subject has 
enrolled in this study will be recorded separately and not listed as a prior medication. 
• The investigator or qualified designee will record medication, if any, to be taken by the 
subject during the trial.  
• Screening evaluations and studies (as outlined in study schedule) are to be conducted 
within 28 days prior to start of systemic therapy. 
6.4
Enrollment 
Once patient has signed informed consent and screening, and investigator or qualified 
designee has confirmed that patient has met eligibility criteria, patient will be enrolled in the 
study.  Patient will be assigned to a cohort based on PD-L1 status, and then may undergo 
randomization as described in Section 4.6.  Study treatment should begin within 7 days of 
randomization.  
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
60
6.5
Research Blood and Tissue Collection 
6.5.1
Biopsy Collection for Correlative Studies 
Baseline tissue samples are required prior to initiation of study treatment.  Archival tissue 
may be used if available and collected within 3 months of signing consent (see lab manual 
for detailed tissue requirements).  If no archival tissue is available, pre-treatment biopsy will 
be required with tissue collected for research purposes.  This can be the same biopsy 
collected for PD-L1 testing if required.  All patients are required to undergo on-treatment 
biopsy within 7 days prior to C2D1.  Patients may be exempted from the pre-treatment or on-
treatment biopsy by the Sponsor Investigator if there is a contraindication to biopsy at that 
time.  Tissue may also be collected from patients at the time of progression if biopsy is 
indicated for clinical reasons.  This tissue will be stored for potential future analysis to 
explore mechanisms of resistance.  Any additional samples obtained from clinically indicated 
biopsies while the patient is treated on study will be stored for possible future analysis.
For full details on tissue collection and analysis, please refer to the Laboratory Manual. 
6.5.2
Research Blood Sample Collection for Correlative Studies  
Research blood samples will be collected as per the Study Calendars (Section 6.1).  For full 
details on research blood collection and analysis, please refer to the Laboratory Manual. 
6.6
On Study Visits 
On study visits will be conducted as per the Study Calendars (Section 6.1) every 21 days 
(+/- 3 days) on the day of pembrolizumab infusion and issuance of the sitravatinib cycle.  
Mid-cycle safety visit will take place on Cycle 1 Day 8 (+/- 3 days) for patients in Group A 
and on C2D8 (+/-3 days) for patients in Group B, with procedures as indicated for standard 
study visit as outlined below. 
6.6.1
Laboratory Testing  
Details regarding specific laboratory procedures/assessments to be performed in this trial 
are provided in Section 7.2.3 and in the Study Calendars (Section 6.1).
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
61
6.6.2
Toxicity Assessment/Adverse Event Monitoring
The investigator or qualified designee will assess each subject to evaluate for potential new 
or worsening AEs at each study visit as per Study Calendars (Section 6.1), and more 
frequently if clinically indicated.  Adverse events will be graded and recorded throughout the 
study and during the follow-up period according to NCI CTCAE Version 5.0.  Toxicities will 
be characterized in terms of seriousness, causality, toxicity grading, and action taken with 
regard to trial treatment.  Please refer to Section 8 for detailed information regarding the 
assessment, recording and reporting of AEs.  
6.6.3
Vital Signs
The investigator or qualified designee will take vital signs at screening, prior to administration 
of pembrolizumab and at treatment discontinuation, as specified in the Study Calendars 
(Section 6.1).  Vital signs should include temperature, pulse, respiratory rate, weight and 
blood pressure.  Height will be measured at screening only.
6.6.4
Physical Exam 
The investigator or qualified designee will perform a complete physical exam during the 
screening period.  Clinically significant abnormal findings should be recorded at that time.  A 
full physical exam should be performed during screening, on C1D1 and at the End of 
Treatment visit.  At all other visits, a symptom directed physical exam is permissible 
according to the Treating Investigator’s discretion. 
6.6.5
ECOG performance status
The investigator or qualified designee will assess ECOG performance status at screening, 
prior to the administration of each dose of pembrolizumab and at discontinuation of trial 
treatment, as specified in Study Calendars (Section 6.1)
6.6.6
Tumor Imaging/Disease Assessment 
Tumor imaging and assessment of disease will be performed every 6 weeks (from C1D1) for 
the first 3 months of treatment, every 9 weeks for 9 months and every 12 weeks thereafter 
as per Study Calendars  (Section 6.1).  Please see Section 7.1 for further details on imaging 
assessments.  
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
62
6.7
End of Treatment Visit 
End of Treatment Visit should occur 28-35 days after last dose of study treatment.  
Evaluations at that time should be performed as per the Study Calendars (Section 6.1).  
Assessments completed in the previous 4 weeks do not need to be repeated with the 
exception of assessment of AEs and hematology and chemistry lab testing.  Subjects with 
an AE of Grade > 1 will be followed for at least 28 days after the last dose of study drug, 
resolution of the AE or progression to chronic condition, or until the beginning of a new anti-
neoplastic therapy, whichever occurs first.  SAEs that occur within 90 days of the end of 
treatment or before initiation of a new anti-cancer treatment should also be followed and 
recorded.  See Section 8 for further details of AE monitoring and reporting.  
6.8
Treatment Beyond Progression 
If radiologic assessment shows progressive disease (PD), tumor assessment should be 
repeated >4 weeks later in order to confirm PD with the option of continuing treatment while 
awaiting radiologic confirmation of progression. If repeat imaging shows a reduction in tumor 
burden compared to the initial scan demonstrating PD, treatment may be continued as per 
treatment calendars.  If repeat imaging confirms progressive disease, subject will be 
discontinued from study therapy unless the Treating Investigator believes that the patient is 
deriving clinical benefit.  Patients may continue treatment with study drugs beyond PD if they 
are determined by the Treating Investigator to be deriving clinical benefit from treatment and 
meet the following criteria: no signs or symptoms of clinically significant disease progression; 
continued adequate performance status; absence of rapid disease progression with threat to 
vital organs or critical anatomical sites; no significant, unacceptable or irreversible toxicities 
related to study treatment.  The decision to continue treatment beyond initial progression 
should be discussed with the study Sponsor Investigator.  Separate written consent must be 
obtained for treatment beyond radiologic disease progression.
Additionally, in cases where the majority of the disease is stable or responding, progressing 
lesions may be treated with local therapy (i.e. resection or radiotherapy) at the discretion of 
the Sponsor Investigator and the patient may be continued on trial following local therapy.
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
63
6.9
Study Follow up
6.9.1
Initial Follow Up
Patients discontinuing treatment for reasons other than objective disease progression (e.g., 
due to an adverse event or delivery of maximal number of cycles per standard-of-care) will 
be moved into the follow-up phase, and should be monitored by radiographic evaluation at 
the intervals established for disease assessment in the Study Calendars (Section 6.1) until 
objective disease progression or start of subsequent anti-cancer therapy, whichever is 
sooner.  Survival status and start of subsequent therapy will be collected and recorded.  
Survival status and start of subsequent therapies will be recorded for all patients.   
6.9.2
Long Term Follow Up
Survival status and subsequent therapies will be collected during long term follow-up every 3 
months (+/-14 days) until death or loss to follow-up. Follow-up may be performed by 
telephone contact or email. Treatments received following participation in the study will be 
collected in the CRF.
6.10 Removal of Subjects/Patient Discontinuation/Withdrawal
Patients may discontinue from study treatment or from study follow-up at any time at their 
own request, or they may be discontinued at any time at the discretion of the Treating 
Investigator or Sponsor Investigator for safety, behavioral reasons, or the inability of the 
patient to comply with the protocol required schedule of study visits or procedures at a given 
study site.  Criteria that may be used to discontinue patients from receipt of study medication 
will include, but will not be limited to:

Objective disease progression according to RECIST 1.1 as determined by the 
Investigator (patients who may derive clinical benefit may continue on treatment at the 
discretion of the Sponsor Investigator in accordance with the above section 6.8);

Global deterioration of health status requiring discontinuation;

Adverse event;

Significant protocol violation;

Lost to follow-up;

Refusal for further treatment;

Study termination by Sponsor Investigator;

Pregnancy;
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
64

Death.
Reasons for discontinuation from study follow-up may include:

Study terminated by Sponsor Investigator;

Lost to follow-up;

Refusal for further follow-up for survival;

Death
If a patient does not return for a scheduled visit, every effort should be made to contact the 
patient. At least 2 attempts should be made to contact the patient, and each attempt should 
be recorded in the source documents. In any circumstance, every effort should be made to 
document patient outcome if possible. The Investigator should inquire about the reason for 
withdrawal, request that the patient returns for a final visit, and if applicable, follow-up with 
the patient regarding any unresolved AEs.
If the patient withdraws from the study treatment and also withdraws consent for disclosure 
of future information, no further evaluations should be performed, and no additional data 
should be collected. The Sponsor Investigator may retain and continue to use any data 
collected before such refusal for further follow-up.
7 Study Assessments  
7.1
Efficacy Assessments
7.1.1
Radiographic Disease Assessment
All patients enrolled in the study are to undergo disease evaluations as outlined in the Study 
Calendars (Section 6.1).   If symptoms develop or clinical deterioration occurs, patients may 
be imaged prior to the pre-specified time points for imaging. Patients discontinuing 
treatment prior to objective disease progression will be followed by radiographic evaluation 
until disease progression is documented or until the start of subsequent anti-cancer therapy, 
whichever is sooner.  
Screening/baseline tumor assessments should include CT (with contrast, unless 
contraindicated) of the chest and abdomen (plus pelvis if indicated) and MRI of the brain 
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
65
with and without gadolinium (preferred) or head CT with contrast if MRI is contraindicated.  
The allowable windows for screening/baseline assessments is 28 days prior to 
randomization.
Disease assessments performed on-study will include CT of the chest/abdomen (plus pelvis 
if indicated) and assessment of all known and suspected sites of disease.  MRI brain should 
be performed on schedule with other radiologic disease evaluations if there is known CNS 
disease.  If no known CNS metastases, MRI brain should be performed as clinically 
indicated.  Assessments will be performed as per study calendars: every 6 weeks (starting 
from C1D1) for 3 months, every 9 weeks for 9 months and every 12 weeks thereafter.  The 
allowable windows for on-study assessments is +/- 7 days.  Assessments will be performed 
until objective disease progression is documented by the Investigator, or subsequent anti-
cancer therapy is begun.  
The Investigator’s assessment of disease response and progression per RECIST 1.1 (for 
extracranial disease) and RANO-BM criteria (for intracranial disease) will be the basis for 
patient management and statistical analyses of radiology-based study endpoints.  RECIST 
v1.1 and RANO-BM criteria are summarized in Appendices 3 and 4.   
7.1.2
Survival Assessments
Overall survival and Progression Free Survival are secondary efficacy endpoints for this 
study. Survival status and information concerning subsequent therapies will be collected 
during initial and long-term follow-up as discussed in Section 6.9.  For more details on OS 
and PFS assessment and analysis see Section 9.2.3.   In the event a patient discontinues 
treatment due to loss to follow-up or withdraws consent for use of data from medical records, 
surveillance of public sources of death information (e.g., published obituaries) should be 
undertaken and reported date of death recorded in the CRF.
7.1.3
CNS Disease Assessment 
Intracranial Objective Response Rate (iORR), Intracranial Duration of Response (iDOR) and 
Intracranial Progression Free Survival (iPFS) are all exploratory endpoints of this study.  MRI 
or CT head with contrast (as above) will be assessed at baseline for evidence of CNS 
disease and ongoing CNS imaging evaluation will be performed thereafter at intervals as per 
the Study Calendars (Section 6.1).  CNS tumor response assessment will be performed 
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
66
according to RANO-brain-metastasis criteria, summarized in Appendix 4.   Clinical status 
and steroid requirement will be assessed and documented at each study visit as per Study 
Calendars (Section 6.1).  
7.2
Safety Assessments 
7.2.1
Medical History
Medical history, including clinically significant past and present medical conditions, will be 
recorded at screening visit.  Lung cancer history will be recorded separately at that time. 
Signs and symptoms of the patient’s cancer diagnosis and/or comorbidities present prior to 
the first dose of study treatment should be noted and recorded separately.  Interval history of 
symptoms should be collected at each visit.  Any worsening or newly identified signs or 
symptoms after C1D1 will be recorded in the AE log.    
7.2.2
Physical Exam and Vital Signs
Exam and vital signs should be performed as per Section 6.6.  Clinically significant findings 
noted during screening and prior to first dose of study treatment will be documented 
separately, while those noted after C1D1 will be collected in the AE log.
7.2.3
Laboratory Safety Assessments
Safety labs will be collected for each cycle prior to pembrolizumab infusion and sitravatinib 
release.  Labs to be collected are summarized in Table 7.
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
67
Table 7: Laboratory Safety Parameters
Hematology Panel
Blood Chemistry Panel
Hemoglobin/Hematocrit
Aspartate aminotransferase
Platelet count
Alanine aminotransferase
White blood cell count
Alkaline phosphatase
Neutrophil count
Total bilirubin (if Total bilirubin is ≥2×ULN and no evidence 
of Gilbert’s syndrome, then fractionate into direct and 
indirect bilirubin)
Lymphocyte count
Urinalysis
Sodium
Blood
Potassium
Protein
Chloride
Bicarbonate or carbon dioxide (CO2)
Thyroid Function Test
Blood urea nitrogen (BUN) or urea
Thyroid-stimulating hormone with reflex free T4
Creatinine
Albumin
Total Calcium
  
7.2.4
Electrocardiograms
Triplicate 12 lead EKGs to be performed as outlined in the Study Calendars (Section 6.1) for 
baseline/screening, and on C1D8 and C2D1 for the main study group (Group A) and C2D8 
and C3D1 for the pembrolizumab run-in group (Group B).  Thereafter EKGs will be 
performed as clinically indicated. 
7.2.5
Echocardiogram 
Echocardiogram will be performed at baseline/screening, within 7 days prior to C3D1, and at 
end of treatment.  ECHO can be performed thereafter as clinically indicated at the Treating 
Investigator’s discretion if there are signs or symptoms of cardiotoxicity.
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
68
8 Adverse Event Reporting 
8.1
Evaluating Adverse Events
8.1.1
Definitions
An Adverse Event (AE) is any reaction, side effect or other undesirable medical event that 
occurs during participation in a clinical trial, regardless of treatment group or suspected 
causal relationship to study treatment. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding, for example), symptom, or 
disease temporally associated with the use of a medicinal product or protocol-specified 
procedure, whether or not considered related to the medicinal product or protocol-specified 
procedure.  Any worsening (i.e., any clinically significant adverse change in frequency and/or 
intensity) of a preexisting condition that is temporally associated with the use of study drugs, 
is also an adverse event.  Adverse events may also occur in screened subjects during any 
pre-allocation baseline period as a result of a protocol-specified intervention, including 
washout or discontinuation of usual therapy, diet, placebo treatment or a procedure.
An abnormal laboratory test result should be recorded as an AE in the CRF only if it is 
associated with one or more of the following: clinical symptoms; additional testing, treatment 
or intervention; change in study dosing; discontinuation from study treatment; or if it is 
considered by the Sponsor or Treating Investigator to be an AE. 
Progression of the cancer under study is not considered an adverse event unless it is 
considered to be drug related by the Treating Investigator.  
Assessment of AEs will include type, incidence, severity (graded by the National Cancer 
Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE, Version 5.0]), 
timing, seriousness, and relatedness to study treatment. 
8.1.2
Recording AEs
All observed or volunteered AEs will be recorded in source documents and reported in the 
CRF along with severity, relatedness and expectedness as defined below (Sections 8.1.3, 
8.1.4, 8.1.5). The best available medical terminology should be used to describe AEs in 
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
69
source documents and CRFs. Terms describing the diagnosis are preferred over individual 
signs and symptoms of the diagnosis. If determination of the diagnosis is delayed, record 
signs and symptoms and add the diagnosis as an additional AE when available; follow all 
recorded AEs to resolution. The actual date of onset should be recorded in all cases. 
Ongoing AEs that change in attribution or severity should have the date of change entered 
as the “end date” and a new AE record should be opened with the changed details.
8.1.3
Severity Assessment
AEs occurring during this study will be graded in accordance with the NCI CTCAE Version 
5.0. Documentation of AE grading in the source documents and CRF should be consistent 
with provided definitions.
8.1.4
Causality 
For each AE, the Treating Investigator will determine and document whether there exists a 
reasonable possibility that the study treatment caused or contributed to the AE. Potential 
attribution of an adverse event associated with trial therapy will be provided for all study 
drugs, sitravatinib and/or pembrolizumab.  The Investigator’s assessment should be 
recorded in the source document. The CRF will provide the options for attribution to each 
study treatment as “related” or “not related.” If the Investigator's causality assessment is 
"unknown but not related to investigational product," this should be recorded in the CRF as 
“not related.” If the Investigator does not know whether or not the study treatment is causally 
related to the event, reporting for study purposes will be as “related” to study treatment.
8.1.5
Expectedness 
The Treating Investigator will be responsible for determining whether an AE is expected or 
unexpected.  An AE will be considered unexpected if the nature, severity, or frequency of the 
event is not consistent with the risk information listed in the reference safety information.  
Reference safety information is the US Package Insert for pembrolizumab and the most 
current version of the Investigator’s Brochure for Sitravatinib. 
8.2
Serious Adverse Events 
A Serious Adverse Event (SAE) is any event that meets any of the following criteria:
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
70

Results in death

Is life-threatening (immediate risk of death)

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/permanent damage (substantial disruption of 
the ability to conduct normal life functions)

Results in congenital anomaly/birth defect

Other: Important medical events that may not result in death, be life-threatening, or 
require hospitalization, may be considered an SAE when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such 
events are: Intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in inpatient 
hospitalization; development of drug dependency or drug abuse
8.3
Reporting of AEs and SAEs
8.3.1
Reporting Period
Please refer to the Manual of Procedures (MOPs) for SAE reporting procedures.
The reporting period for non-serious AEs begins from the day of the first dose of study 
treatment and continues until at least 28 days after last administration of study treatment, or 
until resolution of AEs to Grade 0-1. If a patient begins a subsequent anticancer therapy the 
AE reporting period ends at the time the new treatment is started.  Signs and symptoms of 
the patient’s cancer diagnosis and/or comorbidities present prior to the first dose of study 
treatment should be noted and recorded separately (not as an AE).
The active reporting period for SAEs begins from the time that the patient provides informed 
consent (i.e., prior to undergoing any study-specific procedure or assessment) and continues 
until at least 28 days after the last administration of study treatment.  All SAEs ongoing at the 
end of treatment should be followed until they have resolved or stabilized to a chronic 
condition, whichever is later. If a patient begins a subsequent anticancer therapy, the 
reporting period for new SAEs ends at the time the new treatment is started.  Serious 
adverse events occurring after the active reporting period has ended should be reported to 
Mirati if the Treating Investigator becomes aware of them and if the Sponsor Investigator 
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
71
assesses at least a reasonable possibility of being related to study treatment. These SAEs 
should be followed until resolved or stabilized to a chronic condition.
8.3.2
Reporting Requirements
Please refer to the Manual of Procedures (MOPs) for SAE reporting procedures.
All AEs (including SAEs) must be documented in source documents and reported in the 
CRF.  Please note that the CRF and SAE report forms may collect information in somewhat 
different formats. Where the requested data overlap in different formats, the information 
should be consistent between the two forms.
All SAEs will be reported to the Sponsor Investigator within 24 hours of becoming aware of 
the event.  Local investigators will complete the provided SAE form and send to the 
assigned Project Manager and Sponsor Investigator via email.  The Sponsor Investigator will 
review the event and determine final attribution to study treatment.  The Sponsor Investigator 
is responsible for expedited reporting to the FDA, when required, including meeting all 
timelines.  Each site is responsible for following local procedures for submitting SAEs to the 
IRB of record.  
8.3.3
SAE reporting to Mirati Therapeutics Inc.
For patients who sign the study informed consent form (ICF), SAE collection starts at time of 
main study informed consent whether the patient is a screen failure or not. The Sponsor, by 
way of the assigned Project Manager, is also required to notify Mirati Therapeutics, using the 
contact details supplied in Section 8.3.4. within 24 hours/1 business day of learning of its 
occurrence. Follow-up information is sent to the same contact(s) to whom the original SAE 
Report Form was sent, using a new SAE Report Form stating that this is a follow-up to the 
previously reported SAE and giving the date of the original report. Each re-occurrence, 
complication, or progression of the original event should be reported as a follow-up to that 
event regardless of when it occurs. The follow-up information should describe whether the 
event has resolved or continues, if and how it was treated, whether the blind was broken or 
not, and whether the patient continued or withdrew from study participation.
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
72
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the study treatment, the Sponsor, by way of 
the assigned Project Manager, will send a notification to Mirati Therapeutics, as it sees 
appropriate, who may need to issue an Investigator Notification (IN), to inform all 
Investigators involved in any study with the same drug that this SAE has been reported. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported 
to the competent authorities (except FDA as Sponsor is responsible for reporting) and 
relevant ethics committees.
Mirati Therapeutics Contact:
Mirati Therapeutics
Email: wilsafety@ppdi.com
Fax: +1-888-488-9697
Phone (for fax issues): +1-800-201-8725
Investigative site must also indicate, either in the SAE report or the cover page, the causality 
of events in relation to all study medications and if the SAE is related to disease progression, 
as determined by the principal investigator.
All SAEs have to be reported to Mirati Therapeutics, whether or not considered causally 
related to the investigational product. All SAEs will be documented. The investigator is 
responsible for informing the IRB and/or the Regulatory Authority of the SAE as per local 
requirements.
8.3.4
Reporting of SUSARs to Yale Cancer Center
Mirati Therapeutics will forward SUSARs occurring with Sitravatinib to the Yale Cancer 
Center in the following timelines:

Reports of fatal or life threatening Serious Adverse Drug Reactions will be sent within 
five (5) calendar days of Receipt Date.

Reports of Serious Adverse Drug Reactions (other than fatal or life threatening) will 
be sent within twelve (12) calendar days of Receipt Date.
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
73
8.3.5
Reporting to the FDA
This study will be conducted under an IND (Investigational New Drug application) that will be 
held by Dr. Goldberg. The Sponsor Investigator, by way of the assigned Project Manager 
and the IND/IDE Management Office, will report in an expedited manner all SAEs meeting 
the criteria of “serious”, “unexpected” and “related to study treatment”.  Written safety reports 
will use a MedWatch Form 3500A.  A “fillable pdf” version with instructions is available at: 
http://www.fda.gov/medwatch/safety/FDA-3500A_Fillable_08-16-2006.pdf 
There are two types of expedited safety reports to the FDA:
1.
7-Calendar-Day FDA Telephone or Fax Report:  The sponsor-investigator will directly 
notify the FDA, within 7 calendar days after his initial receipt of the information, of any 
adverse event that is ALL of the following:
Death or immediately life-threatening
Unexpected
Associated with the use of study drug
Notification to the FDA will be made directly to the new drug review division in the Center for 
Drug Evaluation and Research or in the product review division for the Center for Biologics 
Evaluation and Research, whichever was responsible for the review of the IND. 
[21CFR312.32(c)] A written report of the event is to follow within 8 calendar days from the 
submission of the initial report.
2.
15-Calendar-Day FDA Written Report:  The sponsor-investigator will directly notify the 
FDA within 15 calendar days of any adverse event that is ALL of the following:
Serious (due to non-fatal and non-life threatening criteria
Unexpected
Associated with the use of study drug 
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
74
Note:  Serious Adverse Events which do not meet the criteria for expedited reporting will be 
reported to the FDA in the IND Annual Report.
8.4
Reporting of Pregnancy and Lactation
Exposure during pregnancy (i.e., exposure in-utero [EIU]) may occur in a female study 
participant,  or the female partner of a male study participant if:

A female becomes or is found to be pregnant during treatment or within 6 months after 
discontinuing treatment or having been directly exposed to the investigational product;

A male is exposed to the investigational product within 6 months of conception or during 
the pregnancy of his partner.
If EIU occurs, the subject will immediately be removed from the study.  The site will contact 
the subject at least monthly and document the subject’s status until the pregnancy has been 
completed or terminated.  The outcome of the pregnancy will be reported to the Sponsor 
Investigator and Mirati without delay and within 24 hours to the Sponsor Investigator if the 
outcome is a serious adverse event (e.g., death, abortion, congenital anomaly, or other 
disabling or life-threatening complication to the mother or newborn).  
The study investigator will make every effort to obtain permission to follow the outcome of 
the pregnancy and report the condition of the fetus or newborn to the Sponsor Investigator 
and Mirati.  If the outcome of the pregnancy meets the criteria for an SAE (i.e., ectopic 
pregnancy, spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital 
anomaly), an SAE report should be submitted to Sponsor Investigator and Mirati.
8.5
Safety Reporting and Monitoring (DSMP)
8.5.1
Data and Safety Monitoring Committee
The Yale Cancer Center (YCC) Data and Safety Monitoring Committee (DSMC) will provide 
the primary oversight of data and safety monitoring. The Yale DSMC will review and monitor 
compliance, toxicity and deviations from this study. The committee is composed of clinical 
specialists with experience in oncology and who have no direct relationship with the study. 
Information that raises any questions about participant safety will be addressed with the 
Sponsor Investigator.
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
75
The DSMC will review this protocol bi-annually, at a minimum. Information to be provided to 
the committee includes: a study narrative by the PI, a summary DSMC report (which 
includes participant accrual, response, trial status history, SAEs, adverse events, deviations 
and survival); audit results, and monitoring reports, as applicable. Other information (e.g., 
scans, laboratory values, etc.) will be provided upon request. Upon completing the review, 
the DSMC will approve whether the study should continue as planned, require modification/ 
amendment, or be placed on administrative hold with accrual temporarily suspended.
Trials being monitored by the YCC DSMC will remain under the YCC DSMC purview until a 
DSMC review has occurred that includes the research activity of the last subject who 
completed the intervention, or until the DSMC feels there are no patient safety concerns that 
require further monitoring. The DSMC will determine the length of continued DSMC review.
The DSMC has authority to intervene in the conduct of these studies as necessary to ensure 
the safety of the participants and to maintain the highest quality in the clinical research 
performed at YCC. The DSMC has the authority to require additional monitoring and/ or 
more frequent reporting on study progress and serious adverse events.
8.5.2
Study Site Monitoring
Study site monitoring is necessary to assure adequate protection of the rights of human 
subjects and the safety of all subjects involved in clinical investigations and the quality and 
integrity of the resulting data submitted. 
The Sponsor-Investigator-designated monitor(s) conducts monitoring visits to ensure that 
clinical investigators and study team members are compliant with the protocol, ICH good 
clinical practice, federal, state and local regulations and institutional policies and procedures, 
that data are of high quality and integrity, and that the facilities and staffing are adequate for 
continued study participation. This will be performed by conducting monitoring visits 
including a site initiation visit, regularly scheduled interim monitoring visits and/or remote 
interim monitoring visits while subjects are on study, and a site close-out visit at Choose an 
item.. Following each site visit, a visit report will be generated containing information on site 
activities and a summary of pertinent points and action items. The report will be provided 
with a follow-up letter. Site-specific data status reports will be distributed to the site regularly 
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
76
to outline planned, missing or incomplete case report forms and any outstanding data 
queries.
During monitoring visits, the following may be reviewed:
•
Protection of the rights, safety and welfare of subjects through review of informed 
consentinformed consent process and documentation, adverse events (AEs) and 
serious adverse events (SAEs) and safety procedures
•
Subject eligibility
•
Source verification
•
Protocol compliance
•
Deviations and Non-compliance
•
Investigator Site File
•
GCP compliance
•
If applicable, include: Investigational Drug/ Device Storage and Accountability 
(including quantity and disposal procedures)
•
If applicable, include: Laboratory Facilities
•
If applicable, include: Equipment maintenance and calibration
•
Additional study supplies inventory and assessment
•
Study progress and/or follow-up on issues with Site Principal Investigator (PI) and 
relevant members of the study team
The Sponsor-Investigator and YCCI will define the required study monitoring activities in a 
Study Monitoring Plan.
9 STATISTICS 
9.1
Statistical Methods
9.1.1
Statistical Design
This is a Phase 2 trial of the novel therapeutic sitravatinib in combination with 
pembrolizumab for the first-line treatment of patients with PD-L1 positive non-squamous 
metastatic NSCLC.  The primary endpoint of this study is ORR as defined by RECIST 1.1, 
for patients treated with this combination.  This study will enroll patients into two cohorts 
defined by PD-L1 status: PD-L1 TPS>50% and TPS 1-49%.   We will implement a Simon’s 
Two-Stage Design to evaluate the efficacy of sitravatinib in combination with pembrolizumab 
for each cohort separately.  
Each cohort will contain 35 patients, for a total of 70 patients (see discussion of sample size 
calculation below, section 9.1.3).  Within each cohort, 30 patients will comprise the “main 
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
77
study population” or Group A (see Study Schema 4.1), who will receive sitravatinib and 
pembrolizumab in combination starting on C1D1 of the study.  It is hypothesized that this 
combination will result in at least 25% improvement in ORR when compared with historical 
control ORR of 39% for TPS>50% and 17% in TPS 1-49%(6).  Secondary endpoints include 
OS, PFS, Duration of Response (DOR) and Clinical Benefit Rate (CBR) in this population.    
Initially patients will be randomized until five patients from each cohort have been assigned 
to Group B (to receive a 3-week run-in with pembrolizumab alone followed by the addition of 
sitravatinib on C2D1).  The patients from this “pembrolizumab run-in” group, or Group B (see 
Study Schema 4.1), will not be included in the main statistical analysis of the primary 
endpoint.  ORR, OS, PFS, DOR and CBR in Group B will be analyzed separately and will be 
secondary endpoints for this study.  
9.1.2
General Analysis Plan
In general, summary statistics will be presented as percentages in the case of categorical 
variables and as means with standard deviations in the case of continuous variables. When 
applicable, t-tests or Wilcoxon rank-sum tests will be used to make comparisons between 
responders and non-responders, depending on the distribution of data. Paired t-tests or 
Wilcoxon signed-rank tests will be used to compare continuously distributed markers 
measured at different time points. Chi-square tests or Fisher’s exact tests will be used to 
make comparisons between patient subgroups of interest for categorical variables. 
Summaries of safety data will be tabulated. Additional summaries or listings of adverse 
events for AEs of special interest may also be provided if appropriate.  All analyses will be 
done separately for Cohorts A and B.
9.1.3
Sample Size Considerations
In Group A, for the cohort with TPS>50%, we intend to enroll a maximum of 30 evaluable 
patients using Simon’s minimax design. The sample size calculation is based on the desire 
to discriminate a promising ORR of 64% from a disappointing ORR of 39%(6). At stage 1, 17 
subjects will be entered on the study. If ≤ 7 responses are seen, the study will be terminated. 
At stage 2, 13 additional subjects will be entered. At the end of stage 2, if 16 or more 
subjects experience a response, the combination will be considered worthy of further study. 
This design yields a type I error rate of 0.07 and power of 90% when the true response rate 
is 64%.
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
78
In Group A, for the cohort with TPS 1-49%, we intend to enroll a maximum of 30 evaluable 
patients using the admissible two-stage design. The sample size calculation is based on the 
desire to discriminate a promising ORR of 42% from a disappointing ORR rate of 17%.(6) At 
stage 1, 16 subjects will be entered on the study. If ≤ 3 responses are seen, the study will be 
terminated. At stage 2, 14 additional subjects will be entered. At the end of stage 2, if 9 or 
more subjects experience a response, the combination will be considered worthy of further 
study. This design yields a type I error rate of 0.05 and power of 91% when the true 
response rate is 42%.
9.2
Efficacy Endpoints Definition and Analyses 
9.2.1
Analysis Population
All of the patients who met the eligibility criteria (with the possible exception of those who 
received no study medication) will be included in the main analysis of the response rate and 
the other efficacy analyses.  Conclusions will be based on all eligible patients.  Sub analyses 
may then be performed on the basis of a subset of patients, excluding those for whom major 
protocol deviations have been identified (e.g., early death due to other reasons, early 
discontinuation of treatment, major protocol violations, etc.).  However, these sub analyses 
may not serve as the basis for drawing conclusions concerning treatment efficacy, and the 
reasons for excluding patients from the analysis should be clearly reported.  
Safety analysis will be performed on all patients who receive at least one dose of study 
treatment.  
9.2.2
Objective Response Rate (ORR)
Objective Response Rate (ORR) per RECIST in Group A (main study population) is the 
primary endpoint of this study and is defined as the percent of patients with confirmed 
Complete Response (CR) or Partial Response (PR).  ORR in Group B is an exploratory 
endpoint.  ORR, along with the 95% exact confidence interval, will be estimated using the 
Clopper–Pearson method.
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
79
9.2.3
Overall Survival and Progression Free Survival Analysis 
Overall Survival (OS) and Progression Free Survival (PFS) in the main study populations (ie 
groups 1A and 2A) are secondary endpoints for this study.  OS and PFS in groups 1B and 
2B are exploratory endpoints.
OS is defined as the time from date of treatment start to death due to any cause.  PFS is 
defined as the time from first dose to first progressive disease (PD) or death due to any 
cause in the absence of documented PD. Survival status will be collected during initial and 
long-term follow-up as outlined in the Study Calendars (Section 6.1).  If a patient 
discontinues treatment due to loss to follow-up or withdraws consent for use of data from 
medical records, surveillance of public sources of death information (e.g., published 
obituaries) should be undertaken and reported date of death recorded in the CRF.  Patients 
with no event will be censored at the last available tumor assessment for PFS and at the last 
timepoint known alive for OS.  
Kaplan-Meier estimates (product-limit estimates) will be presented for the analysis of PFS 
and OS together with a summary of associated statistics (median survival time, landmark 
survival rate estimates and estimates for every 6 months thereafter if applicable) including 
the corresponding two-sided 95% confidence intervals. The confidence intervals for the 
median will be calculated according to Brookmeyer and Crowley (1982) and confidence 
intervals for the survival function estimates at above defined time points will be derived using 
the log-log transformation according to Kalbfleisch and Prentice (1980). The estimate of the 
standard error will be computed using Greenwood's formula.
9.2.4
Duration of Response 
Duration of Response (DOR) for patients in Group A is a secondary endpoints for this study; 
DOR for Group B is an exploratory endpoint. DOR is defined as the time that measurement 
criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or 
progressive disease is objectively documented or to death due to any cause in the absence 
of documented PD.
The Kaplan-Meier method will be used for the subgroup of patients with a confirmed 
objective response in order to obtain the estimate of median DOR. Censoring for the DOR 
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
80
endpoint will be assigned on the date of the last tumor assessment if no assessment of 
tumor progression is recorded and the patient does not die and prior to the start of 
subsequent anti-cancer therapy. Descriptive statistics will be provided for the DOR in 
responding patients (i.e., median duration of response and 95% CIs) by cohort, including the 
associated Kaplan-Meier curves. 
9.2.5
Clinical Benefit Rate 
Clinical Benefit Rate (CBR) in Group A is a secondary endpoints for this study, while CBR in 
Group B is an exploratory endpoint.  CBR is defined as the percent of patients documented 
to have a confirmed Complete Response (CR), confirmed Partial Response (PR), or Stable 
Disease (SD) documented on at least 1 on-study assessment and including at least 5 weeks 
on study.  An approach similar to that described for analysis of ORR (Section 9.2.1) will be 
used to assess CBR.
9.2.6
Intracranial Objective Response Rate 
Intracranial Objective Response Rate (iORR) in patients with baseline CNS metastases is an 
exploratory endpoint of this study.  iORR will be determined by the proportion of patients with 
a brain metastasis response in clinically evaluable lesions using RANO-brain metastasis 
criteria.  RANO-brain metastases criteria is summarized briefly in Appendix 4. 
 
9.2.7
Intracranial Duration of Response 
Intracranial duration of response in patients with baseline CNS metastases is an exploratory 
endpoint of this study.  iDOR is defined as the time from first complete intracranial response 
or partial intracranial response (whichever is documented first) to date of intracranial disease 
progression (not considering extracranial disease progression).  An approach similar to that 
described above for DOR will be used to assess iDOR (Section 9.2.4). 
9.2.8
Intracranial Progression Free Survival 
Intracranial Progression Free Survival (iPFS) in all patients regardless of the presence of 
baseline CNS metastases is an exploratory endpoint of this study.  iPFS is defined as the 
time from first dose to the date of first intracranial progressive disease (as per RANO-brain 
metastasis criteria).  An approach similar to that described for the analysis of PFS (Section 
9.2.3) will be used.  
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
81
9.3
Safety Analysis
Evaluation of the safety and toxicity profile of the combination of sitravatinib and 
pembrolizumab in the first-line treatment of patients with non-squamous metastatic NSCLC 
is a secondary objective in this study.  Secondary endpoint is adverse events as per CTCAE 
v.5.  The Safety population is defined as all patients who received any dose of study 
treatment (i.e., sitravatinib and/or pembrolizumab) and will be used for all safety analyses.  
9.4
Correlative Analyses Plan 

Wilcoxon’s rank-sum test will be used to compare the % of Teffector, % of myeloid 
activation, % of CD 8+ T cells and % of FOXP3+ T cells between AXL hi versus lo (
50% 
≥
and <50%, respectively) and MERTK high versus low groups. 

Comparisons between pre- and post-treatment will be evaluated by Wilcoxon signed 
rank test.

To compare differences (% change) between sitravatinib + pembrolizumab versus 
pembrolizumab alone, Wilcoxon’s rank-sum test will be used. 

To compare differences in sitravatinib + pembrolizumab treatment across cohorts with 
distinct PD-L1 status Wilcoxon’s rank-sum test will be used. 

Baseline or changes in immune cell populations will be compared between responders 
and non-responders using Wilcoxon rank sum test.   

Single-cell RNA sequencing and bulk RNA sequencing are exploratory pilot 
assessments.
9.5
Handling of Missing Data
For all variables, only the observed data from patients will be used in the statistical analyses; 
there is no plan to estimate missing data. Patients without a valid clinical response 
assessment will be assigned a best overall response of not evaluable (NE). Data from 
patients who are lost to follow-up or have missing observations before reaching an endpoint 
in any of the time-to-event analyses will be treated as censored at the last available tumor 
assessment (or last time known alive).  
10 Trial Administration
10.1 Ethical Considerations: Informed Consent/Assent and HIPAA Authorization
This study will be conducted in accordance with International Ethical Guidelines for 
Biomedical Research Involving Human Patients (Council for International Organizations of 
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
82
Medical Sciences 2002), Guidelines for Good Clinical Practice (GCP) (International Council 
for Harmonisation [ICH] 1996), ICH E6 (R2) and concepts that have their origin in the 
Declaration of Helsinki (World Medical Association 1996, 2008 & 2013).
Specifically, this study is based on adequately performed laboratory and animal 
experimentation as well as ongoing clinical data; the study will be conducted under a 
protocol reviewed and approved by an IRB; the study will be conducted by scientifically and 
medically qualified persons; the benefits of the study are in proportion to the risks; the rights 
and welfare of the patients will be respected; the physicians conducting the study do not find 
the hazards to outweigh the potential benefits; and each patient will give his or her written 
informed consent before any protocol-driven tests or evaluations are performed.
10.2 Institutional Review Board (IRB) Review
This protocol will be submitted to the IRB for review and approval.  Prior to the shipment of 
clinical supplies or initiation of the study, the clinical trial protocol along with the informed 
consent form (ICF), Investigator’s Brochure, and any other written information or instructions 
for the patient must be submitted to the IRB for written approval. The Investigator is 
responsible for notifying the IRB of any amendments to the protocol or ICF, SAEs occurring 
in patients treated at the study site in accordance with local IRB practice, and all expedited 
safety reports.
Any change to the protocol will require an approved IRB amendment before implementation.  
Other study events (e.g. data breaches, protocol deviations) will be submitted per local IRB's 
policies.
10.3 Subject Confidentiality
Subject confidentiality is held in strict trust by the research team.  Only authorized HIPAA 
and GCP trained study team members will be allowed to extract research data from medical 
records. 
All information generated in this study is considered confidential, is subject to applicable 
privacy rules and regulations, and must not be disclosed to any person or entity not directly 
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
83
involved with the study without the patient’s prior written consent or in accordance with 
applicable law or regulations. 
The identifying patient information collected for and during the clinical trial will be kept 
confidential. However, study information may be published in formal reports and medical 
papers and may include de-identified medical information of the patient. In either way, the 
patient name will not be used in publicly available documents.
10.4 Data Collection
The clinical trial data consisting of all required observations, AEs, and laboratory data are 
entered into a computerized database in a timely manner.  The accuracy and completeness 
of the database, timely submission of SAEs and compliance with the protocol, is reviewed 
during site monitoring visits described in Section 8.5.2.   Safety data will be reviewed in 
accordance with the DSMP (Section 8.5.1).  Regular meetings are held to discuss ongoing 
patient treatment and adverse events.  
10.5 Study Records
A CRF must be completed for each patient for whom informed consent for the study is 
obtained. The CRFs must be maintained by properly trained and delegated site 
representatives. The Sponsor Investigator has responsibility for ensuring the authenticity, 
accuracy, completeness and timeliness of all data collected in the CRF. 
Source documents include hospital or clinical patient charts, pertinent historical medical 
records, laboratory test reports, ECG tracings, pathology reports, radiographs, etc. All 
source documents must be legible. Data reported in CRFs and evidence of patient’s 
informed consent must be documented in source documents.  All documents collected as 
part of this clinical trial are considered study records, to include: regulatory documents, 
protocols, consent forms, and subject medical records.
10.6 Data or Specimen Storage/Security
Data will be collected in an electronic data capture system.  This is maintained on a secure 
server.  Access to the system is password protected.  All study data and specimens will be 
stored for future use and analysis.  
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
84
10.7 Retention of Records
Study documents should be retained for a minimum of 2 years after the last approval of a 
marketing application in an International Conference on Harmonisation (ICH) region and 
until there are no pending or contemplated marketing applications in an ICH region or until at 
least 2 years have elapsed since the formal discontinuation of clinical development of the 
study intervention. These documents should be retained for a longer period, however, if 
required by local regulations. 
10.8 Study Modification
A protocol change intended to eliminate an apparent immediate hazard to patients may be 
implemented immediately, provided the IRB is notified within 5 days. Any urgent safety 
measures taken by the Investigator to protect the study patients against any immediately life-
threatening hazard must be reported immediately to the Sponsor Investigator.
10.9  Study Discontinuation
If the study is prematurely terminated or suspended, the Sponsor Investigator will promptly 
inform study participants, the Institutional Review Board and will provide the reason(s) for 
the termination or suspension.  Study participants will be contacted, as applicable, and be 
informed of changes to study visit schedule.
Circumstances that may warrant termination or suspension include, but are not limited to:

Determination of unexpected, significant, or unacceptable risk to participants

Demonstration of efficacy that would warrant stopping   

Insufficient compliance to protocol requirements

Data that are not sufficiently complete and/or evaluable

Determination that the primary endpoint has been met

Determination of futility
10.10 Study Completion
Study completion is defined as the time at which all patients enrolled in the study have 
completed the last study visit and data from those visits have been reviewed by the 
Investigator or designee.
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
85
10.11 Conflict of Interest Policy
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who 
have a role in the design, conduct, analysis, publication, or any aspect of this trial will be 
disclosed and managed. Furthermore, persons who have a perceived conflict of interest will 
be required to have such conflicts managed in a way that is appropriate to their participation 
in the trial. The study leadership in conjunction with the appropriate conflict of interest review 
committee has established policies and procedures for all study group members to disclose 
all conflicts of interest and will establish a mechanism for the management of all reported 
dualities of interest.  All investigators will follow the applicable conflict of interest policies.
10.12 Funding Source
This study is being funded by Mirati Therapeutics. 
10.13 Publication Plan
Results will be reported by the Sponsor Investigator in abstract form at medical conferences 
and manuscripts will be published in medical journals.  
11Correlative Studies 
11.1 Introduction/Summary 
Correlative studies will be conducted on tumor tissue as well as serial blood samples.   Brief 
summary of planned analyses included below in Table 8.  
Tissue/Biopsy Analysis 
Multiplex Quantitative Immunofluorescence T-Cell
•
Subsets/activation: CD3, Ki67, granzyme B and cytokeratin
•
Macrophage Panel: CD68, CD11b, HLADR, CD163
•
MERTK Pathway: MERTK, AXL, CD68, cytokeratin
•
T cell panel: CD8, FOXP3, CD4 and cytokeratin
Single-cell RNA sequencing of CD45+ sorted cells
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
86
Table 
8: 
Planned Correlative Studies
 
11.2 Sample Collection 
11.2.1 Tissue Collection
Baseline tissue sample, either archival (within 3 months) or by fresh biopsy is required 
unless medically contraindicated.  3 week on-treatment biopsy is also required unless 
medically contraindicated.  If biopsy is performed for clinical reasons at the time of 
progression or at other times during the study, these samples will also be collected and 
stored for future research purposes.  For details on tissue collection and storage please see 
Laboratory Manual.    
11.2.2 Blood Collection 
Serial research bloods will be collected from 35 patients, including all patients in the 
pembrolizumab-run in population.  Samples will be collected prior to treatment on C1D1, 
C2D1, C3D1 and at End of Treatment/Progression.  Samples will be collected and initially 
processed as described in the Laboratory Manual before being transferred to the lab of Dr. 
Carla Rothlin and Dr. Sourav Ghosh (Yale University) for further analysis and storage.   Note 
that research blood is only required for patients treated at a site that has the ability to 
transport blood to Drs. Rothlin and Ghosh’s laboratory within 2 hours.  For full details on 
blood collection and storage please see Laboratory Manual.  
Blood Sample Analysis: 
Isolation of PBMCs (peripheral blood mononuclear cells)
•
Bulk and single-cell RNA sequencing
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
87
11.3 Tumor Tissue Analysis 
11.3.1 Tissue Samples 
For tissue analysis, the primary focus will be the comparison of baseline and on-treatment 
biopsies of patients receiving the pembrolizumab/sitravatinib combination versus patients 
receiving pembrolizumab alone (during the run-in period).  Baseline and 3-week on 
treatment biopsy samples will be processed initially for 15 patients in each cohort: all 
patients from Groups 1B and 2B (pembrolizumab run-in population) and 10 patients each 
from Group 1A and 2A (main study population), with storage of any additional tissue for 
future analysis.    All additional tumor samples that are collected will be stored for potential 
future analysis.  
11.3.2 Multiplex Quantitative Immunofluorescence 
Analysis of the tumor microenvironment will be done using multiplexed quantitative 
immunofluorescence (QIF) to spatially map the MERTK pathway (MERTK, Axl and Tyro3), 
major T-cell subsets (CD4, CD8 and FOXP3) and tumor-associated macrophages (CD11b, 
CD68, HLA-DR or CD163).  QIF will be performed on tumor tissue from baseline and 3 week 
on-treatment tissue samples from 30 patients as outlined above.   A minimum of 4 panels 
are planned as listed below:

Panel 1: Dapi-CK-CD3-GranzymeB-Ki67

Panel 2: Dapi-CD68-Cd11b-CD163-HLA-DR A

Panel 3: Dapi-CK-CD68-MERTK-AXL

Panel 4: Dapi-CK-CD8-CD4-FOXP3
Percentage of activated myeloid cells, effector T cells and AXL+ and MERTK+ macrophages 
in the TME will be measured and compared in pre- and post-treatment samples for patients 
treated with sitravatinib/pembrolizumab combination versus pembrolizumab alone.   The 
expression of AXL and/or MERTK in CD68+ cells will be correlated with the percentage of 
CD8+ T cells, FOXP3+ T regulatory cells, effector T cells and activated myeloid cells across 
multiple stained sections.
Additional panels may be added.  For full details please see Laboratory Manual.  
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
88
11.3.3 Isolation of CD45+ cells and Single-cell RNA Sequencing
CD45+ cells will be isolated from baseline and 3-week on selected treatment tumor samples 
as per section 11.3.1.  Single-cell RNA sequencing will then be performed to detect gene 
expression changes in myeloid and T-cell populations induced by pembrolizumab + 
sitravatinib combination treatment.  As an unbiased genome-wide transcriptome analyses, 
single-cell RNA sequencing may reveal novel population-level complexities and unique gene 
expression markers associated with sitravatinib + pembrolizumab treatment versus 
pembrolizumab treatment alone.  For additional details please see Laboratory Manual.  
11.4 Peripheral Blood Analysis 
Research blood will be collected and analyzed on a subset of patients at multiple time points 
as described above.  Peripheral blood mononuclear cells (PBMCs) will be isolated and used 
for bulk RNA sequencing to evaluate gene expression changes in PBMCs over all serial time 
points with sitravatinib/pembrolizumab treatment versus pembrolizumab alone.  For full 
details please see Laboratory Manual. 
11.5 Other Analyses
Any blood and tissue collected during this trial that is not used for the above analyses will be 
stored for potential future studies.  Additional analyses may include, but are not limited to, 
whole exome DNA sequencing, additional multiplex IHC panels, T-cell receptor (TCR) 
sequencing, cytokine analysis from blood, and circulating tumor DNA (ctDNA).  
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
89
12 Appendices
12.1 Appendix 1: NCI Common Terminology Criteria for Adverse Events 
(CTCAE) 
Please use the following link to the NCI CTCAE website: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
12.2 Appendix 2: Eastern Cooperative Oncology Group (ECOG) Performance 
Status
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance without 
restriction 
1 
Restricted in physically strenuous activity but ambulatory and able 
to carry out work of a light or sedentary nature, e.g., light 
housework or office work 
2 
Ambulatory and capable of all self-care but unable to carry out any 
work activities; up and about > 50% of waking hours 
3 
Capable of only limited self-care, confined to a bed or chair > 50% 
of waking hours 
4 
Completely disabled; cannot carry on any self-care; totally confined 
to bed or chair 
5 
Dead 
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
90
12.3 Appendix 3 Abbreviated Presentation of RECIST Version 1.1 Guidelines 
(21)
Categorizing Lesions at Baseline
Measurable Lesions

Accurately measured in at least one dimension.

When assessed by CT or MRI, longest diameter at least 10 mm or greater (slice 
thickness 5-8 mm), measured in the axial plane. If the slice thickness is greater than 
5 mm (including any inter-slice gap), the longest diameter must be at least twice the 
slice thickness.

Malignant lymph nodes with a short axis (defined as the largest measurement 
perpendicular to the longest diameter of the lesion) 15 mm or greater when assessed 
by CT or MRI.
The shortest axis is used as the diameter for malignant lymph nodes, longest axis for all 
other lesions.
Non-Measurable Disease

Lesions too small to be considered measurable (including nodes with short axis 
between 10 and 14.9 mm) or truly non-measurable disease such as pleural or 
pericardial effusions, ascites, inflammatory breast disease, leptomeningeal disease, 
lymphangitic involvement of skin or lung, and abdominal masses identified by 
physical exam that are not measurable by reproducible imaging techniques.

Bone disease is non-measurable with the exception of soft tissue components that 
can be evaluated by CT or MRI and meet the definition of measurability at baseline.

Previously irradiated lesions (or those subjected to other local treatment) are non-
measurable unless they have progressed since completion of treatment.
Normal Lesions

Non-malignant simple cysts should not be recorded either as target or non-target 
disease. Cystic lesions thought to represent cystic metastases can be measurable 
lesions, if they meet the specific definition above.

Lymph nodes with short axis <10 mm are considered normal and should not be 
followed as disease.
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
91
Tumor Assessments
All sites of disease must be assessed at baseline. Baseline assessments should be done as 
close as possible prior to study start. All required scans must be done within the window of 
time specified in the Schedule of Assessments prior to randomization. If the baseline 
assessment is inadequate, subsequent statuses generally should be not evaluable.
The determination of whether lesions are measurable is performed only at baseline. 
“Measurable” at baseline means eligible for selection as target lesions, and thus for 
quantitative assessment throughout the trial. Once selected as a target lesion, a lesion 
remains target throughout the trial.
Target Lesions
All measurable lesions up to a maximum of 2 lesions per organ, 5 lesions in total, 
representative of all involved organs, should be identified as target lesions at baseline. 
Target lesions should be selected on the basis of size (longest lesions) and suitability for 
accurate repeated measurements. Record the longest diameter for each lesion, except in 
the case of pathological lymph nodes for which the short axis should be recorded. The sum 
of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions at baseline will be the basis for comparison to look for partial response at later 
assessments.

If 2 target lesions coalesce the longest diameter measurement of the coalesced 
mass is used. If a large target lesion splits, the sum of the parts is used.

Measurements for target lesions that become small should continue to be recorded. 
If a target lesion becomes too small to measure, 0 mm should be recorded if the 
lesion is considered to have disappeared; otherwise a default value of 5 mm should 
be recorded.

When nodal lesions decrease to <10 mm (normal), the actual measurement should 
still be recorded.
Non-Target Lesions
All non-measurable disease is non-target. All measurable lesions not identified as target 
lesions are also included as non-target disease. Measurements are not required but rather 
qualitative evaluations of status will be recorded. Multiple non-target lesions in one organ 
may be recorded as a single item on the CRF (e.g., ‘multiple liver metastases’).
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
92
Objective Response Status at Each Evaluation
Disease sites must be assessed using the same technique as baseline, including consistent 
administration of contrast. If not, subsequent objective statuses may be not evaluable.
Target Disease

Complete Response (CR): Complete disappearance of all target lesions with the 
exception of nodal disease. All target nodes must decrease to normal size (short axis 
< 10 mm). All target lesions must be assessed.

Partial Response (PR): Greater than or equal to 30% decrease under baseline of the 
sum of diameters of all target measurable lesions. The short diameter is used in the 
sum for target nodes, while the longest diameter is used in the sum for all other 
target lesions. All target lesions must be assessed.

Stable Disease (SD): Does not qualify for CR, PR or Progression. All target lesions 
must be assessed. Stable can follow PR only in the rare case that the sum increases 
by less than 20% from the nadir, but enough that a previously documented 30% 
decrease no longer holds.

Progressive Disease (PD): 20% increase in the sum of diameters of target 
measurable lesions above the smallest sum observed (over baseline if no decrease 
in the sum is observed during therapy) with a minimum absolute increase of 5 mm.

Not evaluable:

one or more target lesions have not been assessed,

or assessment methods used were inconsistent with those used at baseline and 
impaired assessment,

or one or more target lesions cannot be measured accurately (e.g., poorly visible 
unless due to being too small to measure),

or one or more target lesions were excised or irradiated and have not reappeared 
or increased.
Non-Target Disease

CR: Disappearance of all non-target lesions and normalization of tumor marker 
levels. All lymph nodes must be ‘normal’ in size (<10 mm short axis).

Non-CR/Non-PD: Persistence of any non-target lesions and/or tumor marker level 
above the normal limits.
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
93

PD: Unequivocal progression of preexisting lesions. Generally, the overall tumor 
burden must increase sufficiently to merit discontinuation of therapy. In the presence 
SD or PR in target disease, progression due to unequivocal increase in non-target 
disease should be rare.

Not evaluable: One or more non-target sites were not assessed or assessment 
methods were inconsistent with those used at baseline.
New Lesions
The appearance of any new unequivocal malignant lesion indicates PD. If a new lesion is 
equivocal, for example due to its small size, continued assessment will clarify the etiology. If 
repeat assessments confirm the lesion, then progression should be recorded on the date of 
the initial assessment. A lesion identified in an area not previously scanned will be 
considered a new lesion.
12.4 Appendix 4  Abbreviated Presentation of RANO-Brain Metastases 
Criteria(22) 
Categorizing Lesions at Baseline
Measurable Lesions:

Bidimensionally contrast enhancing lesions with clearly defined margins by CT or MRI 
scan

Two perpendicular diameters of at least 10mm, visible on two or more axial slices that 
are 5mm apart with 0-mm skip

If MRI is performed with thicker slices, size of a measurable lesion at baseline should be 
two times the slice thickness 
Non-Measurable Lesions 

Unidirectional Lesions

Lesions without sharp delineation(e.g. lesions around a cyst or surgical cavity)

Lesions with a size less than 2 times slice thickness 

Dural metastases or leptomeningeal disease 
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
94
Target Lesions:

At least 2 lesions and up to 5 lesions in patients with multiple lesions

Should be selected on the basis of size and as those that can be measured reproducibly

Lesions with prior local treatment can be considered measurable if progression has 
occurred since the time of local treatment

A sum of diameters for all target lesions will be calculated and reported as the baseline 
sum of longest diameters
Non-Target Lesions

All lesions not designated as target lesions should be recorded as non-target lesions

Measurements are not required and these lesions should be classified as present, 
absent, or unequivocal progression, and followed up 
Response Assessment of Target and Non-Target Lesions:
Target Lesions:

Complete Response (CR): Disappearance of all CNS target lesions sustained for at least 
4 weeks; with no new lesions, no use of corticosteroids, and patient is stable or improved 
clinically.

Partial response (PR): At least a 30% decrease in the sum longest diameter of CNS 
target lesions, taking as reference the baseline sum longest diameter sustained for at 
least 4 weeks; no new lesions; stable to decreased corticosteroid dose; stable or 
improved clinically.

Progressive disease: At least a 20% increase in the sum longest diameter of CNS target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if 
that is the smallest on study). In addition to the relative increase of 20%, at least one 
lesion must increase by an absolute value of 5 mm or more to be considered 
progression.

Stable disease: Neither sufficient shrinkage to qualify for partial response nor sufficient 
increase to qualify for progressive disease, taking as reference the smallest sum longest 
diameter while on study.
Non-Target Lesions
Non-target lesions should be assessed qualitatively at each of the timepoints specified in the 
protocol.
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
95

Complete response: Requires all of the following: disappearance of all enhancing CNS 
non-target lesions, no new CNS lesions.

Non-complete response or non-progressive disease: Persistence of one or more non-
target CNS lesion or lesions.

Progressive disease:  Any of the following: unequivocal progression of existing 
enhancing non-target CNS lesions, new lesion(s) (except while on immunotherapy-
based treatment), or unequivocal progression of existing tumor-related non-enhancing 
(T2/FLAIR) CNS lesions. In the case of immunotherapy-based treatment, new lesions 
alone may not constitute progressive disease.
12.5 Appendix 5: Medications or Substances to be Avoided or Used with 
Caution During Treatment with Sitravatinib 
Drugs with a Known Risk of Torsades de Pointes*
Generic Name
Brand Names (Partial List)
Drug Class
Therapeutic Use
Aclarubicin (Only on Non 
US Market)
Aclacin, Aclacinomycine, Aclacinon, 
Aclaplastin, Jaclacin
Anti-cancer
Cancer
Amiodarone
Cordarone, Pacerone, Nexterone
Antiarrhythmic
Arrhythmia
Anagrelide
Agrylin, Xagrid
Phosphodiesterase 3 
inhibitor
Thrombocythemia
Arsenic trioxide
Trisenox
Anti-cancer
Cancer (leukemia)
Astemizole (Removed 
from US Market)
Hismanal
Antihistamine
Allergic rhinitis
Azithromycin
Zithromax, Zmax
Antibiotic
Bacterial infection
Bepridil
Vascor
Antianginal
Angina Pectoris (heart 
pain)
Cesium Chloride
Energy Catalyst
Toxin
Alternative therapy cancer
Chloroquine
Aralen
Antimalarial
Malaria
Chlorpromazine
Thorazine, Largactil, Megaphen
Antipsychotic / 
Antiemetic
Nausea, Schizophrenia, 
many others
Chlorprothixene (Only 
on Non US Market)
Truxal
Antipsychotic
Schizophrenia
Cilostazol
Pletal
Phosphodiesterase 3 
inhibitor
Intermittent claudication
Ciprofloxacin
Cipro, Cipro-XR, Neofloxin
Antibiotic
Bacterial infection
Cisapride (Removed 
from US Market)
Propulsid
GI stimulant
Increase GI motility
Citalopram
Celexa, Cipramil
Antidepressant, 
SSRI
Depression
Clarithromycin
Biaxin, Prevpac
Antibiotic
Bacterial infection
Cocaine
Cocaine
Local anesthetic
Anesthesia (topical)
Disopyramide
Norpace
Antiarrhythmic
Arrhythmia
Dofetilide
Tikosyn
Antiarrhythmic
Arrhythmia
Domperidone (Only on 
Non US Market)
Motilium, Motillium, Motinorm Costi, 
Nomit
Antiemetic
Nausea, vomiting
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
96
Generic Name
Brand Names (Partial List)
Drug Class
Therapeutic Use
Donepezil
Aricept
Cholinesterase 
inhibitor
Dementia (Alzheimer's 
Disease)
Dronedarone
Multaq
Antiarrhythmic
Arrhythmia
Droperidol
Inapsine, Droleptan, Dridol, Xomolix
Antipsychotic / 
Antiemetic
Anesthesia (adjunct), 
nausea
Erythromycin
E.E.S., Robimycin, EMycin, Erymax, 
Ery- Tab, Eryc Ranbaxy, Erypar, Eryped, 
Erythrocin Stearate Filmtab, Erythrocot, 
E-Base, Erythroped, Ilosone, MY-E, 
Pediamycin, Abboticin, Abboticin-ES, 
Erycin, PCE Dispertab, Stiemycine, 
Acnasol, Tiloryth
Antibiotic
Bacterial infection, 
increase GI motility
Escitalopram
Cipralex, Lexapro, Nexito, Anxiset-E, 
Exodus, Esto, Seroplex, Elicea, Lexamil, 
Lexam, Entact, Losita, Reposil, 
Animaxen, Esitalo, Lexamil
Antidepressant, 
SSRI
Depression (major), 
anxiety disorders
Flecainide
Tambocor, Almarytm, Apocard, Ecrinal, 
Flécaine
Antiarrhythmic
Arrhythmia
Fluconazole
Diflucan, Trican
Antifungal
Fungal infection
Gatifloxacin (Removed 
from US Market)
Tequin
Antibiotic
Bacterial infection
Grepafloxacin (Removed 
from US Market)
Raxar
Antibiotic
Bacterial infection
Halofantrine (Only on 
Non US Market)
Halfan
Antimalarial
Malaria
Haloperidol
Haldol, Aloperidin, Bioperidolo, 
Brotopon, Dozic, Duraperidol, Einalon S, 
Eukystol, Halosten, Keselan, Linton, 
Peluces, Serenace, Serenase, 
Sigaperidol
Antipsychotic
Schizophrenia, agitation
Hydroquinidine 
(Dihydroquinidine) (Only 
on Non US Market)
Serecor
Antiarrhythmic
Arrhythmia
Hydroxychloroquine
Plaquenil, Quineprox
Antimalarial, Anti- 
inflammatory
Malaria, SLE, rheumatoid 
arthritis
Ibogaine (Only on Non 
US Market)
Psychedelic
Narcotic addiction, 
unproven
Ibutilide
Corvert
Antiarrhythmic
Arrhythmia
Levofloxacin
Levaquin, Tavanic
Antibiotic
Bacterial infection
Levomepromazine 
(Methotrimeprazine) 
(Only on Non US 
Market)
Nosinan, Nozinan, Levoprome
Antipsychotic
Schizophrenia
Levomethadyl acetate 
(Removed from US 
Market)
Orlaam
Opioid agonist
Narcotic dependence
Levosulpiride (Only on 
Non US Market)
Lesuride, Levazeo, Enliva
Antipsychotic
Schizophrenia
Mesoridazine (Removed 
from US Market)
Serentil
Antipsychotic
Schizophrenia
Methadone
Dolophine, Symoron, Amidone, 
Methadose, Physeptone, Heptadon
Opioid agonist
Narcotic dependence, pain
Moxifloxacin
Avelox, Avalox, Avelon
Antibiotic
Bacterial infection
Nifekalant (Only on Non 
US Market)
Shinbit
Antiarrhythmic
Arrhythmia
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
97
Generic Name
Brand Names (Partial List)
Drug Class
Therapeutic Use
Ondansetron
Zofran, Anset, Ondemet, Zuplenz, 
Emetron, Ondavell, Emeset, Ondisolv, 
Setronax
Antiemetic
Nausea, vomiting
Oxaliplatin
Eloxatin
Anti-cancer
Cancer
Papaverine HCl (Intra- 
coronary)
Vasodilator, 
Coronary
Diagnostic adjunct
Pentamidine
Pentam
Antifungal
Fungal infection 
(Pneumocystis pneumonia)
Pimozide
Orap
Antipsychotic
Tourette's Disorder
Probucol (Removed 
from US Market)
Lorelco
Antilipemic
Hypercholesterolemia
Procainamide
Pronestyl, Procan
Antiarrhythmic
Arrhythmia
Propofol
Diprivan, Propoven
Anesthetic, general
Anesthesia
Quinidine
Quinaglute, Duraquin, Quinact, 
Quinidex, Cin-Quin, Quinora
Antiarrhythmic
Arrhythmia
Roxithromycin (Only on 
Non US Market)
Rulide, Xthrocin, Roxl-150, Roxo, Surlid, 
Rulide, Biaxsig, Roxar, Roximycinv, 
Roxomycin, Rulid, Tirabicin, Coroxin
Antibiotic
Bacterial infection
Sevoflurane
Ultane, Sojourn
Anesthetic, general
Anesthesia
Sotalol
Betapace, Sotalex, Sotacor
Antiarrhythmic
Arrhythmia
Sparfloxacin (Removed 
from US Market)
Zagam
Antibiotic
Bacterial infection
Sulpiride (Only on Non 
US Market)
Dogmatil, Dolmatil, Eglonyl, Espiride, 
Modal, Sulpor
Antipsychotic, 
atypical
Schizophrenia
Sultopride (Only on Non 
US Market)
Barnetil, Barnotil, Topral
Antipsychotic, 
atypical
Schizophrenia
Terfenadine (Removed 
from US Market)
Seldane
Antihistamine
Allergic rhinitis
Terlipressin (Only on 
Non US Market)
Teripress, Glypressin, Terlipin, 
Remestyp, Tresil, Teriss
Vasoconstrictor
Septic shock
Terodiline (Only on Non 
US Market)
Micturin, Mictrol
Muscle relaxant
Bladder spasm
Thioridazine
Mellaril, Novoridazine, Thioril
Antipsychotic
Schizophrenia
Vandetanib
Caprelsa
Anti-cancer
Cancer (thyroid)
*
Woosley RL, Heise CW, Gallo T, Tate J, Woosley D and Romero KA, 
www.CredibleMeds.org, QTdrugs List, [Accession Date: 10 April 2020], AZCERT, Inc. 
1822 Innovation Park Dr., Oro Valley, AZ 85755; for the most current information, access 
the website: www.CredibleMeds.org.
Drugs with Conditional Risk of Torsades de Pointes*
Generic Name
Brand Names (Partial List)
Drug Class
Therapeutic Use
Abiraterone
Zytiga, Abiratas, Abretone, Abirapro
Anti-androgen
Cancer (Prostate)
Amantadine
Symmetrel, Symadine
Antiviral
Viral infection (Influenza), 
Parkinson's disease
Amisulpride
Barhemsys, Solian, Supitac, Soltus, 
Amitrex, Amazeo
Antiemetic, 
Antipsychotic
Nausea and vomiting, 
postoperative
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
98
Generic Name
Brand Names (Partial List)
Drug Class
Therapeutic Use
Amitriptyline
Elavil (Discontinued 6/13), Tryptomer, 
Tryptizol, Laroxyl, Saroten, Sarotex 
Lentizol, Endep
Antidepressant, 
Tricyclic
Depression
Amphotericin B
Fungilin, Fungizone, Abelcet, 
AmBisome, Fungisome, Amphocil, 
Amphotec
Antifungal
Fungal infection
Amsacrine (Acridinyl 
anisidide)(Only on Non 
US Market)
Amsidine
Antineoplastic Agent
Cancer (Acute 
Lymphoblastic Leukemia)
Atazanavir
Reyataz, Evotaz
Antiviral
Viral infection (HIV/AIDS)
Bendroflumethiazide 
(Bendrofluazide)
Aprinox, Corzide
Diuretic, thiazide
Hypertension, diuresis
Chloral hydrate
Aquachloral, Novo-Chlorhydrate, 
Somnos, Noctec, Somnote
Sedative
Sedation, insomnia
Cimetidine
Tagamet
Antacid
Gastric hyperacidity, 
GERD
Clomipramine
Anafranil
Antidepressant, 
Tricyclic
Depression
Diphenhydramine
Benadryl, Nytol, Unisom, Sominex, 
Dimedrol, Daedalon, Banophen
Antihistamine
Allergic rhinitis, insomnia
Doxepin
Sinequan, Silenor, Aponal, Adapine, 
Doxal, Deptran, Sinquan
Antidepressant, 
Tricyclic
Depression
Eperisone (Only on Non 
US Market)
Myonal, Epry
Antispasmodic
Spasticity
Esomeprazole
Nexium, Nexum, Inexium
Proton Pump 
Inhibitor
Gastric hyperacidity, 
GERD
Famotidine
Pepcid, Fluxid, Quamatel
H2-receptor 
antagonist
Gastric hyperacidity, 
GERD
Fluoxetine
Prozac, Sarafem, Fontex
Antidepressant, 
SSRI
Depression
Fluvoxamine
Faverin, Fevarin, Floxyfral, Dumyrox, 
Luvox
Selective Serotonin 
Reuptake Inhibitor
Depression, Obsessive 
Compulsive Disorder
Furosemide (frusemide)
Lasix, Fusid, Frumex, Lasilix
Diuretic
Hypertension, diuresis
Galantamine
Reminyl, Nivalin, Razadyne-ER, 
Lycoremine
Cholinesterase 
inhibitor
Dementia (Alzheimer's 
Disease)
Garenoxacin (Only on 
Non US Market)
Geninax
Antibiotic
Bacterial infection
Hydrochlorothiazide
Apo-Hydro, Aquazide H, BP Zide, 
Dichlotride, Hydrodiuril, HydroSaluric, 
Microzide, Esidrex, Oretic
Diuretic
Hypertension, diuresis
Hydroxyzine
Atarax, Vistaril, Aterax, Alamon, Durrax, 
Equipose, Masmoran, Orgatrax, Paxistil 
Quiess, Tran-Q, Tranquizine
Antihistamine
Allergic reaction, anxiety 
disorders
Indapamide
Lozol, Natrilix, Insig
Diuretic
Hypertension, diuresis
Itraconazole
Sporanox, Onmel
Antifungal
Fungal infection
Ivabradine
Procoralan, Coralan, Corlentor, Coraxan, 
Ivabid, Bradia
Antianginal
Angina Pectoris (heart 
pain)
Ketoconazole
Nizoral, Sebizole, Ketomed, Keton
Antifungal
Fungal infection
Lansoprazole
Prevacid, Ogast
Proton Pump 
Inhibitor
Gastric hyperacidity, 
GERD
Loperamide
Imodium
Opioid agonist
Diarrhea
Metoclopramide
Reglan, Afipran, Maxolon, Cerucal, 
Clopamon, Clopra, Maxeran, Maxolon, 
Antiemetic
Nausea, vomiting
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
99
Generic Name
Brand Names (Partial List)
Drug Class
Therapeutic Use
Metozolv, Plasil, Pramin, Primperan, 
Perinorm
Metolazone
Zytanix, Zaroxolyn, Mykrox
Diuretic
Hypertension, diuresis
Metronidazole
Flagyl
Antibiotic
Trichomoniasis, amebiasis, 
bacterial infection
Nelfinavir
Viracept
Antiviral
Viral infection (HIV/AIDS)
Olanzapine
Zyprexa, Zydis, Relprevv
Antipsychotic, 
atypical
Schizophrenia, bipolar 
disorder
Omeprazole
Losec, Prilosec, Zegerid, Mopral
Proton Pump 
Inhibitor
Gastric hyperacidity, 
GERD
Pantoprazole
Protonix, Inipomp, Eupantol
Proton Pump 
Inhibitor
Gastric hyperacidity, 
GERD
Paroxetine
Paxil, Aropax, Pexeva, Seroxat, 
Sereupin, Seroxat, Deroxat
Antidepressant, 
SSRI
Depression
Piperacillin/Tazobactam
Tazosyn, Zosyn
Antibiotic
Bacterial infection
Posaconazole
Noxafil, Posamol
Antifungal
Fungal infection
Propafenone
Rythmol SR, Rytmonorm
Sodium channel 
blocker
Arrhythmia
Quetiapine
Seroquel
Antipsychotic, 
atypical
Schizophrenia
Quinine sulfate
Qualaquin, Hexaquine
Antimalarial
Malaria, leg cramps
Ranolazine
Ranexa, Ranozex
Antianginal
Angina Pectoris (heart 
pain)
Risperidone
Risperdal
Antipsychotic, 
atypical
Schizophrenia
Sertraline
Zoloft, Lustral
Antidepressant, 
SSRI
Depression
Solifenacin
Vesicare
Muscle relaxant
Bladder spasm
Telaprevir
Incivo, Incivek
Antiviral
Viral infection (hepatitis C)
Torsemide (Torasemide)
Demadex, Diuver, Examide
Diuretic
Hypertension, diuresis
Trazodone
Desyrel, Oleptro, Beneficat, Deprax, 
Desirel, Molipaxin, Thombran, Trazorel, 
Trialodine, Trittico, Mesyrel
Antidepressant, 
SARI
Depression, insomnia
Voriconazole
VFend
Antifungal
Fungal infection
Ziprasidone
Geodon, Zeldox
Antipsychotic, 
atypical
Schizophrenia
*
Woosley RL, Heise CW , Gallo T, Tate J, Woosley D and Romero KA, 
www.CredibleMeds.org, QTdrugs List, [Accession Date: 10 April 2020], AZCERT, Inc. 
1822 Innovation Park Dr., Oro Valley, AZ 85755; for the most current information, access 
the website: www.CredibleMeds.org.
Sensitive Substrates and Substrates with Narrow Therapeutic Index for P-gp and 
BCRP transporters
Enzyme
P-gp
Aliskiren, ambrisentan, colchicine, dabigatran etexilate, digoxin, everolimus, fexofenadine, imatinib, 
lapatinib, maraviroc, nilotinib, posaconazole, ranolazine, saxagliptin, sirolimus, sitagliptin, talinolol, 
tolvaptan, topotecan
BCRP
Methotrexate, mitoxantrone, imatinib, irinotecan, lapatinib, rosuvastatin, sulfasalazine, topotecan
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
100
Sensitive Substrates and Substrates with Narrow Therapeutic Index for the indicated 
CYP3A4 Enzymes
Enzyme
CYP3A4
Alfentanil, avanafil, budesonide, buspirone, conivaptan, darifenacin, darunavir, dasatinib dronedarone, 
ebastine, eletriptan, eplerenone, everolimus, felodipine, ibrutinib, indinavir, lomitapide, lovastatin, 
lurasidone, maraviroc, midazolam, naloxegol, nisoldipine, quetiapine, saquinavir, sildenafil, simvastatin, 
sirolimus, tacrolimus, ticagrelor, tolvaptan, triazolam, vardenafil
12.6 Appendix 6 – Pill Diary 
STUDY MEDICATION CALENDAR
(Research Nurse to fill out all this top information)
Patient’s Name/ ID#:
Total #Pills Dispensed/Cycle_______________
HIC#               
Total #Pills Returned/Cycle________________
Cycle#
Total # Pills Taken/Cycle__________________
RN signature/Date________________________
Day of the week
Day of the week
Day of the week
Day of the week
Day of the week
Day of the week
Day of the week
1
Day of
Cycle
____# of Pills Taken
___:___ AM
___:___ PM
2
Day of
Cycle
____# of Pills Taken
___:___ AM
___:___PM
3
Day of
Cycle
____# of Pills Taken
___:___ AM
___:___PM
4
Day of Cycle
____# of Pills Taken
___:___ AM
___:___PM
5
Day of
Cycle
____# of Pills Taken
___:___ AM
___:___ PM
6
Day of
Cycle
____# of Pills Taken
___:___ AM
___:___ PM
7
Day of Cycle
____# of Pills Taken
___:___ AM
___:___ PM
8
Day of
Cycle
____# of Pills Taken
___:___ AM
___:___ PM
9
Day of
Cycle
____# of Pills Taken
___:___ AM
___:___ PM
10
Day of
Cycle
____# of Pills Taken
___:___ AM
___:___ PM
11
Day of Cycle
____# of Pills Taken
___:___ AM
___:___ PM
12
Day of
Cycle
____# of Pills Taken
___:___AM
___:___PM
13
Day of
Cycle
____# of Pills Taken
___:___ AM
___:___PM
14
Day of Cycle
_
___# of Pills Taken
___:___ AM
__:___ PM
15
Day of
Cycle
____# of Pills Taken
___:___ AM
___:___ PM
16
Day of
Cycle
____# of Pills Taken
___:___ AM
___:___ PM
17
Day of
Cycle
____# of Pills Taken
___:___ AM
___:___ PM
18
Day of Cycle
____# of Pills Taken
___:___ AM
___:___ PM
19
Day of
Cycle
____# of Pills Taken
___:___ AM
___:___ PM
20
Day of
Cycle
____# of Pills Taken
___:___ AM
___:___ PM
21
Day of Cycle
____# of Pills Taken
___:___ AM
___:___ PM
22
Day of
Cycle
____# of Pills Taken
___:___ AM
___:___ PM
23
Day of
Cycle
____# of Pills Taken
___:___ AM
___:___PM
24
Day of
Cycle
____# of Pills Taken
___:___ AM
___:___ PM
25
Day of Cycle
___# of Pills Taken
___:___ AM
___:___PM
26
Day of
Cycle
____# of Pills Taken
___:___ AM
___:___PM
27
Day of
Cycle
____# of Pills Taken
___:___ AM
__:___ PM
28
Day of Cycle
____# of Pills Taken
___:___ AM
___:___PM
29
Day of
Cycle
___# of Pills Taken
___:___ AM
___:___ PM
30
Day of
Cycle
___# of Pills Taken
___:___ AM
___:___ PM
31
Day of
Cycle
___# of Pills Taken
___:___ AM
___:___ PM
Please be sure to bring this calendar and all your remaining pills and pill bottles 
with you for your return appointment at the end of each cycle, and return them
to the person who gave them to you. Please sign that you have returned all the
pills and/or pill bottles.
Patient signature____________________________Date____________
 
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
101
13 References
1.
Bray F FJ, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN 
estimates of incidence and mortality worldwide for 36 cancers in 185 countries 2015 
[Available from: https://gco.iarc.fr/today/data/factsheets/cancers/15-Lung-fact-sheet.pdf.
2.
Noone AM HN, Krapcho M, et al. Feuer EJ, Cronin KA SEER Cancer Statistics 
Review. 1975-2015.
3.
Mellman I CG, Dranoff G. Cancer immunotherapy comes of age. Nature.480:480-9.
4.
Topalian SL DC, Pardoll DM. Immune checkpoint blockade: a common denominator 
approach to cancer therapy. Cancer Cell. 2015;27:450-61.
5.
Mu CY HJ, Chen Y, et al. High expression of PD-L1 in lung cancer may contribute to 
poor prognosis and tumor cells immune escape through suppressing tumor infiltrating 
dendritic cells maturation. Med Oncol. 2011;3:682-8.
6.
Mok TSK, Wu Y-L, Kudaba I, Kowalski DM, Cho BC, Turna HZ, et al. Pembrolizumab 
versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or 
metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, 
controlled, phase 3 trial. The Lancet. 2019;393(10183):1819-30.
7.
Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, et al. 
Pembrolizumab versus Chemotherapy for PD-L1–Positive Non–Small-Cell Lung Cancer. 
2016;375(19):1823-33.
8.
Herbst RS, Giaccone G, de Marinis F, Reinmuth N, Vergnenegre A, Barrios CH, et al. 
Atezolizumab for First-Line Treatment of PD-L1–Selected Patients with NSCLC. 
2020;383(14):1328-39.
9.
Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, et al. 
Pembrolizumab for the Treatment of Non–Small-Cell Lung Cancer. 2015;372(21):2018-28.
10.
Herbst RS, Baas P, Kim D-W, Felip E, Pérez-Gracia JL, Han J-Y, et al. 
Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-
small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. The Lancet. 
2016;387(10027):1540-50.
11.
Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, et al. 
Pembrolizumab plus Chemotherapy in Metastatic Non–Small-Cell Lung Cancer. 
2018;378(22):2078-92.
12.
Akalu YT, Rothlin CV, Ghosh S. TAM receptor tyrosine kinases as emerging targets 
of innate immune checkpoint blockade for cancer therapy. Immunol Rev. 2017;276(1):165-
77.
13.
Blume-Jensen P HT. Oncogenic kinase signalling. Nature. 2001;411(6835):355-65.
14.
Graham DK, DeRyckere D, Davies KD, Earp HS. The TAM family: 
phosphatidylserine sensing receptor tyrosine kinases gone awry in cancer. Nat Rev Cancer. 
2014;14(12):769-85.
15.
M. Oliva DC, A. Prawira, A. Spreafico, S. Bratman, T. Shek, J. de Almeida, I. Yeung, 
A. Hansen, A. Hope, D. Goldstein, R. Gilbert, D. Vines, P. Gullane, D. Brown, I. Weinreb, B. 
Perez-Ordoñez, T. Pugh, P. Ohashi, B. Wang, J. Irish, P. Olson, H. Der-Torossian, I. Chen, 
L.L. Siu. SNOW: Sitravatinib and Nivolumab in Oral Cavity Cancer Window of Opportunity 
Study.  Society for Immunotherapy of Cancer National Harbor, MD2019.
16.
Du W, Huang H, Sorrelle N, Brekken RA. Sitravatinib potentiates immune checkpoint 
blockade in refractory cancer models. JCI insight. 2018;3(21).
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022


APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022
2000030093 Goldberg
102
17.
Rothlin CV, Carrera-Silva EA, Bosurgi L, Ghosh S. TAM receptor signaling in immune 
homeostasis. Annual review of immunology. 2015;33:355-91.
18.
Rothlin CV, Ghosh S, Zuniga EI, Oldstone MB, Lemke G. TAM receptors are 
pleiotropic inhibitors of the innate immune response. Cell. 2007;131(6):1124-36.
19.
Filardy AA, Pires DR, Nunes MP, Takiya CM, Freire-de-Lima CG, Ribeiro-Gomes FL, 
et al. Proinflammatory clearance of apoptotic neutrophils induces an IL-12(low)IL-10(high) 
regulatory phenotype in macrophages. Journal of immunology (Baltimore, Md : 1950). 
2010;185(4):2044-50.
20.
Tibrewal N, Wu Y, D'Mello V, Akakura R, George TC, Varnum B, et al. 
Autophosphorylation docking site Tyr-867 in Mer receptor tyrosine kinase allows for 
dissociation of multiple signaling pathways for phagocytosis of apoptotic cells and down-
modulation of lipopolysaccharide-inducible NF-kappaB transcriptional activation. The Journal 
of biological chemistry. 2008;283(6):3618-27.
21.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J 
Cancer. 2009;45(2):228-47.
22.
Lin NU, Lee EQ, Aoyama H, Barani IJ, Barboriak DP, Baumert BG, et al. Response 
assessment criteria for brain metastases: proposal from the RANO group. The Lancet 
Oncology. 2015;16(6):e270-e8.
APPROVED BY THE YALE UNIVERSITY IRB 10/6/2022