A Randomized Phase 3 Study of Sitravatinib in Combination With Nivolumab Versus Docetaxel in Patients With Advanced Non-Squamous Non-Small Cell Lung Cancer With Disease Progression On or After Platinum-Based Chemotherapy and Checkpoint Inhibitor Therapy SAPPHIRE
Phase: PHASE3
Conditions: Metastatic Non-Squamous Non-Small Cell Lung Cancer
Sponsor: Mirati Therapeutics Inc.

Official Title of Study: 
A Randomized Phase 3 Study of Sitravatinib in Combination with Nivolumab Versus Docetaxel in Patients 
with Advanced Non-Squamous Non-Small Cell Lung Cancer with Disease Progression On or After 
Platinum-Based Chemotherapy and Checkpoint Inhibitor Therapy (SAPPHIRE) 
 
PROTOCOL(S) 516-005 
 
NCT Number: NCT03906071 
  
Document Date (Date in which document was last revised): 07 October 2021 

 
 
 
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CLINICAL RESEARCH PROTOCOL 
DRUG(S): 
Sitravatinib (MGCD516) 
Nivolumab (OPDIVO®) 
Docetaxel
STUDY NUMBER: 
516-005 
PROTOCOL TITLE: 
A Randomized Phase 3 Study of Sitravatinib in 
Combination with Nivolumab Versus Docetaxel in 
Patients with Advanced Non-Squamous Non-Small Cell 
Lung Cancer with Disease Progression On or After 
Platinum-Based Chemotherapy and Checkpoint Inhibitor 
Therapy (SAPPHIRE) 
IND NUMBER: 
141664 
Eudra CT NUMBER: 
2019-001043-41 
SPONSOR: 
Mirati Therapeutics, Inc. 
3545 Cray Court 
San Diego, California, 92121, USA 
ORIGINAL PROTOCOL 
DATE: 
21 November 2018 
VERSION NUMBER: 
V5.0 
VERSION DATE: 
07 October 2021 
 
CONFIDENTIALITY STATEMENT 
This document contains confidential information and/or trade secrets of Mirati Therapeutics, 
Inc. As such, this document is protected from unauthorized disclosure or use by confidentiality 
agreement(s) and/or is exempt from public disclosure pursuant to applicable FDA and foreign 
counterpart regulations. 

 
 
 
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DOCUMENT HISTORY 
Document 
Version Date 
Summary of Changes 
Original Protocol, 
Version 1.0 
21 November 2018 
NA 
Version 2.0 
30 January 2020 
Title: 
• Protocol title updated to reflect the patient 
population to be enrolled in the study. 
Study Summary: 
• Revised the target population to include patients in 
the third-line treatment setting, post-CIT in 
addition to patients in the second line treatment 
setting based on feedback from investigators, 
review of treatment and clinical trial landscape and 
data from our ongoing Phase 2 study (MRTX-500). 
• Added background information on the mOS with 
docetaxel in the third-line treatment setting, post-
CIT as per the expanded patient population to be 
enrolled in the study. 
• Replaced stratification factor of ‘duration of 
previous CIT treatment (< 9 months vs ≥ 9 
months)’ with ‘prior lines of therapy in the 
advanced setting (1 vs 2)’ to align with the change 
in eligibility criteria allowing patients to enroll 
after 1st and 2nd line treatment. 
• Revised statistical considerations from an adaptive 
sample size re-estimation design to a group 
sequential design with one interim OS analysis for 
efficacy and futility and removed the interim ORR 
analysis resulting in a decrease in total number of 
patients for the study. 
• Added an exploratory objective to characterize the 
immunogenicity of nivolumab in combination with 
sitravatinib. 
Schedule of Assessments (Table 1): 
• Added clarification around the screening window. 
• Added clarification around the allowable window 
for Day 1 visits beyond Cycle 1 Day 1. 
• Added clarification around the Investigator 
Evaluation of Progression on most recent CIT 
regimen. 

 
 
 
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Document 
Version Date 
Summary of Changes 
• Added clarification on timepoint for Nivolumab 
ADA sample collection in the table and footnote 
#10 (per Protocol Administrative Letter dated 08 
October 2019). 
• Added clarification on allowable window around 
Cycle 3 Day 1 ECHO or MUGA. 
• Added clarification on the collection timepoint for 
PRO Questionnaires in the table and footnote #13 
(per Protocol Administrative Letter dated 08 
October 2019). 
• Footnote #1: clarified timing of treatment start in 
relation to date of randomization. 
• Footnote #3: revised to indicate that the ctDNA 
blood sample is optional and not a mandatory 
assessment. 
• Footnote #7 and #8: clarified allowable window 
around the timing of safety lab assessments. 
• Footnote #12: clarified the timing of on-study 
disease evaluations to be calculated based on the 
calendar from the date of randomization (per 
Protocol Administrative Letter dated 08 October 
2019). 
• Footnote #14: revised the reporting period for 
serious and non-serious immune-related AEs, the 
reporting period for irAES will continue until at 
least 100 days after the last administration of 
nivolumab or until subsequent immunotherapy is 
administered, whichever occurs earlier. 
Schedule of PK sample collections for Sitravatinib and 
triplicate ECG Assessments (Table 2) and 
Section 5.2.3 Nivolumab administration: 
• Footnote #1: clarified timing of the PK and ECG 
assessments in relation to dosing with sitravatinib 
and nivolumab on days when these are required. 
Section 1.1.3 Second- and Third-Line Chemotherapy 
for Non-Small Cell Lung Cancer: 
• Added background information on the mOS with 
docetaxel in the third-line treatment setting, post-
CIT as per the expanded patient population to be 
enrolled in the study. 

 
 
 
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Document 
Version Date 
Summary of Changes 
Section 1.3.1 Sitravatinib Drug Substance: 
• Removed the word “salt” from the sitravatinib 
malate name. 
Sections 1.3.2 Non-clinical Data, 1.3.3 Sitravatinib 
Clinical Experience: 
• Added guidance, throughout, that the Investigator’s 
Brochure should be referenced for current data. 
Section 1.3.3.3 Sitravatinib Clinical Efficacy: 
• Added update on preliminary efficacy data in the 
ongoing Phase 2 study (MRTX-500) which 
continues to demonstrate a robust median overall 
survival in a similar patient population to the 
population being enrolled into this study. 
Section 1.3.3.4 Sitravatinib Capsule Formulation Study 
and 5.1.1 Sitravatinib Formulation, packaging and 
Storage: 
• Removed specifics around the sitravatinib capsule 
properties, these will be added to the Pharmacy 
Manual. 
Section 1.3.3.5 Sitravatinib Dosing with Food: 
• Simplified the details around the food effect sub-
study being conducted in the ongoing Phase 2 
study (MRTX-500). 
Section 1.4 Nivolumab: 
• Added guidance, throughout protocol, that the 
current OPDIVO USPI and SmPC should be 
referenced for current data. 
Section 1.6 Docetaxel: 
• Added guidance, throughout protocol, that the 
current TAXOTERE USPI and SmPC should be 
referenced for current data. 
• Added guidance that TAXOTERE or generic 
equivalent (docetaxel) are acceptable for use in this 
study. 
Section 2.1.3 Exploratory Objective and 2.1.6 
Exploratory Endpoints: 
• Addition of exploratory objective to characterize 
the immunogenicity of nivolumab in combination 
with sitravatinib. 

 
 
 
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Document 
Version Date 
Summary of Changes 
Section 3 Study Design: 
• Revised the target population to include patients in 
the third-line treatment setting, post-CIT in 
addition to patients in the second line treatment 
setting based on feedback from investigators, 
review of treatment and clinical trial landscape and 
data from the ongoing Phase 2 study (MRTX-500). 
• Replaced stratification factor of ‘duration of 
previous CIT treatment (< 9 months vs ≥ 9 
months)’ with ‘prior lines of therapy in the 
advanced setting (1 vs 2)’ to align with the change 
in eligibility criteria allowing patients to enroll 
after 1st and 2nd line treatment. 
• Revised statistical considerations from an adaptive 
sample size re-estimation design to a group 
sequential design with one interim OS analysis for 
efficacy and futility and removed the interim ORR 
analysis resulting in a decrease in total number of 
patients for the study. 
Section 4.1 Inclusion Criteria: 
• Inclusion Criterion #1: added staging for metastatic 
and locally advanced disease for clarity. 
• Inclusion Criterion #2: Revised to include patients 
that have received 2 lines of treatment in the 
advanced disease setting and guidance around 
acceptable first and second lines of treatment in 
order to meet eligibility. 
• Inclusion Criterion #3 and #4: clarified refences to 
the CIT are to the most recent CIT prior to coming 
on study and duration of prior CIT. 
Section 4.2 Exclusion Criteria: 
• Throughout: clarified that timing for certain 
exclusions is in reference to date of randomization 
and not from treatment start for consistency. 
• Exclusion Criterion #9: Revised to clarify 
exceptions to current or prior use of 
immunosuppressive medications for non-immune 
conditions within 28 days of randomization. 
• Exclusion Criterion #11: Revised to clarify that 
treatment with antacids and /or H2 antagonist are 
permitted. 

 
 
 
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Document 
Version Date 
Summary of Changes 
• Exclusion Criterion #16: Revised to add 
timeframes after each sub-criterion. 
• Exclusion Criterion #23: Revised to align with 
OPDIVO USPI guidance that breastfeeding or 
planning to breastfeed within 5 months following 
the last dose of nivolumab is exclusionary. 
Section 4.4 Randomization: 
• Revised to actual process being followed. 
Section 5.1.4 Sitravatinib Dose Modification or 
Discontinuation: 
• Removed language that indicated that following 
sitravatinib dose reduction and control of adverse 
event, re-challenge at a higher sitravatinib dose is 
permitted at the discretion of the Investigator. 
Section 5.2 Nivolumab Study Drug: 
• Revised language to indicate that nivolumab will 
be provided by Sponsor. 
Section 5.3 Docetaxel Study Drug: 
• Revised language to add that Docetaxel will be 
provided by Sponsor depending on local country 
requirements. 
• Added guidance that TAXOTERE or generic 
equivalent (docetaxel) are acceptable for use in this 
study. 
Section 5.3.3 Docetaxel Administration and 5.3.4 
Docetaxel Dose Modification: 
• Added language to clarify that the initial dose 
(Cycle 1) of docetaxel should remain at 75 mg/m2. 
Section 5.4.1.1 General Management of Non-
Hematological Toxicities:  
• Clarified guidance for sitravatinib dose 
management: 
− 
Symptomatic Grade 2 sitravatinib-related 
non-hematological adverse events occurring 
any time on study, particularly early in 
treatment (e.g., Cycle 1 Day 15 or Cycle 2 
Day 1), are recommended to be managed 
using dose reduction to the next lower dose 
level, per the reduction schedule outlined in 

 
 
 
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Table 3, rather than continued dosing until 
interruption becomes necessary. 
− 
Treatment with sitravatinib may continue 
without dose modification (e.g., interruption 
or reduction) in cases of asymptomatic 
amylase and/or lipase increases in the 
absence of other clinical evidence of 
pancreatitis (eg, symptoms, electrolyte 
abnormalities, radiographic changes) at the 
investigator’s discretion. 
− 
Table 5 and related footnotes were updated. 
Section 5.4.4 Management of Hy’s Law Cases: 
• Added clarifications with regards to when 
sitravatinib and nivolumab should be permanently 
discontinued and steroids administered. 
Section 5.6.1 Concomitant Medication(s): 
• Gastric Acid Medications with Sitravatinib: 
Revised to clarify that treatment with antacids and 
/or H2 antagonist are permitted and to provide 
guidance with regards to timing of antacids and /or 
H2 antagonist administration in relation to 
sitravatinib dosing. 
• Supportive Care/Palliative Care: added language to 
indicate that bisphosphonates (eg, zoledronic acid) 
and RANK-L inhibitors (eg, denosumab) should be 
initiated prior to first dose of study therapy. 
• Vaccines: added language to clarify that live 
attenuated vaccines are to be avoided within 100 
days of nivolumab dosing. 
Section 5.6.3 Other Anticancer or Experimental 
Therapy: 
• Added language indicating that certain ongoing 
hormonal therapies taken to prevent recurrence of a 
malignancy not under study (eg, 
tamoxifen/aromatase inhibitor for breast cancer) 
may be permitted after discussion with and 
agreement of the Sponsor’s Medical Monitor. 
Sections 6.3 End of Treatment Assessments, 8.4.1 
Reporting Period and 9.5.1 Adverse Events: 
• Added language with regards to the reporting 
period for serious and non-serious immune-related 
AEs, the reporting period for irAES will continue 

 
 
 
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until at least 100 days after the last administration 
of nivolumab or until subsequent immunotherapy 
is administered, whichever occurs earlier. 
Section 7.1 Documentation of Disease Progression On 
or After Prior Chemotherapy and Checkpoint Inhibitor 
Therapy: 
• Clarified that refences to the CIT are to the most 
recent CIT prior to coming on study. 
Section 7.2.2 Radiographic Disease Assessments: 
• Removed language indicating that central 
radiology review would only be conducted until 
completion of the interim analysis for ORR based 
on the change in study design there will only be 
one interim analysis and a final analysis of the 
primary endpoint of overall survival, including a 
futility analysis. The previously planned ORR 
endpoint will remain as a secondary endpoint and 
central radiology review will continue until the 
completion of the study. 
• Per FDAs request, removed language referencing 
modifications to RECIST 1.1 to address potential 
temporary treatment effects including tumor 
necrosis, cavitation, flare response and 
pseudoprogression (per Protocol Administrative 
Letter dated 08 October 2019). 
Section 7.3.4 Electrocardiograms: 
• Removed language that that QTc will be manually 
calculated using the Fridericia’s formula. 
Section 7.4.3.1 Circulating Tumor DNA: 
• Revised to indicate that the ctDNA blood sample is 
optional and not a mandatory assessment. 
Section 8.3.2 Exposure During Pregnancy: 
• Clarified timing around male exposure to 
investigational product for consistency. 
Section 9.1.1 Primary Efficacy Hypothesis and 
Section 9.1.1.1 Sample Size Determination: 
• Revised per revision in the study design from 
adaptive design to a group sequential design with 
one interim analysis and one final analysis, without 
a sample size re-estimation. Approximately 372 
total OS events will be required to detect the 

 
 
 
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assumed HR at a 2-sided alpha 0.05 and a power of 
85%. Assuming an enrollment duration of 
approximately 25 months and an additional 13 
months of follow-up, a sample size of 
approximately 532 patients is planned to achieve 
the required number of events. 
Removal of Section 9.1.1.2 Interim Analysis based on 
OS for futility and Sample Size Readjustment and 
Section 9.1.2 Secondary Efficacy Hypothesis: 
• Per revision in the study design from adaptive 
design to a group sequential design with one 
interim analysis and one final analysis, without a 
sample size re-estimation. 
Section 9.4.2 Objective Response Rate: 
• Revised per revision in the study design from 
adaptive design to a group sequential design with 
one interim analysis and one final analysis, without 
a sample size re-estimation. 
Section 9.4.3 Clinical Benefit Rate: 
• Updated definition of Clinical Benefit Rate to align 
with RECIST 1.1. guidance on Stable Disease. 
Section 9.4.4 Duration of Response: 
• Updated to include censoring rules. 
Section 9.4.6 Subgroup Analyses: 
• Updated based on changes to the stratification 
factors and added analysis for geographic regions. 
Section 9.7 Interim Analysis: 
• Revised to reflect the change in study design. 
There will only be one interim analysis and a final 
analysis of the primary endpoint of overall 
survival, including a futility analysis. The 
previously planned ORR endpoint will remain as a 
secondary endpoint and central radiology review 
will continue until the completion of the study. 
Section 16 References: 
• Updated accordingly based on changes throughout 
the protocol. 
Appendix 4 Abbreviated Presentation of RECIST 
Version 1.1 Guidelines: 

 
 
 
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Document 
Version Date 
Summary of Changes 
• Per FDAs request, removed language referencing 
modifications to RECIST 1.1 to address potential 
temporary treatment effects including tumor 
necrosis, cavitation, flare response and 
pseudoprogression (per Protocol Administrative 
Letter dated 08 October 2019). 
Addressed clerical errors and made minor 
clarifications. 
Version 3.0 
20 April 2020 
Throughout: 
• Addressed clerical errors and made minor 
clarifications. 
• Deletion of reference to region specific approved 
product labels and replaced with broader non-
region specific reference to approved product 
labels. 
• Addition of sitravatinib malate capsule 
formulation. [Note that the free base capsule 
formulation will remain available in the USA; 
patients who start the study on the free base 
capsule formulation will remain on free base 
capsule formulation for the duration of study 
treatment.] 
• Addition of starting dose and de-escalation 
schedule for sitravatinib malate capsule 
formulation daily dose as supported by the data 
from study 516-006. 
Schedule of Assessments (Table 1):  
• Revision of “Long Term Follow Up” row to 
“Follow-Up” to clarify and confirm that the 
assessment is follow-up and an “X” added to the 
Initial Follow-up column. Removal of reference to 
footnote #17 under the Assessment column as the 
reference is captured in the Long Term Follow-Up 
column. 
Section 1.3.3.1 Sitravatinib Pharmacokinetics: 
• Addition of interim results from Study 516-006, a 
healthy volunteer study evaluating the 
bioavailability and PK of sitravatinib free base and 
sitravatinib malate capsule formulations. 
Section 1.3.3.2 Sitravatinib Clinical Safety: 

 
 
 
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• Addition of relevant studies contributing to 
sitravatinib’s clinical safety data and update to the 
safety data per sitravatinib’s current Investigators 
Brochure. 
Section 1.3.3.3 Sitravatinib Clinical Efficacy: 
• Removed outdated information. 
Section 1.3.3.4 Sitravatinib Capsule Formulation 
Study: 
• Addition of interim results from Study 516-006, a 
healthy volunteer study evaluating the 
bioavailability and PK of sitravatinib free base and 
sitravatinib malate capsule formulations. 
• Removal of excess information from the MRTX-
500 PK sub-study in order to focus on pertinent 
information and streamline the document. 
Section 1.4.3 Nivolumab Clinical Data: 
• OPDIVO information updated based on USPI 
dated March 2020. 
Section 1.5.2 Evaluation of Potential for Increased 
Toxicity with Combination Use of Sitravatinib and 
Nivolumab: 
• Information updated based on OPDIVO USPI 
dated March 2020 and sitravatinib Investigator’s 
Brochure v6.0, dated 01 November 2019. 
Section 1.6.3 Docetaxel Clinical Data: 
• TAXOTERE information updated based on 
TAXOTERE USPI dated December 2019. 
Section 1.7 Study Rationale: 
• Addition of starting dose information for 
sitravatinib malate capsule formulation. 
Section 3 Study Design: 
• Clarification around allowable window for 
nivolumab infusion. 
• Clarification regarding availability of sitravatinib 
free base capsule formulation only being available 
in the USA and addition of sitravatinib malate 
capsule formulation daily dose. 
• Clarification that patients in the USA who initiate 
study treatment with sitravatinib free base capsule 

 
 
 
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formulation will continue the study with the free 
base capsule formulation until study treatment 
discontinuation. 
• Addition of language defining End of Trial. 
Section 4.1 Inclusion Criteria: 
• Inclusion Criterion #11d: Clarification of ALT and 
AST parameters for patients with documented liver 
metastases 
Section 4.3 Live Style Guidelines: 
• Addition of language requiring at least 2 
acceptable methods of birth control and 
clarification on what constitutes acceptable 
methods of birth control considered highly 
effective. 
Section 5 Study Treatments: 
• Addition of language to clarify investigational 
products versus non-investigational products used 
in this study. 
Section 5.1 Sitravatinib: 
• Introduction of the sitravatinib malate capsule 
formulation product. The malate formulation is 
more stable and has properties that are improved 
for future commercialization. 
Section 5.1.3 Sitravatinib Administration: 
• Addition of sitravatinib malate capsule formulation 
daily dose as supported by the data from study 
516-006. 
Section 5.1.4 Sitravatinib Dose Modification or 
Discontinuation: 
• Addition of sitravatinib malate capsule formulation 
dose modification guidelines as supported by the 
data from study 516-006 and in alignment with the 
dose modification guidelines of the sitravatinib 
free base formulation. 
Section 5.6.1 Concomitant Medication(s): 
• Addition of information regarding P-gp and BCRP 
transporters and CYP3A4 substrates with 
sitravatinib to clarify information provided in 
Appendix 2. 

 
 
 
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• Addition of information regarding strong and 
moderate CYP3A4 inhibitors with docetaxel to 
clarify information provided in Appendix 3. 
Section 10.5 Confidentiality and Privacy Protection: 
• Addition of data privacy protection language for 
compliance with European Union General Data 
Protection Regulation (GDPR) data privacy 
regulations. 
Appendix 2 Medication or Substances to be Avoided or 
Used with Caution During Treatment with Sitravatinib: 
• Addition of a more complete list of examples of 
drugs that have a known or conditional risk of 
Torsades de Pointes. 
• Removed information regarding sensitive 
substrates and substrates with narrow therapeutic 
index for CYP2B6, CYP2C8, and CYP2D6 based 
on further evaluation of sitravatinib’s potential to 
inhibit these enzymes. 
Appendix 3 Examples of Strong and Moderate 
CYP3A4 Inhibitors: 
• Changed title to clarify that the lists in this section 
are examples and not a complete list. 
• Removed bold and italic font since medications 
listed are examples only; information regarding 
avoidance and use with caution of medications that 
are strong or moderate CYP3A4 inhibitors is 
provided in Section 5.6.1 Concomitant 
Medication(s). 
Appendix 5 COVID-19 Pandemic Changes to Study 
Conduct: 
• Addition of appendix allowing temporary changes 
to specific protocol assessments and procedures 
that are allowable only during the COVID-19 
pandemic. 
Version: 3.1(Canada) 
3.2 (Spain) 
3.3 (France) 
3.4 (Italy) 
3.5 (Belgium) 
3.6 (Germany) 
17 June 2020 
07 July 2020 
20 July 2020 
20 August 2020 
12 August 2020 
23 September 2020 
Country specific protocol amendments submitted to 
individual countries during the Clinical Trial 
Application process.  

 
 
 
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3.7 (United Kingdom) 
22 September 2020 
Version 4.0 
06 January 2021 
This protocol amendment is intended to harmonize the 
country specific amendments where possible. 
Throughout: 
• Link to reference added for SmPC wherever the 
Opdivo and Taxotere approved product label is 
referenced. 
Section 3 Study Design 
• Removed “receipt of maximum number of cycles 
per local standard of care” as reason for 
discontinuation of administering treatment to 
patients. 
Section 4.1 Inclusion Criteria 
• Inclusion criterion #1: Added language to clarify 
that patients, who are eligible for concurrent 
radiochemotherapy are excluded 
• Inclusion criterion#2: clarified that for patients 
who received platinum-based adjuvant, 
neoadjuvant, or definitive chemoradiation therapy, 
given for locally advanced disease followed by 
recurrent or metastatic disease within 6 months of 
completing chemotherapy may be considered 
treatment in the advanced disease setting. 
• Inclusion criterion #11e: clarified the required 
serum bilirubin value 
Section 4.2 Exclusion Criteria 
• Exclusion criterion #6: Prior Therapies: revised to 
allow for prior anti-CTLA-4 administered in 
combination with an anti-PD-(L)1. 
• Exclusion criterion #24: revised to exclude patients 
who are unable to give consent 
Section 4.3 Life Style Guidelines 
• Added language to clarify that men with WOCBP 
partners must also use highly effective methods of 
contraception 
Section 5.6.1 Concomitant Medication(s) 
• Revised guidance for Gastric Acid Medications 
with Sitravatinib. 
Schedule of Assessments (Table 1): 

 
 
 
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• Added pregnancy testing for women of 
childbearing potential, at the beginning of every 
cycle and maintained pregnancy testing for at least 
1 month after the last dose of sitravatinib, 5 months 
after the last dose of nivolumab and for 1 month 
after the last dose of docetaxel. 
• Revised footnote #6, #15 and #16 to reflect the 
additional pregnancy testing 
• Revised footnote #15 to clarify the occurrence of 
the EOT visit 
Section 7.3.3 Laboratory Safety Assessments 
• Added language regarding the additional 
pregnancy testing 
Section 14.1 End of Trial in a European Union 
Member State 
• Revised language to clarify that End of Trial is 
defined as the last visit of the last patient, or at a 
later time point as defined in the protocol, in a 
Member State of the European Union. 
For sites in Germany and Switzerland the following 
information was modified: 
Schedule of Assessments (Table 1): 
• Added HIV, Hepatitis B, and Hepatitis C testing at 
screening. 
Section 4.2 Exclusion Criteria 
• Revised Exclusion Criterion 9b to exclude patients 
testing positive for HIV infection at screening. 
• Revised Exclusion Criterion 13 to exclude patients 
testing positive for hepatitis B or hepatitis C 
infection at screening. 
Section 7.3.3 Laboratory Safety Assessments 
• Added details for hepatitis B, hepatitis C, and HIV 
infection testing. 
For sites in Germany only, the following information 
was modified: 
Schedule of Assessments (Table 1): 
• Removed the performance of MUGA scan at 
screening and on study 

 
 
 
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Section 7.3.5 Echocardiogram or Multigated 
Acquisition Scan 
• Deleted the option of MUGA scans and revised the 
section heading accordingly.  
Version 5.0 
07 October 2021 
Cover Page: 
• Sponsor Address updated 
Schedule of Assessments (Table 1): 
• Footnote 11 updated to reference (Table 8) 
Throughout: 
Sections 1.4.3, 1.4.3.4, 1.5.2, 1.6.3, 1.6.3.2, 5.2, 5.3, 
and 5.4 were updated to reflect Investigators Brochure 
v8.1 dated August 2021, OPDIVO USPI dated 
September 2021, and Docetaxel USPI dated May 2021, 
as applicable 
Section 1.4.3.3 Nivolumab Adverse Reactions in 
Clinical Trials 
• Urinary tract infection added to the list of most 
common adverse reactions (≥ 20%) as of 
September 2021 
Section 1.4.3.5 Safety Reported Non-Small Cell Lung 
Cancer Trials Clinical Trials 
• The description of the patient population in the 
Checkmate-017 and Checkmate-057 trials was 
updated 
Section 4.2 Exclusion Criterion 
• Exclusion criterion 11 (need for treatment with a 
protocol pump inhibitor: antacids and/or H2 
antagonists permitted) deleted.  The numbering of 
the list of exclusion criteria was maintained 
Section 5.6.1 Concomitant Medications (s) 
• Language describing use of Gastric Acid 
Medications with Sitravatinib was deleted 
• Language describing the use of P-gp Inhibitors and 
Inducers with Sitravatinib was added 
Section 7.1 Documentation of Disease Progression on 
or After Prior Chemotherapy and Checkpoint Inhibitor 
Therapy 

 
 
 
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Document 
Version Date 
Summary of Changes 
• Clarified that radiology reports are appended to the 
CRF in countries where permitted by applicable 
laws and regulations 
Section 7.4.3.2 Markers in Tumor Tissue 
• Clarified that tumor burden reports are appended to 
the CRF in countries where permitted by 
applicable laws and regulations 
Section 9.4.1 Overall Survival 
• Language clarifying the analysis of overall survival 
was added 
Section 9.4.2 Objective Response Rate 
• Language clarifying the analysis of the objective 
response rate was added 
Section 9.4.4 Duration of Response 
Language regarding censoring of subjects in the 
analysis of duration of response was deleted 
Section 9.4.5 Progression Free Survival 
Language regarding censoring of subjects in the 
analysis of duration of response was deleted 
• The Language was updated for clarification 
Section 10.5 Confidentiality and Privacy Protection 
• Language justifying the collection of race and 
ethnicity data to support population PK analysis  
was added 
 

 
 
 
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STUDY SUMMARY 
Title: 
A Randomized Phase 3 Study of Sitravatinib in Combination with 
Nivolumab Versus Docetaxel in Patients with Advanced Non-Squamous 
Non-Small Cell Lung Cancer with Disease Progression On or After 
Platinum-Based Chemotherapy and Checkpoint Inhibitor Therapy  
(SAPPHIRE: SitrAvatinib Plus Nivolumab in Patients Refractory to 
CHemo and Checkpoint InhibitoR ThErapy) 
Rationale: 
Combining an immunotherapeutic Programmed Cell Death 1 checkpoint 
inhibitor with an agent that has both immune modulatory and antitumor 
properties could enhance the antitumor efficacy observed with either agent 
alone. 
The use of tyrosine kinase inhibitors (TKIs) to treat cancer is well 
established based on robust clinical efficacy achieved with well-tolerated 
inhibitors directed toward oncogenic tyrosine kinases. In addition, selected 
TKIs have been shown to modulate the immunogenic status of tumors, 
improve tumor perfusion by reducing intratumoral pressure and modulate 
subsets of immune cells, thereby increasing the frequency and function of 
effector immune elements while decreasing the number and function of 
immune suppressor cells. Taken together, these effects on the tumor 
microenvironment (TME) may lead to improved efficacy when TKIs are 
combined with checkpoint inhibitors. The TAM (Tyro3, Axl and MERTK) 
receptor tyrosine kinases (RTKs) are expressed by select innate immune 
cell subpopulations including macrophages and dendritic cells. The TAM 
receptors cooperate to create and maintain an immunosuppressive TME. 
MERTK suppresses the M1 macrophage pro-inflammatory cytokine 
response involving IL-12, IL-6 and TNF and enhances M2 macrophage 
anti-inflammatory cytokine production involving IL-10, IL-4, TGFβ and 
hepatocyte growth factor (HGF). In addition, M2 macrophages express 
checkpoint ligands such as PD-L1, PD-L2, B7- H1 and B7-H2 that further 
inhibit T effector cell function. Given that anti-tumor host defense is 
usually mediated by cytotoxic T lymphocytes whose activation and 
stimulation is supported by Th1 type cytokines, the inhibition of Axl and 
MERTK are predicted to enhance an anti-tumor immune response. 
Furthermore, both Axl and MERTK are expressed by natural killer (NK) 
cells and negatively regulate NK cell activity in the TME as part of a 
feedback regulatory mechanism resulting in decreased NK cell anti-tumor 
activity and enhanced tumor progression and metastasis. Given the 
immunosuppressive function of TAM RTKs in the TME, inhibition of Axl 

 
 
 
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and MERTK may complement PD-1/PD-L1 checkpoint inhibition to 
unleash the host anti-cancer immune response. 
The MET (Mesenchymal-Epithelial Transition) RTK is implicated in 
modification of tumor immune responses based on its role in mediating an 
immunosuppressive TME as well as its role in regulating antigen 
presenting cell (APC) function. MET is expressed by immature CD14-
positive monocytes and can induce an immunosuppressive phenotype 
when its ligand, HGF, is secreted by tumor stroma and mesenchymal stem 
cells (MSCs). Depletion of CD14-positive monocytes or neutralization of 
HGF secretion by MSCs reverses the suppression of T effector 
proliferation and triggers a shift back toward a Th1 activated T cell 
phenotype. MSCs are also implicated in expansion of immunosuppressive 
myeloid-derived suppressor cells (MDSCs), which are also dependent on 
the secretion of HGF. APCs (ie, dendritic cells) also express MET and the 
activation of MET by HGF results in suppression of APC function 
including both antigen presenting capacity and antigen-dependent T cell 
responses. Therefore, inhibition of MET may enhance the antitumor 
response by restoring APC function and reducing or eliminating MDSCs 
within the TME. 
Inhibition of the VEGF receptor family and KIT may further enhance 
antitumor immunoreactivity by depletion of immunosuppressive cellular 
subsets from the TME including T regulatory cells (Tregs) and MDSCs. 
Tregs express VEGFR2 and the inhibition of VEGFR2 utilizing a specific 
VEGFR2 antibody antagonist or VEGFA neutralizing antibody (but not a 
VEGFR1 antagonist) inhibited Treg cell proliferation in vitro and in 
tumor-bearing mice and patient peripheral blood. MDSCs notably express 
both KIT and VEGFR1 and the inhibition of these RTKs using 
pharmacologic or genetic approaches resulted in the inhibition of MDSC 
viability in vitro and depletion of this cell population in mouse tumor 
models. 
Sitravatinib is a spectrum-selective RTK inhibitor that inhibits several 
closely related RTKs including the TAM family (Tyro3/Axl/MERTK), 
VEGFR2, KIT, and MET. Based on the role of these receptors in key 
immune cell types, sitravatinib and checkpoint inhibitor therapy (CIT) are 
predicted to have complementary effects in triggering a tumor-directed 
immune response. 
Nivolumab is a fully human immunoglobulin G4 (IgG4) monoclonal 
antibody that binds to the PD-1 receptor and selectively blocks its 
interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated 
inhibition of the immune response, including the anti-tumor immune 

 
 
 
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response. Nivolumab has been approved for the treatment of patients with 
advanced or metastatic NSCLC who have disease progression during or 
following platinum-containing chemotherapy. 
While anti-PD-1/PD-L1 antibodies, including nivolumab, produce durable 
responses in some patients with NSCLC and other cancers, the majority of 
patients do not respond to single agent CIT or eventually progress. The 
mechanism of action of PD-1 inhibitors has been an area of intense 
research and multiple factors have emerged that correlate with resistance, 
including both factors intrinsic to tumor cells as well as an 
immunosuppressive tumor microenvironment. 
Combining an immunotherapeutic PD-1/PD-L1 checkpoint inhibitor with 
an agent that has both immune modulatory and antitumor properties could 
enhance the antitumor efficacy observed with either agent alone. 
Docetaxel is approved as a single-agent chemotherapy option for the 
treatment of patients with advanced NSCLC previously treated with 
platinum-based chemotherapy. Median overall survival reported in 
randomized clinical trials using docetaxel in the second-line treatment 
setting has varied between approximately 5.7 and 9.5 months. Median 
overall survival with docetaxel in the third-line treatment setting, post-CIT, 
is not expected to be significantly different than in the second-line setting 
with median overall survival of approximately 6.8 to 9.0 months reported 
in retrospective analyses. 
This study will compare the efficacy of sitravatinib in combination with 
nivolumab versus docetaxel in patients with advanced non-squamous 
NSCLC who have previously experienced radiographic disease 
progression on or after platinum-based chemotherapy and checkpoint 
inhibitor therapy. 
Target 
Population: 
Patients with non-squamous NSCLC with no known oncogenic EGFR, 
ALK, or ROS-1 genomic tumor aberrations, who have radiographic disease 
progression on or after CIT either administered in combination with 
platinum-based chemotherapy or following platinum-based chemotherapy 
in the advanced disease setting. 
Number in 
Trial: 
Approximately 532 patients will be randomized into the study.  
Primary 
Objective: 
To compare Overall Survival (OS) in patients with non-squamous NSCLC 
who have experienced disease progression on or after platinum-based 

 
 
 
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chemotherapy and CIT, treated with sitravatinib and nivolumab versus 
docetaxel. 
Secondary 
Objectives: 
• To evaluate the safety of sitravatinib in combination with nivolumab in the 
study population. 
• To evaluate the relative tolerability of sitravatinib and nivolumab versus 
docetaxel. 
• To evaluate secondary efficacy endpoints in the study population. 
• To evaluate the pharmacokinetics (PK) of sitravatinib (MGCD516) 
administered in combination with nivolumab. 
• To evaluate health-related quality of life and lung cancer-specific symptoms 
in the study population. 
Exploratory 
Objective: 
• To assess correlations between baseline tumor immune biomarkers and gene 
mutations and treatment-related outcomes. 
• To evaluate efficacy endpoints using exploratory disease response criteria. 
• To characterize the immunogenicity of nivolumab in combination with 
sitravatinib. 
Primary 
Endpoint: 
Overall Survival (OS) 
Secondary 
Endpoints: 
• Safety characterized by type, incidence, severity, timing, seriousness and 
relationship to study treatment of adverse events, laboratory abnormalities, 
and number of patients discontinuing study treatment due to an adverse event. 
• Secondary efficacy endpoints: 
− Objective Response Rate (ORR) as defined by Response 
Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). 
− Duration of Response (DOR); 
− Clinical Benefit Rate (CBR); 
− Progression-Free Survival (PFS); and 
− 1-Year Survival Rate. 
• Blood plasma concentrations of MGCD516. 
• Patient reported outcome (PROs): 
− Lung Cancer Symptom Scale (LCSS); and 
− European Quality of Life Five Dimensions Questionnaire (EQ-
5D-5L). 
Exploratory 
Endpoints: 
• Tumor PD-L1 expression. 
Tumor gene alterations. 
• Circulating tumor deoxyribonucleic acid (ctDNA). 

 
 
 
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• Efficacy parameters as evaluated per iRECIST. 
• Nivolumab anti-drug antibody (ADA) 
Study Design: 
Study 516-005 is an open-label, randomized (1:1), multicenter, Phase 3 
clinical trial evaluating the efficacy and safety of nivolumab in 
combination with the investigational agent sitravatinib compared to 
docetaxel in patients with advanced non-squamous NSCLC who have 
previously experienced radiographic disease progression on or after 
treatment with CIT either administered in combination with platinum-
based chemotherapy or following platinum-based chemotherapy. The 
primary objective is to compare OS in the two treatment arms. Secondary 
objectives include evaluation of safety and tolerability, secondary efficacy 
endpoints, PK of sitravatinib, and patient reported outcomes. Correlative 
science endpoints include tumor PD-L1 expression, tumor gene mutations, 
nivolumab ADA and ctDNA. The Schedule of Assessments to be 
performed in the study is presented in Table 1. 
Patient eligibility for study enrollment based on radiographic disease 
progression on or after treatment with CIT and platinum-based 
chemotherapy will be evaluated by the Investigator. Data entered into the 
case report form (CRF) are to include the date of at least one radiographic 
evaluation prior to the occurrence of disease progression on most recent 
CIT treatment and the date the radiographic evaluation demonstrating 
disease progression, as well as specifics about organ systems (eg, lung, 
liver, lymph node, bone and/or brain) having tumors that increase in size or 
are new. 
Patient randomization will be stratified based on: 
1. Prior treatment regimens in the advanced setting (1 versus 2); 
2. ECOG Performance Status at baseline (0 versus 1); and 
3. Presence of brain metastasis at baseline (presence versus absence). 
Patients randomized to the experimental arm will receive treatment with 
nivolumab in combination with sitravatinib, delivered in 28-day cycles. 
Nivolumab will be administered as an infusion over approximately 
30 minutes at 240 mg every 2 weeks or 480 mg every 4 weeks, at the 
discretion of the Investigator. Patients that are randomized under this 
protocol version will receive sitravatinib malate capsule formulation 
administered orally at starting dose of 100 mg once daily (QD). Patients 
enrolled in the USA who began treatment with the sitravatinib free base 
capsule formulation will remain on the free base capsule formulation 

 
 
 
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throughout the duration of the study; the starting dose of sitravatinib free 
base capsule formulation is 120 mg QD. 
Patients randomized to the comparator arm will receive treatment with 
docetaxel, delivered in 21-day cycles. Docetaxel will be administered by 
intravenous infusion at 75 mg/m2 over 1 hour or according to institutional 
practices, every 3 weeks. Premedication with dexamethasone (or 
institutional equivalent) will be required in accordance with regional 
standards. 
Disease assessments and patient-reported outcomes questionnaires must be 
performed as scheduled according to the calendar to prevent the 
introduction of bias based on toxicity into the assessment of efficacy. 
Disease response and progression per RECIST 1.1 as documented by the 
Investigator in the CRF will be the basis for patient management and 
supportive statistical analyses of radiology-based study endpoints. 
Central radiology review for disease response and progression will be 
conducted. Timely and complete disease assessments and transfer of 
radiographic documentation to the Central Radiology Laboratory is critical 
to the integrity of this clinical trial. 
Patients will receive study treatment as assigned at randomization until 
disease progression, unacceptable adverse events, investigator decision, 
patient refusal or death. Patients experiencing clinical benefit in the 
judgment of the Investigator may continue study treatment beyond disease 
progression as defined by RECIST 1.1 if the progression is not rapid, 
symptomatic, or requiring urgent medical intervention. Patients 
considering continuation of study treatment beyond RECIST 1.1 defined 
disease progression must be provided with and sign an informed consent 
detailing any available therapies and potential clinical benefit that the 
patient may be foregoing by continuing study treatment. Patients 
remaining on study treatment beyond RECIST 1.1. defined progression 
will continue to undergo disease assessments until study treatment is 
discontinued. Post- treatment disease assessment will continue until 
objective disease progression and PRO assessments will continue until 
start of subsequent anti-cancer therapy. No crossover to the alternative 
treatment assignment is provided in this study. 
A sample size of approximately 532 patients is planned for this study; a 
total of 372 OS events will be required to detect the hypothesized HR. The 
study will employ a group sequential design with one planned interim 
analysis and a final analysis for the primary endpoint of OS. 
 

 
 
 
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Table 1: 
Schedule of Assessments 
The Schedule of Assessments provides an overview of the protocol visits and procedures. Refer to Sections 6 and 7 for detailed 
information on each assessment. Additional, unplanned assessments should be performed as clinically indicated, including for the 
purpose of fully evaluating adverse events. 
Assessments 
Screen/ 
Baseline 
Nivo/Sitra Arm Cycles 1 and 2 
Doce Arm Cycles 1, 2 and 3 
Nivo/Sitra Arm ≥Cycle 3 
Doce Arm ≥Cycle 4 
Post Treatment 
Within 28 
days of 
randomization 
Day 1 
(± 2 days 
beyond C1) 
N/S Arm Day 15 
Doce Arm Day 8 
(± 2 days) 
Day 1 
(± 2 days) 
N/S Arm Day 15 
(± 2 days) 
Necessary only if 
Nivolumab Q2W 
End of Treatment1 
(28-35 days after 
last dose) 
Initial 
Follow-up2 
Long Term 
Follow-up3 
Study Participation Informed 
Consent4 
Before study 
specific 
assessments 
 
 
 
 
 
 
 
Randomization4  
X 
 
 
 
 
 
 
 
Medical History, Disease 
History, Prior Therapy 
X 
 
 
 
 
 
 
 
Investigator Evaluation of 
Radiographic Progression on 
most recent CIT regimen 
X 
 
 
 
 
 
 
 
Tumor Tissue Collection for 
PD-L1 Expression and 
Tumor Gene Alterations5 
X 
 
 
 
 
 
 
 
ctDNA Blood Sample6 
X 
 
 
 
 
 
 
 
ECOG Performance Status 
X 
Cycle 3 only 
 
Cycle 3 only 
 
X 
 
 
Physical Exam7 
X 
 
 
 
 
X 
 
 
Abbreviated Physical Exam7 
 
X 
X 
X 
X 
 
 
 

 
 
 
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Table 1: 
Schedule of Assessments (Continued) 
Assessments 
Screen/ 
Baseline 
Nivo/Sitra Arm Cycles 1 and 2 
Doce Arm Cycles 1, 2 and 3 
Nivo/Sitra Arm ≥Cycle 3 
Doce Arm ≥Cycle 4 
Post Treatment 
Within 28 
days of 
randomization 
Day 1 
(± 2 days 
beyond C1) 
N/S Arm Day 15 
Doce Arm Day 8 
(± 2 days) 
Day 1 
(± 2 days) 
N/S Arm Day 15 
(± 2 days) 
Necessary only if 
Nivolumab Q2W 
End of Treatment1 
(28-35 days after 
last dose) 
Initial 
Follow-up2 
Long Term 
Follow-up3 
Vital Signs8 
X 
X 
X 
X 
X 
X 
 
 
Pregnancy Test9 
X 
X 
 
X 
 
X 
X 
 
Hematology10,11 
X 
X 
X 
X 
 
X 
 
 
Urinalysis10,11 
X 
As clinically indicated 
 
 
Serum Chemistry10,11 
X 
X 
X 
X 
 
X 
 
 
Thyroid Function Test10,11 
 
X 
 
X 
 
X 
 
 
HIV, HBV, HCV serology12 
X 
 
 
 
 
 
 
 
Blood for Sitravatinib PK13 
 
See Table 2 
 
 
 
Blood for Nivolumab 
ADA14 
 
X (Cycle 1 Day 1) 
Coincide with disease evaluations and continue at the same intervals 
until either at least 80 days after last dose of nivolumab or start of 
subsequent therapy, whichever is sooner 
 
Single 12-Lead ECG15 
X 
As clinically indicated 
X 
 
 
Triplicate 12-Lead ECG15 
 
See Table 2 
 
 
 
ECHO (preferred) or 
MUGA16 
X 
(-35 Day 
Window) 
Cycle 3 Day 1 only (± 7 days) 
As clinically indicated after C3 
X 
 
 
Disease Evaluation17 
X 
Every 8 weeks (± 10 days) for ~12 months 
and then every 16 weeks until disease progression or start of subsequent therapy, whichever is sooner 
 

 
 
 
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Table 1: 
Schedule of Assessments (Continued) 
Assessments 
Screen/ 
Baseline 
Nivo/Sitra Arm Cycles 1 and 2 
Doce Arm Cycles 1, 2 and 3 
Nivo/Sitra Arm ≥Cycle 3 
Doce Arm ≥Cycle 4 
Post Treatment 
Within 28 
days of 
randomization 
Day 1 
(± 2 days 
beyond C1) 
N/S Arm Day 15 
Doce Arm Day 8 
(± 2 days) 
Day 1 
(± 2 days) 
N/S Arm Day 15 
(± 2 days) 
Necessary only if 
Nivolumab Q2W 
End of Treatment1 
(28-35 days after 
last dose) 
Initial 
Follow-up2 
Long Term 
Follow-up3 
PRO Questionnaires18 
 
X (Cycle 1 
Day 1) 
Coincide with disease evaluations and continue at the same intervals until start of subsequent 
therapy 
 
Sitravatinib Dispensing 
and/or Reconciliation 
 
X 
 
X 
 
Reconciliation 
 
 
Nivolumab Administration 
 
Throughout as directed in product label and protocol 
 
 
 
Docetaxel Administration 
 
Throughout as directed in product label and protocol, 
including standard-of-care pre-medication 
 
 
 
Adverse Events19 and 
Concomitant Medications 
SAEs only 
Throughout 
 
Follow-Up 
 
 
X 
X 
1 End of Treatment: Visit occurs prior to the beginning of subsequent anticancer therapy or 28-35 days after last dose of study treatment (sitravatinib, nivolumab 
or docetaxel), whichever is earlier. Assessments completed in the previous 4 weeks do not need to be repeated with the exception of assessment of AEs, 
hematology and chemistry. 
2 Initial Follow-up: If study treatment is discontinued prior to disease progression, disease assessments should continue every 8 weeks ± 10 days (or 16 weeks ± 
10 days if on treatment more than 1 year) until either progression of disease or start of subsequent therapy, whichever occurs earlier. PRO assessments should 
continue every 8 weeks ± 10 days (or 16 weeks ± 10 days if on treatment more than 1 year) until start of subsequent therapy. For patients randomized to 
sitravatinib/nivolumab, blood sampling for ADA assessment should be collected either at least 80 days after the last dose of nivolumab or immediately before 
start of subsequent therapy, whichever occurs earlier. Survival status and subsequent therapies will be collected. Women of childbearing potential will complete 
pregnancy testing at a monthly frequency, which will be maintained for at least 1 month after the last dose of sitravatinib, 5 months after the last dose of 
nivolumab and for 1 month after the last dose of docetaxel. 
3 Follow-up: Survival status and subsequent therapies will be collected during long term follow-up every 2 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. 

 
 
 
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4 Study Participation Informed Consent: May be performed more than 28 days prior to randomization and must be completed prior to initiation of any study 
specific assessments. Treatment should start within 3 business days of randomization. 
5 Tumor Testing for PD-L1 Expression and Tumor Gene Alterations: Submission of pre-study tumor samples is highly desirable but not mandatory for study 
participation. Fresh, pre-treatment tumor tissue biopsies are preferred, when possible. Archival tumor tissue is allowed. Biopsy may precede informed consent 
if performed as Standard of Care (SOC) or to assess eligibility for a different clinical trial. Prior PD-L1 test results including % tumor and/or immune cell 
staining and, when available, previously reported tumor gene mutation profile and total mutation burden estimates from next generation sequencing data will be 
collected. 
6 Blood samples for ctDNA analysis is highly desirable but not mandatory for study participation: Blood will be collected in two 10 mL Streck brand Cell-Free 
DNA Blood Collection tubes allowing shipping and stability at ambient temperatures. 
7 Physical Examinations: A complete physical examination required at Screening and End of Treatment only. Height will be recorded at screening only. All other 
evaluations will be symptom-directed, abbreviated evaluations. 
8 Vital Signs: Weight, temperature, blood pressure, and pulse rate to be assessed prior to dosing as indicated. 
9 Pregnancy 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. Pregnancy testing will also be performed at the beginning of every treatment cycle and the same frequency (approximately monthly) will be 
maintained for at least 1 month after the last dose of sitravatinib, 5 months after the last dose of nivolumab and for 1 month after the last dose of docetaxel. 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. 
10 Selected Day 1 Assessments: Repeat assessment not required if screening assessment performed within 7 days before the first dose. Thyroid function test can 
also be performed within 7 days before first dose. 
11 Safety Laboratory Assessments: Hematology, chemistry, thyroid function and urinalysis evaluations (see Table 8) will be performed by local laboratories. Lab 
assessments may be performed up to 3 days prior to clinic visits. 
12 Sites in Germany and Switzerland only: Patients must be tested for HIV, hepatitis B virus (HBV) and hepatitis C virus (HCV) infection (by local laboratory) at 
screening. Patients testing positive for HIV infection are excluded from study. Patients with active hepatitis B (acute or chronic) defined as a positive HBsAg 
test result are excluded from study; patients with past or resolved HBV infection (defined as HBsAg negative and HBcAb positive) are eligible only if their 
HBV DNA test is negative. Patients with positive hepatitis C antibody test during screening are excluded from study unless HCV RNA is negative. 
13 Pharmacokinetic Samples: In patients randomized to sitravatinib/nivolumab, blood samples to be collected following ECGs and assessment of vital signs as 
scheduled in Table 2. In addition, unscheduled PK blood samples should be drawn before a daily sitravatinib dose (trough sample) in association with two 
kinds of safety events: 1) as soon as possible after a Serious Adverse Event (SAE), and 2) at a clinic visit at least one week following a dose modification of 
sitravatinib. 
14 Nivolumab Anti-Drug Antibody (ADA) Samples: In patients randomized to sitravatinib/nivolumab, blood sampling for ADA assessment will occur on C1D1 
prior to the first dose of nivolumab on study, during study treatment to coincide with disease assessments, and continue at the same intervals until at least 80 
days after last dose of nivolumab or start of subsequent therapy, whichever is sooner. 

 
 
 
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15 12-Lead ECGs: In patients randomized to sitravatinib/nivolumab, triplicate ECGs will accompany PK sampling as described in Table 2. In addition, ECGs are 
to be performed as clinically indicated. Assessments will include an evaluation of heart rate, QT, and QTc intervals. RR interval should be recorded during 
each ECG assessment in order to calculate QTcF. 
16 MUGA option is not available for sites in Germany. 
17 Disease Evaluations: To be performed at screening (28-day window allowed) and every 8 weeks from Randomization (± 10-day window for all other 
assessments except screening) until week 49 (~12 months) and then every 16 weeks until objective disease progression or start of subsequent therapy. All on-
study disease evaluations should be based on a calendar beginning from the date of randomization. At screening/baseline, assessments are to include Computed 
Tomography Scan (CT) with contrast of the chest, CT or Magnetic Resonance Imaging (MRI) of the abdomen and pelvis, as well as brain MRI with and 
without gadolinium or CT with contrast, a whole-body bone scan (or Positron Emission Tomography (PET) or PET/CT if local standard for clinical trials) and 
evaluation of any superficial lesions. Subsequent disease assessments should include CT of the chest, CT or MRI of the abdomen and all sites of disease 
identified at baseline by the investigator or central review laboratory or, suspected to have developed; bone scans may be performed half as often (every 16 
weeks) as other radiology evaluations and, in patients having lesions at baseline, should be performed during assessment for confirmation of disease response. 
Materials to be forwarded for independent central radiology review will include all imaging studies performed at screening/baseline and on-study until notified 
otherwise by the Sponsor. More detailed guidance on exceptional circumstances is provided in Section 8.2 and Appendix 4. 
18 Patient Reported Outcomes: EQ-5D-5L should always be completed before LCSS and both should be completed prior to other assessments performed during a 
visit. PRO assessments are to be completed on C1D1 prior to any assessments, then coincide with disease evaluations and continue at the same intervals until 
start of subsequent therapy; if the disease evaluation does not coincide with a clinic visit, the PRO should be completed at the clinic visit closest to the disease 
evaluation. 
19 Adverse Events: Serious Adverse Events (SAEs) will be reported from the time of informed consent until at least 28 days after the last administration of a study 
treatment. Adverse events will be reported from the first day of study treatment until at least 28 days after last dose of study drug, and until resolution or 
stabilization of acute adverse events and/or ongoing SAEs. The reporting period for serious and non-serious immune-related AEs (irAEs) will continue until at 
least 100 days after the last administration of nivolumab or until subsequent immunotherapy is administered, whichever is earlier. 
 
 

 
 
 
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Table 2: 
Schedule of PK Sample Collection for Sitravatinib and Triplicate ECG Assessments 
Screen/ 
Baseline 
Cycle 1 Day 1 
Cycle 1 Day 15 
(± 2 days) 
Cycle 2, 3, 5 
Day 1 only 
(± 2 days) 
Collection Time and 
Allowable Window 
Within 28 
days of 
randomization 
Pre-dose 
(-0.5-0 hour) 
30 min 
(± 10 min) 
5 hours1 
(± 2 hours) 
Pre-dose 
(-0.5-0 hour) 
5 hours 
(± 2 hours) 
Pre-dose 
(-0.5-0 hour) 
PK Sample2,3 
 
X 
X 
X 
X 
X 
X 
Triplicate ECG1 
 
X 
(-1 hour) 
X 
(-0.5 hour) 
 
X 
X 
X 
X 
1 ECGs should be taken in triplicate, each reading approximately 2 minutes apart. On Cycle 1 Day 1 only, two sets of triplicate ECGs should be done within 1 
hour prior to dosing (eg, at 30-minute intervals prior to dosing) to firmly establish the baseline for the patient. One set of triplicate ECGs is required at all other 
timepoints. In general, ECGs should be performed prior to the respective PK blood collection. Examples of the schedule are presented below: 
• 
Example for Cycle 1 Day 1 pre-dose ECGs/PK: ~-1.0 hr (Triplicate ECGs); ~-30 mins (Triplicate ECGs); ~-15 mins (Vitals/PK) 
• 
Example for all other pre-dose ECG/PK assessments: ~-30 mins (Triplicate ECGs); ~-15 mins (Vitals/PK) 
2 Scheduled vital signs and triplicate ECGs precede PK sample collection. Sitravatinib dosing should precede nivolumab infusion. Nivolumab infusion can be 
administered any time after oral dose of sitravatinib is administered, except on C1D1 where the 30 min post sitravatinib dose PK sample has to be collected 
before the nivolumab infusion. 
3 In addition to the scheduled samples, an unscheduled PK blood sample should be drawn before a daily sitravatinib dose (trough sample) as soon as possible 
after a Serious Adverse Event (SAE), and at a clinic visit at least one week following a dose modification of sitravatinib. 
 

 
 
 
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TABLE OF CONTENTS 
DOCUMENT HISTORY.................................................................................................................2 
STUDY SUMMARY.....................................................................................................................18 
LIST OF ABBREVIATIONS ........................................................................................................37 
1. 
INTRODUCTION AND RATIONALE .....................................................................41 
1.1. 
Disease and Therapeutic Strategy ...............................................................................41 
1.1.1. 
Non-Small Cell Lung Cancer .....................................................................................41 
1.1.2. 
First-Line Chemotherapy for Non-Small Cell Lung Cancer ......................................41 
1.1.3. 
Second- and Third-Line Chemotherapy for Non-Small Cell Lung Cancer ................41 
1.1.4. 
Checkpoint Pathway ...................................................................................................43 
1.1.5. 
Checkpoint Inhibitor Therapy in Non-Small Cell Lung Cancer ................................43 
1.2. 
Overall Rationale for the Proposed Combination Regimen .......................................45 
1.3. 
Sitravatinib ..................................................................................................................45 
1.3.1. 
Sitravatinib Drug Substance .......................................................................................46 
1.3.2. 
Non-Clinical Data .......................................................................................................46 
1.3.3. 
Sitravatinib Clinical Experience .................................................................................48 
1.3.3.1. 
Sitravatinib Pharmacokinetics ....................................................................................48 
1.3.3.2. 
Sitravatinib Clinical Safety .........................................................................................49 
1.3.3.3. 
Sitravatinib Clinical Efficacy .....................................................................................50 
1.3.3.4. 
Sitravatinib Capsule Formulation Study .....................................................................51 
1.3.3.5. 
Sitravatinib Dosing with Food ....................................................................................52 
1.4. 
Nivolumab ..................................................................................................................52 
1.4.1. 
Nivolumab Drug Substance ........................................................................................53 
1.4.2. 
Nivolumab Non-Clinical Data ....................................................................................53 
1.4.3. 
Nivolumab Clinical Data ............................................................................................53 
1.4.3.1. 
Nivolumab Pharmacokinetics .....................................................................................53 
1.4.3.2. 
Nivolumab Anti-Drug Antibodies ..............................................................................53 
1.4.3.3. 
Nivolumab Adverse Reactions in Clinical Trials .......................................................54 
1.4.3.4. 
Nivolumab Immune-Related Adverse Events ............................................................54 
1.4.3.5. 
Safety Reported in Non-Small Cell Lung Cancer Trials Clinical Trials ....................54 

 
 
 
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1.5. 
Expectations for Safety of the Combination of Sitravatinib and Nivolumab .............55 
1.5.1. 
Potential for Drug-Drug Interactions ..........................................................................55 
1.5.2. 
Evaluation of Potential for Increased Toxicity with Combination Use of 
Sitravatinib and Nivolumab ........................................................................................55 
1.6. 
Docetaxel ....................................................................................................................56 
1.6.1. 
Docetaxel Drug Substance ..........................................................................................57 
1.6.2. 
Docetaxel Non-Clinical Data ......................................................................................57 
1.6.3. 
Docetaxel Clinical Data ..............................................................................................57 
1.6.3.1. 
Docetaxel Pharmacokinetics .......................................................................................57 
1.6.3.2. 
Docetaxel Adverse Reactions Common in Clinical Trials .........................................58 
1.7. 
Study Rationale ...........................................................................................................58 
2. 
STUDY OBJECTIVES ..............................................................................................60 
2.1. 
Objectives ...................................................................................................................60 
2.1.1. 
Primary Objective .......................................................................................................60 
2.1.2. 
Secondary Objectives .................................................................................................60 
2.1.3. 
Exploratory Objective .................................................................................................60 
2.1.4. 
Primary Endpoint ........................................................................................................61 
2.1.5. 
Secondary Endpoints ..................................................................................................61 
2.1.6. 
Exploratory Endpoints ................................................................................................61 
3. 
STUDY DESIGN .......................................................................................................61 
4. 
SUBJECT SELECTION AND ENROLLMENT .......................................................63 
4.1. 
Inclusion Criteria ........................................................................................................63 
4.2. 
Exclusion Criteria .......................................................................................................65 
4.3. 
Life Style Guidelines ..................................................................................................68 
4.4. 
Randomization ............................................................................................................69 
5. 
STUDY TREATMENTS............................................................................................69 
5.1. 
Sitravatinib ..................................................................................................................70 
5.1.1. 
Sitravatinib Formulation, Packaging and Storage ......................................................70 
5.1.2. 
Sitravatinib Preparation, Dispensing, and Accountability ..........................................70 
5.1.3. 
Sitravatinib Administration ........................................................................................71 

 
 
 
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5.1.4. 
Sitravatinib Dose Modification or Discontinuation ....................................................72 
5.2. 
Nivolumab Study Drug ...............................................................................................73 
5.2.1. 
Nivolumab Formulation and Packaging .....................................................................73 
5.2.2. 
Nivolumab Preparation and Dispensing .....................................................................73 
5.2.3. 
Nivolumab Administration .........................................................................................74 
5.2.4. 
Nivolumab Dose Modification or Discontinuation ....................................................74 
5.3. 
Docetaxel Study Drug .................................................................................................75 
5.3.1. 
Docetaxel Formulation and Packaging .......................................................................75 
5.3.2. 
Docetaxel Preparation and Dispensing .......................................................................75 
5.3.3. 
Docetaxel Administration ...........................................................................................75 
5.3.4. 
Docetaxel Dose Modification .....................................................................................76 
5.4. 
Management of Adverse Events .................................................................................76 
5.4.1. 
Sitravatinib-Related Adverse Events ..........................................................................76 
5.4.1.1. 
General Management of Non-Hematological Toxicities ............................................76 
5.4.1.2. 
General Management of Hematological Toxicities ....................................................77 
5.4.1.3. 
Management of Selected Adverse Event ....................................................................78 
5.4.2. 
Nivolumab Adverse Event Management Guidelines .................................................80 
5.4.3. 
Management of Immune-Related Adverse Events .....................................................80 
5.4.3.1. 
Diarrhea/Colitis ...........................................................................................................80 
5.4.3.2. 
Increased Transaminases ............................................................................................81 
5.4.4. 
Management of Hy’s Law Cases ................................................................................81 
5.4.5. 
Docetaxel Adverse Event Management Guidelines ...................................................82 
5.5. 
Medication Error .........................................................................................................82 
5.6. 
Concomitant Therapies ...............................................................................................82 
5.6.1. 
Concomitant Medication(s) ........................................................................................82 
5.6.2. 
Concomitant Surgery or Radiation Therapy ...............................................................84 
5.6.3. 
Other Anticancer or Experimental Therapy ...............................................................84 
6. 
STUDY ASSESSMENTS ..........................................................................................84 
6.1. 
Screening ....................................................................................................................84 
6.2. 
Study Period................................................................................................................85 

 
 
 
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6.3. 
End of Treatment Assessment ....................................................................................85 
6.4. 
Initial Follow-up .........................................................................................................85 
6.5. 
Long-Term Follow-up ................................................................................................85 
6.6. 
Patient Discontinuation/Withdrawal ...........................................................................85 
7. 
PROCEDURES ..........................................................................................................86 
7.1. 
Documentation of Disease Progression On or After Prior Chemotherapy and 
Checkpoint Inhibitor Therapy.....................................................................................87 
7.2. 
Efficacy .......................................................................................................................87 
7.2.1. 
Overall Survival ..........................................................................................................87 
7.2.2. 
Radiographic Disease Assessment .............................................................................87 
7.3. 
Safety Assessments .....................................................................................................89 
7.3.1. 
Medical History ..........................................................................................................89 
7.3.2. 
Physical Examination and Vital Signs ........................................................................89 
7.3.3. 
Laboratory Safety Assessments ..................................................................................90 
7.3.4. 
Electrocardiograms .....................................................................................................91 
7.3.5. 
Echocardiogram or Multigated Acquisition Scan .......................................................91 
7.4. 
Laboratory Studies ......................................................................................................91 
7.4.1. 
Pharmacokinetic Evaluation .......................................................................................91 
7.4.2. 
Nivolumab Anti-Drug Antibody Evaluation ..............................................................92 
7.4.3. 
Molecular Marker Evaluation .....................................................................................92 
7.4.3.1. 
Circulating Tumor DNA .............................................................................................92 
7.4.3.2. 
Markers in Tumor Tissue ............................................................................................92 
7.5. 
Patient Reported Outcomes ........................................................................................93 
8. 
ADVERSE EVENT REPORTING ............................................................................93 
8.1. 
Sponsor Medical Monitor Personnel ..........................................................................93 
8.2. 
Adverse Events ...........................................................................................................93 
8.2.1. 
Laboratory Abnormalities ...........................................................................................94 
8.2.2. 
Severity Assessment ...................................................................................................95 
8.2.3. 
Causality .....................................................................................................................95 
8.3. 
Serious Adverse Events ..............................................................................................95 

 
 
 
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8.3.1. 
Definition of a Serious Adverse Events ......................................................................95 
8.3.2. 
Exposure During Pregnancy .......................................................................................96 
8.4. 
Reporting of SAEs and AEs .......................................................................................97 
8.4.1. 
Reporting Period .........................................................................................................97 
8.4.2. 
Reporting Requirements .............................................................................................98 
9. 
STATISTICS ..............................................................................................................98 
9.1. 
Hypotheses and Sample Size ......................................................................................98 
9.1.1. 
Primary Efficacy Hypothesis ......................................................................................98 
9.1.1.1. 
Sample Size Determination ........................................................................................99 
9.2. 
Data Handling .............................................................................................................99 
9.3. 
Analysis Populations ..................................................................................................99 
9.3.1. 
Intent-to-Treat Population ..........................................................................................99 
9.3.2. 
Safety Population ........................................................................................................99 
9.3.3. 
Pharmacokinetic Evaluable Population ......................................................................99 
9.3.4. 
Molecular Marker Evaluable Population ..................................................................100 
9.4. 
Efficacy Endpoint Definitions and Analyses ............................................................100 
9.4.1. 
Overall Survival ........................................................................................................100 
9.4.2. 
Objective Response Rate ..........................................................................................100 
9.4.3. 
Clinical Benefit Rate .................................................................................................101 
9.4.4. 
Duration of Response ...............................................................................................101 
9.4.5. 
Progression Free Survival .........................................................................................101 
9.4.6. 
Subgroup Analyses ...................................................................................................102 
9.5. 
Safety Data Presentations and Summaries ...............................................................102 
9.5.1. 
Adverse Events .........................................................................................................102 
9.5.2. 
Prior and Concomitant Medications .........................................................................103 
9.5.3. 
Clinical and Laboratory Assessments .......................................................................103 
9.5.4. 
Patient Demographics, Baseline Characteristics and Disposition ............................103 
9.5.5. 
Analysis of Study Treatment Dosing ........................................................................104 
9.6. 
Other Study Endpoints ..............................................................................................104 
9.6.1. 
Pharmacokinetic Analysis ........................................................................................104 

 
 
 
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9.6.2. 
Patient Reported Outcomes Analysis .......................................................................104 
9.7. 
Interim Analysis ........................................................................................................104 
9.8. 
Data Monitoring Committee .....................................................................................105 
10. 
ETHICS AND RESPONSIBILITIES .......................................................................105 
10.1. 
Ethical Conduct of the Study ....................................................................................105 
10.2. 
Obligations of Investigators ......................................................................................106 
10.3. 
Institutional Review Board/Ethics Committee/Research Ethics Board ....................106 
10.4. 
Informed Consent Form ............................................................................................106 
10.5. 
Confidentiality and Privacy Protection .....................................................................107 
10.6. 
Reporting of Serious Breaches of the Protocol or ICH GCP ....................................108 
11. 
RECORDS MANAGEMENT ..................................................................................108 
11.1. 
Source Documentation ..............................................................................................108 
11.2. 
Study Files and Records Retention ...........................................................................108 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................109 
12.1. 
Monitoring Procedures .............................................................................................109 
12.2. 
Auditing and Inspection Procedures .........................................................................109 
13. 
CHANGES IN STUDY CONDUCT ........................................................................109 
13.1. 
Protocol Amendments ..............................................................................................109 
13.2. 
Protocol Deviations ..................................................................................................110 
14. 
END OF TRIAL .......................................................................................................110 
14.1. 
End of Trial in a European Union Member State .....................................................110 
14.2. 
End of Trial in all other Participating Countries ......................................................110 
14.3. 
Premature Termination .............................................................................................110 
15. 
STUDY REPORT AND PUBLICATION POLICY ................................................111 
16. 
REFERENCES .........................................................................................................112 
16.1. 
Literature and Guidances ..........................................................................................112 
16.2. 
Approved Labels .......................................................................................................117 
APPENDIX 1. ECOG PERFORMANCE STATUS.................................................................118 
APPENDIX 2. MEDICATIONS OR SUBSTANCES TO BE AVOIDED OR USED 
WITH CAUTION DURING TREATMENT WITH SITRAVATINIB ...................119 

 
 
 
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APPENDIX 3. EXAMPLES OF STRONG AND MODERATE CYP3A4 
INHIBITORS ............................................................................................................127 
APPENDIX 4. ABBREVIATED PRESENTATION OF RECIST VERSION 1.1 
GUIDELINES ...........................................................................................................128 
APPENDIX 5. COVID-19 PANDEMIC CHANGES TO STUDY CONDUCT .....................132 
 
LIST OF TABLES 
Table 1: 
Schedule of Assessments ............................................................................................24 
Table 2: 
Schedule of PK Sample Collection for Sitravatinib and Triplicate ECG 
Assessments ................................................................................................................29 
Table 3: 
Sitravatinib Sequential Dose Reductions for Individual Patients on Free Base 
Capsule Formulation ...................................................................................................72 
Table 4: 
Sitravatinib Sequential Dose Reductions for Individual Patients on Malate 
Capsule Formulation ...................................................................................................73 
Table 5: 
Sitravatinib Dose Modifications – Non-Hematological Drug- Related 
Toxicities1 ...................................................................................................................77 
Table 6: 
Sitravatinib Dose Modification for Increased Blood Pressure ...................................78 
Table 7: 
Sitravatinib Dose Modification for Increased Hepatic Transaminase ........................81 
Table 8: 
Laboratory Safety Parameters .....................................................................................90 
 
 

 
 
 
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ADA 
Anti-Drug Antibody 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALT 
Alanine Aminotransferase 
APC 
Antigen Presenting Cells 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Curve 
BCRP 
Breast Cancer Resistance Protein 
CBR 
Clinical Benefit Rate 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CIT 
Checkpoint Inhibitor Therapy 
Cmax 
Maximum Plasma Concentration 
CR 
Complete Response 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CT 
Computed Tomography Scan 
CTA 
Clinical Trial Application 
CTCAE 
Common Terminology Criteria for Adverse Events 
Ctrough 
Trough Concentration 
ctDNA 
Circulating Tumor Deoxyribonucleic Acid 
DDI 
Drug-Drug Interaction 
DLT 
Dose Limiting Toxicity 
DR 
Duration of Response 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EIU 
Exposure In-Utero 
EQ-5D-5L 
European Quality of Life Five Dimensions Questionnaire 
FDA 
Food and Drug Administration 

 
 
 
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LIST OF ABBREVIATIONS (Continued) 
Abbreviation 
Definition 
GCP 
Good Clinical Practice 
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 Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IFN-γ 
Interferon Gamma 
IgG4 
Immunoglobulin G4 
IND 
Investigational New Drug 
irAE 
Immune-related Adverse Event 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IUD 
Intrauterine Device 
kg 
Kilogram 
LCSS 
Lung Cancer Symptom Scale 
LVEF 
Left Ventricular Ejection Fraction 
mAb 
Monoclonal Antibody 
MDSC 
Myeloid-Derived Suppressor Cell 
MedDRA 
Medical Dictionary for Regulatory Activities 
MET 
Mesenchymal-Epithelial Transition 
mg 
Milligram 
mins 
Minutes 
mL 
Milliliter 
MMRM 
Mixed Effect Model Repeated Measurement 

 
 
 
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LIST OF ABBREVIATIONS (Continued) 
Abbreviation 
Definition 
MRI 
Magnetic Resonance Imaging 
mRNA 
Messenger Ribonucleic Acid 
MSCs 
Mesenchymal Stem Cells 
MUGA 
Multigated Acquisition Scan 
NCI 
National Cancer Institute 
NE 
Not Evaluable 
NGS 
Next Generation Sequencing 
NK 
Natural Killer 
NPCB 
No Prior Clinical Benefit 
NSCLC 
Non-Small Cell Lung Cancer 
ORR 
Objective Response Rate 
OS 
Overall Survival 
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 
PFS 
Progression-Free Survival 
P-gp 
P-glycoprotein 
PK 
Pharmacokinetics 
PKAP 
Pharmacokinetic Analysis Plan 
PK/PD 
Pharmacokinetic/Pharmacodynamic 
PR 
Partial Response 
PRO 
Patient Reported Outcome 
Q2W 
Every 2 Weeks 
QD 
Once Daily 
QTc 
Corrected QT Interval 
REB 
Research Ethics Board 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RTKs 
Receptor Tyrosine Kinases 

 
 
 
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LIST OF ABBREVIATIONS (Continued) 
Abbreviation 
Definition 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
SOC 
System Organ Class 
SUSAR 
Suspected, Unexpected Serious Adverse Reaction 
TAM 
Tyro3, Axl and MERTK 
TB 
Total Bilirubin 
TEAE 
Treatment Emergent Adverse Event 
TESAE 
Treatment Emergent Serious Adverse Event 
TKIs 
Tyrosine Kinase Inhibitors 
TMB 
Tumor Mutation Burden 
TME 
Tumor Microenvironment 
Tregs 
T Regulatory Cells 
ULN 
Upper Limit of Normal 
WHO 
World Health Organization 
WOCBP 
Women of Child Bearing Potential 
μg 
Microgram 
μM 
Micromolar 
USA 
United States of America 
USPI 
US Prescribing Information 
 

 
 
 
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1. 
INTRODUCTION AND RATIONALE 
1.1. 
Disease and Therapeutic Strategy 
1.1.1. 
Non-Small Cell Lung Cancer 
Lung cancer remains the leading cause of cancer-related death worldwide, with GLOBOCAN 
estimating approximately 2.1 million new cases diagnosed in 2018 and approximately 1.76 
million deaths attributed to lung cancer (Bray, 2018). Non-small cell lung cancer accounts for 
approximately 83% of lung cancer cases (Noone, 2018), of which approximately half are 
classified as adenocarcinoma of the lung; squamous cell carcinoma accounts for approximately 
one-quarter of NSCLC cases and large cell carcinoma is infrequently diagnosed. 
1.1.2. 
First-Line Chemotherapy for Non-Small Cell Lung Cancer 
In 1995, the use of cisplatin-based chemotherapy was reported to lead to modest improvement in 
survival in patients with advanced NSCLC as compared to best supportive care, with a 27% 
reduction in death as reported in a meta-analysis of 11 trials (NSCLC Collaborative Group, 
1995). Subsequently, other chemotherapeutic agents have been reported to be active in NSCLC, 
leading to a comparison of 4 platinum-based doublets in the first-line treatment setting, all of 
which demonstrated similar activity (Schiller, 2002). The importance of histology in the 
selection of first-line treatment for NSCLC was later described in the development of 
bevacizumab and pemetrexed. In a Phase 3 clinical trial, treatment with bevacizumab, a mAb 
directed against vascular endothelial growth factor (VEGF), demonstrated an improvement in 
survival when added to doublet chemotherapy, specifically in patients with non-squamous 
NSCLC (Sandler, 2006). Similarly, treatment with pemetrexed, an antifolate chemotherapeutic 
agent, resulted in an improvement in survival when used as part of a chemotherapy doublet in 
patients with non-squamous NSCLC, but with a probable decrease in survival among patients 
with squamous cell NSCLC (Scagliotti, 2008). Based on the results of these and other trials, 
platinum-based chemotherapy doublets, with or without bevacizumab in selected patients, 
remain a standard of care for most patients with advanced NSCLC in the first-line treatment 
setting. 
1.1.3. 
Second- and Third-Line Chemotherapy for Non-Small Cell Lung Cancer 
Docetaxel and pemetrexed are approved chemotherapy options in patients previously treated 
with platinum-based chemotherapy. Median OS reported in randomized clinical trials using these 
single agents as experimental or comparator therapies has varied between approximately 5.7 and 
9.5 months and ORR between 5.5 and 12% (Shepherd, 2000), (Hanna, 2004), 
(Krzakowski, 2010), (Al-Saleh, 2012), (Scagliotti, 2009), (Tomasini, 2016). The benefits of 
docetaxel in particular are associated with considerable toxicity. Several studies evaluating 
docetaxel and pemetrexed within clinical trials of CITs are discussed in the Section 1.1.5. 
Landmark clinical trials established docetaxel and pemetrexed as standard-of-care single-agent 
chemotherapy regimens for patients with NSCLC previously treated with platinum-based 

 
 
 
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chemotherapy. In a Phase 3 trial in patients with advanced or metastatic NSCLC who had 
previously been treated with platinum-based chemotherapy, 1:1 randomization to docetaxel or 
best supportive care was planned; the dose of docetaxel was decreased during the study, resulting 
in groups treated with docetaxel 100 mg/m2 (n=49), docetaxel 75 mg/m2 (n=55) or best 
supportive care (n=100) (Shepherd, 2000). Median survival was 7.0 months in the combined 
docetaxel arms versus 4.6 months for the control arm (p= 0.047); the difference in OS was more 
signiﬁcant for docetaxel 75 mg/m2 (7.5 versus 4.6 months; p=0.010). Among 84 patients with 
measurable disease treated with docetaxel, the ORR was 7.1%, with 3 patients having a response 
at each dose level. Median DOR was approximately 6 months. Febrile neutropenia occurred in 
11 patients treated with docetaxel 100 mg/m2, three of whom died, and in one patient treated 
with docetaxel 75 mg/m2. With the exception of diarrhea, Grade 3 or 4 nonhematologic toxicity 
occurred at a similar rate in the 3 study arms. A Phase 3 trial comparing docetaxel 100 mg/m2 
(n=125), or docetaxel 75 mg/m2 (n=125), to control single agent chemotherapy (vinorelbine or 
ifosfamide) (n=123) reported ORR of 10.8, 6.7%, and 0.8% in the treatment arms, respectively, 
and median DOR of 7.5 and 9.1 months, in the docetaxel arms, respectively (Fossella, 2000). 
In a Phase 3 study evaluating the efficacy and toxicity of pemetrexed versus docetaxel in patients 
with advanced NSCLC previously treated with chemotherapy, patients received treatment with 
pemetrexed 500 mg/m2 (n=283) or docetaxel 75 mg/m2 (n-288) (Hanna, 2004). OS was 8.3 
versus 7.9 months (not signiﬁcant) for pemetrexed and docetaxel, respectively, and ORR was 
9.1% versus 8.8%. Median PFS was 2.9 months in both arms. Grade 3 or 4 neutropenia was 
more common in the docetaxel group (40.2% v 5.3%), as were SAEs related to neutropenia. 
Treatment with pemetrexed resulted in similar efﬁcacy outcomes, but with signiﬁcantly fewer 
side effects compared with docetaxel, particularly AEs related to neutropenia. Based on 
comparable results in efficacy endpoints and a more favorable safety profile, pemetrexed 
received accelerated approval as monotherapy for the treatment of patients with locally advanced 
or metastatic NSCLC who had received prior chemotherapy (Cohen, 2005), which was 
subsequently limited to NSCLC with non-squamous histology (Cohen, 2009). 
Based on emerging evidence of differential expression of thymidylate synthase, the primary 
target of pemetrexed, between adenocarcinoma and squamous cell carcinoma of the lung, a 
retrospective analysis based on tumor histology was conducted (Scagliotti, 2009). The study 
included 399 patients with non-squamous cell NSCLC and 172 patients with squamous-cell 
NSCLC. In patients with non-squamous histology, the median OS was 9.3 months with 
pemetrexed versus 8.0 months for docetaxel (adjusted HR 0.78). 
On the contrary, in patients with squamous-cell histology, the median OS was 6.2 months with 
pemetrexed versus 7.4 months for docetaxel (adjusted HR 1.56). ORR with pemetrexed was 
11.5% versus 9.0% for patients with non-squamous cell NSCLC versus squamous-cell 
carcinoma. 
The treatment landscape of NSCLC is rapidly changing with the approvals of CIT in the first- 
and second-line settings (see Section 1.1.5). Consensus on the appropriate treatment of NSCLC 
in the third-line setting is lacking (Planchard, 2019), (NCCN, 2019). However, single-agent 

 
 
 
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chemotherapy is commonly used in the third-line, with docetaxel, gemcitabine, vinorelbine, and 
pemetrexed most frequently administered (Davies, 2017). Median overall survival for docetaxel 
administered as third-line treatment of NSCLC has been reported as approximately 6.8 to 9.0 
months based on retrospective analyses (Costantini, 2018), (Park, 2018), (Schvartsman, 2017). 
1.1.4. 
Checkpoint Pathway 
The PD-1 receptor along with the ligands PD-L1 and PD-L2 constitutes an immune checkpoint 
pathway that inhibits T-cell activation when engaged (Mellman, 2011), (Topalian, 2015). PD-1 is 
expressed on T-cells whereas PD-L1 and PD-L2 are expressed on some cancer cells and immune 
cell types. PD-L1 is the predominant ligand expressed in solid tumors and is upregulated by 
interferon gamma (IFN-γ). PD-L1 functions to limit collateral damage in normal tissues where 
an immune response has been triggered. 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 (Mu, 2011). 
1.1.5. 
Checkpoint Inhibitor Therapy in Non-Small Cell Lung Cancer 
Three CITs have been proven to be effective in the treatment of advanced NSCLC, nivolumab, 
pembrolizumab and atezolizumab. 
Nivolumab, a fully human IgG4, PD-1 receptor antagonist, binds to the PD-1 receptor and blocks 
its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the anti-
tumor immune response. Nivolumab is approved by the US Food and Drug Administration 
(FDA) for the treatment of patients with metastatic NSCLC with progression during or after 
platinum-based chemotherapy. A randomized Phase 3 trial (CHECKMATE-057) of nivolumab 
versus docetaxel was conducted in patients with non-squamous NSCLC that had progressed 
during or after platinum-based doublet chemotherapy. The primary endpoint was OS. Patients 
received 3 mg/kg of nivolumab (n=292) by intravenous infusion Q2W or docetaxel (n=290) 
administered intravenously at 75 mg/m2 every 3 weeks (Q3W). Median survival was 12.2 
months for nivolumab as compared to 9.4 months for docetaxel (HR 0.73, p-value 0.002). 
Progression-free survival was longer for docetaxel compared to nivolumab, median 4.2 months 
vs 2.3 months, respectively (HR 0.92, p-value 0.39). ORR was 19% for nivolumab and 12% for 
docetaxel, with median DOR of 17.2 months for nivolumab and 5.6 months for docetaxel 
(Borghaei, 2015). Nivolumab was also evaluated in a Phase 3 clinical trial (CHECKMATE-017) 
in patients with squamous NSCLC that had progressed during or after one prior platinum-based 
doublet chemotherapy regimen. The primary endpoint was OS. Patients received 3 mg/kg of 
nivolumab (n=135) by intravenous infusion Q2W or docetaxel (n=137) administered 
intravenously at 75 mg/m2 Q3W. Median survival was 9.2 months for nivolumab as compared to 
6.0 months for docetaxel (HR 0.59, p-value 0.0002) (Brahmer, 2015). Nivolumab was approved 
in the US in March 2015 for squamous NSCLC and October 2015 for non-squamous NSCLC. 
Pembrolizumab is a humanized mAb that blocks the interaction between PD-1 and its ligands, 
PD-L1 and PD-L2. In a large Phase 1 clinical trial, pembrolizumab was given to 495 patients 

 
 
 
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with advanced NSCLC to evaluate safety, side-effect profile, and antitumor activity 
(Garon, 2015). Patients (some of whom had received previous therapy and some of whom had 
not) were treated with various doses and regimens of pembrolizumab. Pembrolizumab had an 
acceptable side-effect profile and showed anti-tumor activity. Among all patients, the objective 
response rate was 19.4%, and the median DOR was 12.5 months. The median duration of PFS 
was 3.7 months, and the median duration of OS was 12.0 months. A Phase 2/3 study randomized 
patients with advanced or metastatic NSCLC previously treated with a platinum-based 
chemotherapy and PD-L1 expression tumor proportion score of 1% or greater into three 
treatment arms: pembrolizumab 2 mg/kg (n=345), pembrolizumab 10 mg/kg (n = 346) or, 
docetaxel 75 mg/m2 (n=343). Median OS was 10.4, 12.7 and 8·5 months in the three arms, 
respectively. The hazard ratio (HR) for pembrolizumab 2 mg/kg versus docetaxel was 
0.71 (p-value 0.0008), and for 10 mg/kg versus docetaxel was 0.61 (p-value < 0·0001). Median 
PFS was approximately 4 months in each treatment arm. ORR was 18 and 19% in the 
pembrolizumab treated arms and 9% in the docetaxel arm, with median DOR not reached with 
median follow-up greater than 13 months for pembrolizumab and 6 months for docetaxel 
(Herbst, 2016). Keytruda® (pembrolizumab) was approved by the FDA in October 2015 for the 
treatment of patients with metastatic squamous or non-squamous NSCLC with progression on or 
after platinum-based chemotherapy. Subsequently, a Phase 3 trial of pembrolizumab versus 
standard chemotherapy in patients with untreated, advanced NSCLC characterized by ≥ 50% 
tumor PD-L1 expression demonstrated an advantage for pembrolizumab. Improvement was 
reported across multiple efficacy endpoints including survival, along with a favorable safety 
profile (Reck, 2016), leading to US approval of pembrolizumab in the first-line treatment setting 
in this patient population. 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 (Gandhi, 2018). 
Atezolizumab is a humanized mAb against PD-L1 and blocks the interaction between PD-L1 and 
its receptor PD-1. A Phase 3 trial enrolled 1225 patients with advanced or metastatic NSCLC 
who had previously received platinum-based chemotherapy. Patients were randomized to receive 
atezolizumab 1200 mg or docetaxel 75 mg/m² Q3W. The primary analysis was conducted in the 
first 850 patients enrolled. Median OS was 13.8 months in the atezolizumab arm versus 
9.6 months in the docetaxel arm (HR 0.73, p=0·0003). Overall results in secondary efficacy 
endpoints included median PFS 2.8 months versus 4.0 months, ORR 14% versus 13%, and DOR 
16.3 versus 6.2 months (HR 0.34, p<0.0001) in the atezolizumab versus docetaxel treatment 
arms, respectively (Rittmeyer, 2017). Atezolizumab was approved in the US in April 2017 for 
patients with NSCLC who have disease progression on or after platinum-based chemotherapy. 
Despite the advances with CIT, most patients with advanced NSCLC have incurable disease; 
additional, effective treatment options are needed, particularly after failure of a platinum-based 
chemotherapy regimen and resistance to CIT. 
Combining an immunotherapeutic PD-1/PD-L1 checkpoint inhibitor with an agent that has both 
immune modulatory and antitumor properties and targets the molecular and cellular mechanisms 
of resistance to CIT may improve outcomes by overcoming resistance to CIT. 

 
 
 
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1.2. 
Overall Rationale for the Proposed Combination Regimen 
Immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway have demonstrated efficacy 
across a range of cancer types, including non-small cell lung cancer (Brahmer, 2015), 
(Borghaei, 2015), (Garon, 2015), (Herbst, 2016), (Reck, 2016), (Gandhi, 2018), 
(Rittmeyer, 2017). While this therapy leads to durable clinical responses in a subset of patients, 
strategies to improve its clinical efficacy and overcome innate or acquired resistance to 
checkpoint inhibitor monotherapy are needed. Combination therapy with agents that target the 
molecular and cellular mechanisms of resistance to CIT is a rational approach to improving 
outcomes in these patients. 
Resistance mechanisms have been described based on fundamental knowledge of the immune 
system as well as emerging clinical data. Expression of PD-L1 appears to correlate with response 
in multiple clinical studies (Herbst, 2014), (Tumeh, 2014). In the TME, PD-L1 can be 
upregulated in tumor cells via oncogenic signaling or in response to immune stimulatory factors 
such as IFN-γ. Therefore, the absence of PD-L1 expression may reflect a tumor cell population 
and microenvironment with a suppressed immune response. A potentially related state termed 
immunological ignorance is characterized by a near complete absence of immune markers in the 
tumor. Tumors harboring a non-functional immune response or an excluded immune cell 
infiltrate represent additional cellular patterns found associated with resistance to checkpoint 
inhibition (Herbst, 2014). Several immune cell types normally function to suppress immune 
responses, are often found in abundance in cancer, and may underlie resistance mechanisms to 
checkpoint blockade (Vanneman, 2012). T Regulatory cells, MDSCs and M2-polarized 
macrophages, in particular, are immunosuppressive in nature as they counteract pro- 
inflammatory immune responses and lead to tolerance. Inhibition of the accumulation and/or 
function of these cell types therefore represents a rational combination strategy to reprogram the 
immunosuppressive TME and increase the effectiveness of PD-1/PD-L1 therapy. As described in 
further detail below, sitravatinib selectively inhibits key molecular and cellular pathways 
strongly implicated in checkpoint inhibitor resistance and therefore represents a rational strategy 
to enhance or restore anti-tumor immunity when combined with nivolumab, a CIT. 
1.3. 
Sitravatinib 
Sitravatinib is a spectrum-selective RTK inhibitor that inhibits several closely related RTKs 
including the TAM family (Tyro3/Axl/MERTK), VEGFR2, KIT, and MET. Receptor tyrosine 
kinases are key regulators of signaling pathways leading to cell growth, survival, and migration 
(Blume-Jensen, 2001). These kinases are dysregulated in many cancers through overexpression, 
genetic alteration or co-expression with high affinity ligands (Blume-Jensen, 2001). Multiple 
sitravatinib RTK targets are genetically altered in a variety of cancers and act as oncogenic 
drivers, promoting cancer development and progression. In addition to the immunostimulatory 
effects of Axl and MET inhibition, sitravatinib may further condition the TME in favor of 
antitumor activity by its immunomodulatory effects mediated through 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 

 
 
 
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sitravatinib increases the proliferation and fraction of systemic/spleen CD4+ and CD8+ T 
lymphocytes and reduces the number of systemic MDSCs. Additional studies to investigate the 
effects of sitravatinib in the TME are ongoing or planned. 
Background information in addition to that presented below is available in the Sitravatinib 
(MGCD516) Investigator’s Brochure. 
1.3.1. 
Sitravatinib Drug Substance 
The chemical structure and chemical formula of sitravatinib (MGCD516) free base and malate 
are as follows: 
Sitravatinib (MGCD516) Free Base 
N
S
O
N
H
N
F
H
N
NH
O
O
O
F
 
Sitravatinib (MGCD516) L-Malate 
N
S
O
N
H
N
F
H
N
NH
O
O
O
F
HO2C
OH
CO2H
 
Chemical Formula: 
MGCD516 Free Base: C33H29F2N5O4S 
 
MGCD516 Malate: C37H35F2N5O9S 
 
Molecular Weight: 
MGCD516 Free Base: 629.68 
 
MGCD516 Malate: 763.76 
1.3.2. 
Non-Clinical Data 
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 

 
 
 
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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 vitro results from the hERG (human Ether-a-go-go Related Gene) assay demonstrate a half 
maximal inhibitory concentration (IC50) of 0.6 μM on the potassium current, which far exceeds 
exposures observed clinically. There were no adverse effects on the cardiovascular system, 
including no effect on the QTc interval, when sitravatinib was administered to dogs at doses up 
to 4 mg/kg (mean 6 hr concentration of 0.072 μg/mL). Minor increases in vascular pressures 
were observed during the dog cardiovascular study; however, these were mild and considered of 
limited biological consequence. Assessment of the neurological functional observation battery 
and respiratory evaluations (tidal volume, respiration rate, and minute volume) in rats did not 
reveal any sitravatinib-related effects at doses up to 25 mg/kg. 
In a bidirectional permeability study with Caco-2 cell lines, sitravatinib is classified as a highly 
permeable compound, and not a substrate of P-glycoprotein (P-gp) and Breast Cancer Resistance 
Protein (BCRP). A P-gp and BCRP inhibition study using Caco-2 cells suggested that 
MGCD516 is a significant inhibitor of P-gp and BCRP with IC50 value of 0.838 and 1.51 μM 
(528 and 951 µg/mL), respectively; these values are much higher than the systemic steady state 
exposure levels observed clinically (Ctrough of 68 ng/mL). 
Using an ultra-centrifugation technique sitravatinib was 98.6% bound to human plasma proteins. 
Sitravatinib (MGCD516) was evaluated for cytochrome P-450-mediated metabolism using 
human liver microsomes and recombinant human enzymes. Results suggest that multiple 
enzymes, including CYP 1A2, 2A6, 2B6, 2C8, 2C9, 2D6, 2E1, and 3A4 are involved in the 
metabolism of sitravatinib. 
The effect of treating primary cultures of cryopreserved human hepatocytes with MGCD516 on 
the expression of cytochrome P450 (CYP) enzymes was investigated. Treatment of cultured 
human hepatocytes with up to 30 µM MGCD516 caused little or no increase (< 2.0-fold change 
or < 20% of the positive control) in CYP1A2 activity, CYP1A2 messenger ribonucleic acid 
(mRNA) levels, or CYP3A4 activity. However, MGCD516 (up to 3 and 10 µM, 1889 and 6297 
ng/mL) caused concentration dependent increases (> 2-fold change and > 20% of the positive 
control) in CYP2B6 activity, CYP2B6 mRNA levels, and CYP3A4 mRNA levels in one or more 
human hepatocyte cultures. 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 
MGCD516 or time- or metabolism-dependent inhibition of any of the CYP enzymes evaluated. 
Under the experimental conditions examined, MGCD516 demonstrated direct inhibition of 
CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4/5 (as measured by testosterone 

 
 
 
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6β-hydoxylation and midazolam 1´-hydroxylation) with IC50 values of 2.9 μM, 11 μM, 10 μM, 
1.9 μM, 11 μM and 0.81 μM, respectively. These IC50 values are higher than observed 
MGCD516 concentration levels using the recommended sitravatinib dose of 120 mg QD. It is 
therefore unlikely that inhibition of the cytochrome P450 enzymes tested will be observed during 
clinical use of sitravatinib. 
Because the potency for MGCD516 against its intended clinical targets is generally less than 
0.1 μM, it may be unlikely that concentrations required for robust direct systemic 
inhibition/induction of the tested CYPs will be achieved at projected clinical dose and exposure 
levels. 
For additional non-clinical information, refer to the current Sitravatinib Investigator’s Brochure. 
1.3.3. 
Sitravatinib Clinical Experience 
1.3.3.1. 
Sitravatinib Pharmacokinetics 
Complete and updated information concerning sitravatinib pharmacokinetics is available in the 
Investigator’s Brochure. After single dose administration of sitravatinib free base capsules, 
MGCD516 reaches peak concentration in a median time of approximately 3 to 8 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 42 and 58 hours after oral administration. 
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 (Section 1.3.3.4). 
In Part 1, the same single dose of 80 mg sitravatinib was compared as free base and malate 
capsule formulations. Geometric mean Cmax, AUC0-∞ and AUC0-168 was 1.27-, 1.24- and 
1.24-fold higher following malate capsules administration compared to free base capsules 
administration. From Part 1, it was determined that the malate capsule formulation was 
statistically significantly more bioavailable than the free base formulation, and that a free base to 
malate ratio of approximately 1.2 would give similar PK exposure. 
In Part 2, malate capsule formulation dose was adjusted and the geometric mean Cmax was 
comparable (55.1 and 56.4 ng/mL, respectively) following single dose administration of 120 mg 
sitravatinib free base formulation and a lower 100 mg sitravatinib dose of sitravatinib malate 
capsule formulation. The geometric mean AUC0-168 was 2962 and 2943 ng*h/mL for 120 mg 
sitravatinib free base and 100 mg sitravatinib malate capsule formulations, respectively. The 
geometric mean t1/2 was similar following malate capsule formulation administration compared 
to free base capsule formulation administration, with estimates being 35.0 and 34.3 hours, 
respectively, and individual t1/2 values ranging from 25.4 to 52.0 hours and from 23.2 to 
55.4 hours, respectively. Inferential statistical analysis showed that the ratio and 90% confidence 
interval of the geometric least squares (LS) means of AUC0-∞, AUC0-t and Cmax were 98.9 [91.8, 
106.6], 98.8 [91.6, 106.5] and 102.4% [92.9, 112.7], respectively. Study 516-006 demonstrated 

 
 
 
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bioequivalence between the 120 mg sitravatinib free base and 100 mg sitravatinib malate capsule 
formulations (Section 1.3.3.4). 
1.3.3.2. 
Sitravatinib Clinical Safety 
Sitravatinib monotherapy and sitravatinib in combination with nivolumab are being evaluated as 
part of the clinical development program. During the course of the study, the Investigator’s 
Brochure (IB) should be referenced for current data. 
Sitravatinib has been administered to cancer patients in multiple clinical studies, including 
monotherapy studies (516-001 and BGB-900-104), combination studies with the PD-1 inhibitor 
nivolumab (MRTX-500, 516-002, and 516-003), and combination studies with the PD-1 
inhibitor tislelizumab (BGB-900-103 and BGB-900-104). Sitravatinib has also been 
administered as single agent in healthy subject studies (516-006 and 516-007). Details regarding 
the clinical studies most relevant for this study, 516-001 and MRTX-500, are provided below. 
Study 516-001 is a multi-center Phase 1/1b clinical trial of sitravatinib as monotherapy in 
patients with advanced solid tumor diseases. The Phase 1 dose-escalation segment of the study 
evaluated sitravatinib dose levels between 10 mg and 200 mg administered QD. Dose limiting 
toxicities were reported in 4 patients and included Grade 3 palmar-plantar erythrodysesthesia at 
80 mg, and intolerable Grade 2 neuropathy, intolerable Grade 2 fatigue, and intolerable Grade 2 
mucositis at 200 mg. The maximum tolerated dose was 150 mg QD. Based on long-term 
tolerability, the recommended Phase 2 dose is 120 mg QD. The Phase 1b segment is ongoing, 
evaluating the clinical activity of sitravatinib in patients having tumors with selected histological 
diagnoses and/or tumor gene alterations targeted by sitravatinib. 
Study MRTX-500 is an open-label, parallel Phase 2 evaluation of nivolumab in combination 
with 3 investigational agents, glesatinib, sitravatinib or mocetinostat, in patients with locally 
advanced, unresectable or metastatic non-squamous NSCLC. Only the sitravatinib plus 
nivolumab treatment arm will be discussed in this protocol. Patients who have experienced 
progression of disease on or after treatment with a checkpoint inhibitor (CIT-experienced) as 
well as those who have experienced disease progression after treatment with platinum-based 
doublet chemotherapy (CIT-naïve) are enrolled. The primary objective is to evaluate the clinical 
activity of the combination study treatments using ORR in accordance with RECIST 1.1. 
Secondary objectives include evaluation of safety, secondary efficacy endpoints, and PK for the 
investigational agents. The study began with a lead-in safety evaluation of sitravatinib in 
combination with nivolumab administered by intravenous infusion, 240 mg Q2W. The starting 
dose for sitravatinib was 120 mg administered orally, once daily, in 28-day cycles. No protocol 
defined DLTs were reported in the first 6 evaluable patients treated at the sitravatinib starting 
dose 120 mg daily in combination with nivolumab administered by intravenous infusion, 240 mg 
Q2W. Based on the experience of patients enrolled into Studies 516-001 and MRTX-500, 
120 mg daily was selected as the Phase 2 dose of sitravatinib in combination with nivolumab. 
As of 26 June 2019, safety data are available for a total of 422 patients treated with sitravatinib, 
either as a single agent (n = 189), in combination with the PD-1 inhibitor nivolumab (n = 184), 

 
 
 
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or in combination with the PD-1 inhibitor tislelizumab (n = 49). In addition, safety data are 
available for 16 healthy male subjects administered single-agent sitravatinib. 
Dose-limiting toxicities (DLTs) with single-agent administration of sitravatinib in Study 516-001 
included Grade 3 palmar-plantar erythrodysesthesia (PPE) at 80 mg, and intolerable Grade 2 
neuropathy, intolerable Grade 2 fatigue, and intolerable Grade 2 mucositis at 200 mg. In 
Study MRTX-500, there were no DLTs observed during the lead-in evaluation of the 
combination of nivolumab (240 mg IV every 2 weeks [Q2W]) and sitravatinib (120 mg QD). 
Sitravatinib-related adverse events (AEs) reported in ≥20% of 186 patients treated with 
sitravatinib monotherapy were diarrhea (50%), fatigue (42%), hypertension (39%), nausea 
(29%), decreased appetite (27%), vomiting (24%), and PPE syndrome (20%). Treatment-related 
Grade 3+ AEs reported in ≥5% of patients were hypertension (19%), diarrhea (10%), fatigue 
(7%), lipase increased (5%), and PPE (5%). Treatment-related Grade 4 AEs were reported in 
3 patients and included lipase increased in 2 patients (1%) and febrile neutropenia in 1 patient 
(1%). A treatment-related Grade 5 AE of cardiac arrest was reported in 1 patient (1%). 
Treatment-related AEs reported in ≥20% of 184 patients treated with sitravatinib in combination 
with nivolumab were diarrhea (50%), fatigue (46%), nausea (34%), decreased appetite (33%), 
hypertension (27%), weight decreased (26%), dysphonia (24%), vomiting (23%), and 
hypothyroidism (20%). Treatment-related Grade 3 AEs reported in ≥5% of patients were 
hypertension (19%), diarrhea (10%), fatigue (7%), and lipase increased (5%). Treatment-related 
Grade 4 AEs were reported in 4 patients (2%) overall, and included gastric ulcer perforation, 
hypertensive crisis, lipase increased, and lymphocyte count decreased in 1 patient each (1%). 
Treatment-related Grade 5 AEs of cardiac arrest were reported in 2 patients (1%). 
Based on review of the AEs reported with sitravatinib in context of the mechanism of action, 
nonclinical data, frequency, and investigator assessment of causality, the following AEs have 
been assessed as expected serious adverse drug reactions (SARs) for sitravatinib, or serious 
adverse events (SAEs) with at least a reasonable possibility of a causal relationship to 
sitravatinib administered as monotherapy or in combination with other agents: deep vein 
thrombosis/embolism/pulmonary embolism, diarrhea, ejection fraction decreased, fatigue, 
hypertension, nausea, palmar-plantar erythrodysesthesia (PPE) syndrome, and vomiting. Refer to 
the current IB for updated information during the course of the study. 
Nonclinical toxicology studies as well as clinical safety data from the Phase 1/1b and Phase 2 
studies suggest that AEs associated with sitravatinib are similar to those observed with other 
small molecule inhibitors of the VEGFR pathway. 
Based on reported clinical experience with sitravatinib and similar agents, and nonclinical data 
with sitravatinib, guidance to the Investigator is provided for selected AEs in Section 5.4.1. 
1.3.3.3. 
Sitravatinib Clinical Efficacy 
Efficacy results are awaited from the Phase 1b segment of Study 516-001. 

 
 
 
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Study MRTX-500 uses a Predictive Probability Design (Lee, 2008) for each treatment arm and 
stratum. For patients who are CIT-experienced, enrollment is 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 are CIT-naïve are 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 enrolled into the prior clinical benefit (PCB) stratum of MRTX-500 are the most similar, 
and relevant, to the patients eligible for Study 516-005. Patients in the PCB stratum have 
experienced clinical benefit (RECIST confirmed CR or PR or stable disease for at least 
12 weeks) on their prior CIT. Updated data as of 04 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). 
1.3.3.4. 
Sitravatinib Capsule Formulation Study 
Investigation of alternative formulations is for the purpose of optimizing product characteristics 
and manufacturing efficiency. 
Study 516-006 (interim report) was a Phase 1, 2-part, open-label, single-dose, crossover study 
designed to evaluate the relative bioavailability of sitravatinib free base and sitravatinib malate 
capsule formulations in healthy subjects. In each part, subjects were randomized into 2 treatment 
sequences (either test then reference or reference then test formulations) and participated in two 
7-day treatment periods separated by a washout period. Part 1 assessed the relative 
bioavailability and PK of a single oral dose of 80 mg sitravatinib administered as free base 
capsule formulation (reference product) and malate capsule formulation (test product). From Part 
1, it was determined that the malate capsule formulation is statistically significantly more 
bioavailable than the free base capsule formulation, and that a free base to malate ratio of 
approximately 1.2 would give similar PK exposure. Subsequently, Part 2 assessed the relative 
bioavailability and PK of a single oral dose of 120 mg sitravatinib free base capsule formulation 
(reference product) and 100 mg sitravatinib malate capsule formulation (test product). The 
administration of 100 mg malate capsule formulation compared to 120 mg free base capsule 
formulation were similar based on descriptive statistics; for 100 mg malate capsule formulation 
vs. 120 mg free base capsule formulation, the geometric mean AUC0-∞, AUC0-t and Cmax was 
3074 vs. 3089 ng*h/mL, 2943 vs. 2962 ng*h/mL and 56.4 vs. 55.1 ng/mL, respectively. The 
inferential statistical analysis showed that the ratio and 90% confidence interval of the geometric 
least squares means of AUC0-∞, AUC0-t and Cmax were within the regulatory acceptance range of 
80-125%, demonstrating that the 120 mg sitravatinib free base and 100 mg malate capsule 
formulations are bioequivalent (FDA, 2014), (CPMP, 1998). 
An evaluation of sitravatinib PK using different formulations of capsules is also being conducted 
as a sub-study within Study MRTX-500 and is ongoing. The sub-study will use the sitravatinib 

 
 
 
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free base capsule formulation as the reference product to evaluate the PK of other formulations 
of the malate capsule product. The sub-study will include dedicated patient cohorts for each 
formulation and dose level evaluated. Patients eligible for this sub-study will have locally 
advanced, unresectable or metastatic non-squamous NSCLC. After a lead-in evaluation, 
sitravatinib will be administered in combination with nivolumab. 
1.3.3.5. 
Sitravatinib Dosing with Food 
An evaluation of sitravatinib PK in the fed state is being conducted as a sub-study within Study 
MRTX-500. The potential to administer sitravatinib in the fed or fasted state is being 
investigated to provide flexibility and convenience for future patients enrolling in sitravatinib 
clinical trials. The sub-study includes dedicated patient cohorts for each formulation evaluated. 
Patients eligible for the sub-study will have locally advanced, unresectable or metastatic non-
squamous NSCLC and will have experienced progression of disease on or after treatment with a 
CIT. The definition of the fed state for the purpose of this sub-study is consumption of a high fat 
meal at the time of sitravatinib dosing. 
The sub-study will begin with a 7-day lead-in period comprised of a single dose of the assigned 
sitravatinib formulation followed by sample collection for PK analysis over a 168-hour period. 
Upon completion of the lead-in period, patients will begin Cycle 1 Day 1 of study treatment as 
described in the main part of the MRTX-500 study, using the assigned sitravatinib formulation 
and dose taken with food, in combination with nivolumab. On Cycle 1 Day 15, a steady-state PK 
profile of sitravatinib administered with a high-fat meal will be evaluated with sample collection 
over a 24-hour period. 
Results of this MRTX-500 sub-study will recommend whether the requirement to administer 
sitravatinib capsules in the fasted state can be eliminated, as described in Section 5.1.3. 
1.4. 
Nivolumab 
Nivolumab (OPDIVO®) is a human mAb that blocks the interaction between PD-1 and its 
ligands, PD-L1 and PD-L2. Nivolumab is an IgG4 kappa immunoglobulin. 
Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits 
T-cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some 
tumors and signaling through this pathway can contribute to inhibition of active T-cell immune 
surveillance of tumors. Nivolumab binds to the PD-1 receptor and blocks its interaction with 
PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, 
including the anti-tumor immune response. In syngeneic mouse tumor models, blocking PD-1 
activity resulted in decreased tumor growth. 
Background information in addition to that presented below is available in the current OPDIVO 
approved product label (USPI, SmPC). 

 
 
 
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1.4.1. 
Nivolumab Drug Substance 
Generic Name: 
Nivolumab 
Other Name:  
OPDIVO® 
Molecular Weight: 
146 kDa 
1.4.2. 
Nivolumab Non-Clinical Data 
The non-clinical experience is described in the current OPDIVO approved product label 
(USPI, SmPC). 
1.4.3. 
Nivolumab Clinical Data 
The following reports information included in the OPDIVO USPI dated  September 2021. Refer 
to the current OPDIVO approved product label (USPI, SmPC) for updates during the conduct of 
this clinical trial. 
1.4.3.1. 
Nivolumab Pharmacokinetics 
The PK of single-agent nivolumab was studied in patients over a dose range of 0.1 to 20 mg/kg 
administered as a single dose or as multiple doses of OPDIVO every 2 or 3 weeks as a 60-minute 
infusion. The predicted exposure of nivolumab after a 30-minute infusion is comparable to that 
observed with a 60-minute infusion. The geometric mean (% coefficient of variation [CV%]) 
clearance is 8.2 mL/h (53.9%), geometric mean volume of distribution at steady state (Vss) is 
6.8 L (27.3%), and geometric mean elimination half-life is 25 days (77.5%). Steady-state 
concentrations of nivolumab were reached by 12 weeks when administered at 3 mg/kg Q2W, and 
systemic accumulation was approximately 3.7-fold. The exposure to nivolumab increased dose 
proportionally over the dose range of 0.1 to 10 mg/kg administered Q2W. 
The following factors had no clinically important effect on the clearance of nivolumab: age 
(29 to 87 years), weight (35 to 160 kg), sex, race, baseline lactate dehydrogenase (LDH), PD-L1 
expression, solid tumor type, tumor size, renal impairment (eGFR ≥15 mL/min/1.73 m2) and 
mild (total bilirubin [TB] less than or equal to the ULN and AST greater than ULN or TB greater 
than 1 to 1.5 times ULN and any AST) or moderate hepatic impairment (TB greater than 1.5 to 
3 times ULN and any AST). Nivolumab has not been studied in patients with severe hepatic 
impairment (TB greater than 3 times ULN and any AST). 
1.4.3.2. 
Nivolumab Anti-Drug Antibodies 
Of 2085 patients who were treated with OPDIVO as a single agent at a dose of 3 mg/kg Q2W 
and evaluable for the presence of anti-nivolumab antibodies, 11% tested positive for treatment-
emergent anti-nivolumab antibodies by an electrochemiluminescent (ECL) assay and 0.7% had 
neutralizing antibodies against nivolumab. There was no evidence of altered pharmacokinetic 
profile or increased incidence of infusion reactions with anti-nivolumab antibody development. 

 
 
 
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1.4.3.3. 
Nivolumab Adverse Reactions in Clinical Trials 
Refer to the current OPDIVO approved product label. for information concerning adverse 
reactions occurring in clinical trials. 
As of September 2021, the most common adverse reactions (≥20%) in patients administered 
OPDIVO as a single agent were fatigue, rash, musculoskeletal pain, pruritus, diarrhea, nausea, 
asthenia, cough, dyspnea, constipation, decreased appetite, back pain, arthralgia, upper 
respiratory tract infection, pyrexia, headache, abdominal pain, vomiting, and urinary tract 
infection. 
1.4.3.4. 
Nivolumab Immune-Related Adverse Events 
Refer to the current OPDIVO approved product label (USPI, SmPC), for information concerning 
irAEs occurring during treatment with nivolumab. 
As of September 2021, the OPDIVO USPI includes warnings and precautions for a range of 
irAEs documented in patients across cancer indications, including, pneumonitis, colitis, hepatitis, 
endocrinopathies (such as hypophysitis, adrenal insufficiency, hypothyroidism and 
hyperthyroidism, Type 1 diabetes mellitus), nephritis and renal dysfunction, skin adverse 
reactions, encephalitis, other rarer irAEs, and infusion reactions. 
1.4.3.5. 
Safety Reported in Non-Small Cell Lung Cancer Trials Clinical Trials 
Refer to the current OPDIVO approved product label (USPI, SmPC), for safety information 
concerning OPDIVO in clinical trials enrolling patients with NSCLC. 
The safety of OPDIVO in metastatic NSCLC was evaluated in a randomized open-label, 
multicenter trial in patients with metastatic squamous NSCLC and progression on or after one 
prior platinum doublet-based chemotherapy regimen (CHECKMATE-017) and a randomized, 
open-label, multicenter trial in patients with metastatic non-squamous NSCLC and progression 
on or after one prior platinum doublet-based chemotherapy regimen (CHECKMATE-057). 
Patients received 3 mg/kg of OPDIVO administered intravenously over 60 minutes Q2W or 
docetaxel administered intravenously at 75 mg/m2 Q3W. The median duration of therapy in 
OPDIVO-treated patients in CHECKMATE 017 was 3.3 months (range: 1 day to 21.7+ months) 
and in CHECKMATE-057 was 2.6 months (range: 0 to 24.0+ months). In CHECKMATE-017, 
36% of patients received OPDIVO for at least 6 months and 18% of patients received OPDIVO 
for at least 1 year and in CHECKMATE-057, 30% of patients received OPDIVO for greater than 
6 months and 20% of patients received OPDIVO for greater than 1 year. 
CHECKMATE-017 and CHECKMATE-057 excluded patients with active autoimmune disease, 
medical conditions requiring systemic immunosuppression, or with symptomatic interstitial lung 
disease. For CHECKMATE-017 and CHECKMATE-057, the median age of OPDIVO-treated 
patients was 61 and  62 years respectively, (range: 37 to 85); 41% and 37%, respectively, were 
≥65 years of age,  82% and 52%, respectively, were male, and approximately 90 % were white. 

 
 
 
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Seven to twelve percent of patients had brain metastases and Eastern Cooperative Oncology 
Group (ECOG) performance status was 0 (20%-29%) or 1 (71%-79%). 
In CHECKMATE-057, in the OPDIVO arm, seven deaths were due to infection including one 
case of Pneumocystis jirovecii pneumonia, four were due to pulmonary embolism, and one death 
was due to limbic encephalitis. Serious adverse reactions occurred in 46% of patients receiving 
OPDIVO. OPDIVO was discontinued in 11% of patients and was delayed in 28% of patients for 
an adverse reaction. 
The most frequent serious adverse reactions reported in at least 2% of patients receiving 
OPDIVO were pneumonia, pulmonary embolism, dyspnea, pyrexia, pleural effusion, 
pneumonitis, and respiratory failure. Across both trials, the most common adverse reactions 
(reported in at least 20% of patients) were fatigue, musculoskeletal pain, cough, dyspnea, and 
decreased appetite. 
Other clinically important adverse reactions observed in patients treated with OPDIVO and 
which occurred at a similar incidence in docetaxel-treated patients include: fatigue/asthenia (48% 
all Grades, 5% Grade 3-4), musculoskeletal pain (33% all Grades), pleural effusion (4.5% all 
Grades), pulmonary embolism (3.3% all Grades). 
1.5. 
Expectations for Safety of the Combination of Sitravatinib and 
Nivolumab 
1.5.1. 
Potential for Drug-Drug Interactions 
Sitravatinib administered in combination with nivolumab is unlikely to result in clinically 
relevant drug-drug interactions (DDI) based on absorption, metabolism, elimination or protein 
binding. Nivolumab is a mAb and is intravenously administered, whereas sitravatinib is a small 
molecule therapeutic administered orally; no absorption interactions are expected. 
No studies on the metabolism of nivolumab have been reported in vitro or in humans. Like most 
therapeutic proteins, nivolumab is not expected to be metabolized by liver cytochrome P-450 
(CYP) or other drug metabolizing enzymes and is unlikely to have an effect on CYPs or other 
metabolizing enzymes in terms of inhibition or induction. 
1.5.2. 
Evaluation of Potential for Increased Toxicity with Combination Use of 
Sitravatinib and Nivolumab 
Frequent AEs, such as fatigue, musculoskeletal pain, decreased appetite, cough, and 
constipation, which are non-specific and typical of cancer treatment regimens have been 
observed with nivolumab and sitravatinib monotherapy. Potential exists for these AEs to be 
observed with increased severity or frequency during use of the combined agents. Management 
of these effects in patients receiving cancer therapy is well precedented. 
Importantly, irAEs observed using nivolumab monotherapy include pneumonitis, colitis, 
hepatitis, endocrinopathy, nephritis/renal dysfunction, rash, and encephalitis. While sitravatinib 

 
 
 
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may have immunostimulatory effects, autoimmune adverse effects have not been reported in 
clinical trials of single-agent sitravatinib nor are they recognized as class effects for this agent. 
However, the potential for sitravatinib to exacerbate or promote these AEs when administered in 
combination with nivolumab should be borne in mind. Adverse event incidence data presented 
below are as reported in the OPDIVO USPI dated September 2021 and the Sitravatinib 
Investigator’s Brochure dated August 2021. Updates to these data during the conduct of this 
clinical trial will be found in the current OPDIVO approved product label (USPI, SmPC), and 
Sitravatinib Investigator’s Brochure. 
A clinically relevant overlap in toxicity may arise between the immune-related colitis attributed 
to nivolumab and the non-specific, most often mild to moderate diarrhea observed with 
sitravatinib. Immune-related colitis has been reported in 2.9% (58/1994) of patients treated with 
nivolumab, with a median time to onset of 5.3 months (range: 2 days to 20.9 months). Diarrhea 
has been reported in approximately 50% of patients treated with sitravatinib monotherapy, most 
often beginning within the first month of the start of treatment. Diarrhea (any grade) is less 
common with nivolumab, occurring in 8% of patients with NSCLC treated at 3 mg/kg Q2W in 
the CHECKMATE 057 clinical trial (Borghaei, 2015). The time to onset may be helpful in 
distinguishing diarrhea that may be attributed to autoimmune effects versus non-specific toxicity. 
Tyrosine kinase inhibitors in general, and MET inhibitors in particular, have been associated 
with non-specific, most often mild to moderate elevation in AST and ALT. Mild to moderate 
elevations in liver transaminases have also been observed in 18% of patient treated with 
sitravatinib monotherapy. The elevations observed with sitravatinib generally occur within the 
first cycle of treatment and resolve with interruption of treatment. In patients receiving 
nivolumab as a single agent, immune-related hepatitis occurred in 1.8% (35/1994) of patients; 
the median time to onset was 3.3 months (range: 6 days to 9 months). 
Hypothyroidism, including thyroiditis, was reported in 7% (20/287) of NSCLC patients treated 
with nivolumab. Hypothyroidism has been reported in approximately 17% of subjects treated 
with sitravatinib monotherapy. 
A clinically relevant overlap in toxicity may arise between the immune-related rash attributed to 
nivolumab and the non-specific, most often mild (Grade 1) rash observed with sitravatinib. 
Immune-related rash has been reported in 6% (17/287) of NSCLC patients treated with 
nivolumab. Rash of uncertain etiology has been reported in 11% of patients treated with 
sitravatinib monotherapy. 
1.6. 
Docetaxel 
Docetaxel (TAXOTERE®) is an antineoplastic agent belonging to the taxoid family that acts by 
disrupting the microtubular network in cells that is essential for mitotic and interphase cellular 
functions. Docetaxel binds to free tubulin and promotes the assembly of tubulin into stable 
microtubules while simultaneously inhibiting their disassembly. 

 
 
 
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This leads to the production of microtubule bundles without normal function and to the 
stabilization of microtubules, which results in the inhibition of mitosis in cells. 
Background information in addition to that presented below is available in the current 
TAXOTERE approved product label (USPI, SmPC). 
TAXOTERE or generic equivalent (docetaxel) are acceptable for use in this study. 
1.6.1. 
Docetaxel Drug Substance 
Generic Name: 
Docetaxel 
Other Name:  
TAXOTERE® 
1.6.2. 
Docetaxel Non-Clinical Data 
The non-clinical experience is described in the current TAXOTERE approved product label 
(USPI, SmPC). 
1.6.3. 
Docetaxel Clinical Data 
The following reports information included in the TAXOTERE USPI dated May 2021. Refer to 
the current TAXOTERE approved product label (USPI, SmPC) for updates during the conduct of 
this clinical trial. 
1.6.3.1. 
Docetaxel Pharmacokinetics 
The PK of docetaxel have been evaluated in cancer patients after administration of 20 mg/m2 to 
115 mg/m2 in phase 1 studies. The AUC was dose proportional following doses of 70 mg/m2 to 
115 mg/m2 with infusion times of 1 to 2 hours. Docetaxel's PK profile is consistent with a three-
compartment pharmacokinetic model, with half-lives for the α, β, and γ phases of 4 min, 36 min, 
and 11.1 hr, respectively. Mean total body clearance was 21 L/h/m2. Mean steady state volume 
of distribution was 113 L. In vitro studies showed that docetaxel is about 94% protein bound, 
mainly to α1-acid glycoprotein, albumin, and lipoproteins. In three cancer patients, the in vitro 
binding to plasma proteins was found to be approximately 97%. Dexamethasone does not affect 
the protein binding of docetaxel. 
In vitro drug interaction studies revealed that docetaxel is metabolized by the CYP3A4 
isoenzyme, and its metabolism may be modified by the concomitant administration of 
compounds that induce, inhibit, or are metabolized by cytochrome P450 3A4. 
A population PK analysis was carried out after TAXOTERE treatment of 535 patients dosed at 
100 mg/m2. Pharmacokinetic parameters estimated by this analysis were very close to those 
estimated from phase 1 studies. The PK of docetaxel were not influenced by age. The population 
pharmacokinetics analysis described above also indicated that gender did not influence the 
pharmacokinetics of docetaxel. In patients with clinical chemistry data suggestive of mild to 
moderate liver impairment (AST and/or ALT > 1.5 times ULN concomitant with alkaline 
phosphatase > 2.5 times ULN), total body clearance was lowered by an average of 27%, 

 
 
 
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resulting in a 38% increase in systemic exposure (AUC). There is, at present, no measurement 
that would allow recommendation for dose adjustment in such patients. Patients with combined 
abnormalities of transaminase and alkaline phosphatase should not be treated with TAXOTERE. 
Patients with severe hepatic impairment have not been studied. Mean total body clearance for 
Japanese patients dosed at the range of 10 mg/m2 to 90 mg/m2 was similar to that of 
European/American populations dosed at 100 mg/m2, suggesting no difference in the elimination 
of docetaxel in these two populations. 
1.6.3.2. 
Docetaxel Adverse Reactions Common in Clinical Trials 
Refer to the current TAXOTERE approved product label (USPI, SmPC) for information 
concerning adverse reactions occurring in clinical trials. 
As of May 2021, the most common adverse reactions across all TAXOTERE indications are 
infections, neutropenia, anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, 
neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, 
pain, nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, and myalgia. 
1.7. 
Study Rationale 
Immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway have demonstrated efficacy in 
patients with NSCLC. While CIT leads to durable clinical responses in a subset of patients, 
strategies to improve its clinical efficacy and overcome innate or acquired resistance to 
checkpoint inhibitor monotherapy are needed. Combination therapy with agents that target the 
molecular and cellular mechanisms of resistance to CIT is a rational approach to improving 
outcomes in patients. 
The use of TKIs to treat cancer is well established based on robust clinical efficacy achieved 
with well-tolerated inhibitors directed toward oncogenic tyrosine kinases. In addition, selected 
TKIs have been shown to modulate the immunogenic status of tumors, improve tumor perfusion 
by reducing intratumoral pressure and modulate subsets of immune cells, thereby increasing the 
frequency and function of effector immune elements while decreasing the number and function 
of immune suppressor cells. Taken together, these effects on the TME may lead to improved 
efficacy when TKIs are combined with checkpoint inhibitors. The TAM RTKs are expressed by 
select innate immune cell subpopulations including macrophages and dendritic cells 
(Lemke, 2008). The TAM receptors cooperate to create and maintain an immunosuppressive 
TME. MERTK suppresses the M1 macrophage pro-inflammatory cytokine response involving 
IL-12, IL-6 and TNF and enhances M2 macrophage anti-inflammatory cytokine production 
involving IL-10, IL-4, TGFβ and HGF (Camenisch, 1999), (Tibrewal, 2008). In addition, M2 
macrophages express checkpoint ligands such as PD-L1, PD-L2, B7-H1 and B7-H2 that further 
inhibit T effector cell function (Santarpia, 2015). Given that anti-tumor host defense is usually 
mediated by cytotoxic T lymphocytes whose activation and stimulation is supported by Th1 type 
cytokines, the inhibition of Axl and MERTK are predicted to enhance an anti-tumor immune 
response. Furthermore, both Axl and MERTK are expressed by NK cells and negatively regulate 

 
 
 
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NK cell activity in the TME as part of a feedback regulatory mechanism resulting in decreased 
NK cell anti-tumor activity and enhanced tumor progression and metastasis (Paolino, 2014). 
Given the immunosuppressive function of TAM RTKs in the TME, inhibition of Axl and 
MERTK may complement PD-1/PD-L1 checkpoint inhibition to unleash the host anti-cancer 
immune response. 
The MET RTK is implicated in modification of tumor immune responses based on its role in 
mediating an immunosuppressive TME as well as its role in regulating APC function. MET is 
expressed by immature CD14-positive monocytes and can induce an immunosuppressive 
phenotype when its ligand, HGF, is secreted by tumor stroma and MSCs (Chen, 2014). Depletion 
of CD14-positive monocytes or neutralization of HGF secretion by MSCs reverses the 
suppression of T effector proliferation and triggers a shift back toward a Th1 activated T cell 
phenotype (Chen, 2014). MSCs are also implicated in expansion of immunosuppressive MDSCs, 
which are also dependent on the secretion of HGF (Yen, 2013). APCs (ie, dendritic cells) also 
express MET and the activation of MET by HGF results in suppression of APC function 
including both antigen presenting capacity and antigen-dependent T cell responses 
(Okunishi, 2005), (Singhal, 2011), (Benkhoucha, 2010). Therefore, inhibition of MET may 
enhance the antitumor response by restoring APC function and reducing or eliminating MDSCs 
within the TME. 
Inhibition of the VEGF receptor family and KIT may further enhance antitumor 
immunoreactivity by depletion of immunosuppressive cellular subset from the TME including 
regulatory T cells and MDSCs. T regulatory cells express VEGFR2 and the inhibition of 
VEGFR2 utilizing a specific VEGFR2 antibody antagonist or VEGFA neutralizing antibody (but 
not a VEGFR1 antagonist) inhibited Treg proliferation in vitro and in tumor-bearing mice and 
patient peripheral blood (Terme, 2013). MDSCs notably express both KIT and VEGFR1 and the 
inhibition of these RTKs using pharmacologic or genetic approaches resulted in the inhibition of 
MDSC viability in vitro and depletion of this cell population in mouse tumor models (Ko, 2009), 
(Ozao-Choy, 2009), (Farsaci, 2012). 
Sitravatinib is an orally-available, potent small molecule inhibitor of a closely related spectrum 
of RTKs including MET, Axl, MERTK, VEGFR family, PDGFR family, KIT, FLT3, Trk 
family, RET, DDR2, and selected Eph family members. 
Taken together, TAM receptors, KIT, VEGFR family and MET activation work together to 
suppress anti-tumor immunity at several steps in the cancer-immunity cycle. The activation of 
TAM receptors functions as an innate immune cell checkpoint and inhibition of these receptors is 
predicted to complement and augment the activity observed with adaptive CIT (anti-PD-1) alone. 
Since activation of the TAM receptors functions as a mechanism to limit inflammation during 
the natural course of an immune response, it is likely that differing levels of TAM-dependent 
immunosuppression exists in most tumors, thus providing a rationale for testing inhibitors of 
these “innate checkpoints” in combination with adaptive CIT (anti-PD-1) in patients with cancer 
that has progressed on CIT. 

 
 
 
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Nivolumab is a human IgG4 mAb that binds to the PD-1 receptor and blocks its interaction with 
PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, 
including the anti-tumor immune response. 
This study will evaluate the efficacy of nivolumab in combination with sitravatinib. Nivolumab 
will be administered in accordance with approved labeling, by intravenous infusion, 240 mg 
Q2W or 480 mg Q4W. Sitravatinib will be administered orally at a starting dose of 100 mg QD 
for the malate capsule formulation, based on the results of Study 516-006 described in 
Section 1.3.3.4. For patients enrolled in the USA who began treatment with the sitravatinib free 
base capsule formulation, sitravatinib is administered orally at a starting dose of 120 mg QD in 
accordance with findings of the prior nivolumab combination study (MRTX-500); patients who 
began treatment with the sitravatinib free base capsule formulation will remain on the free base 
capsule formulation throughout the duration of the study. Nonclinical studies indicate that 
sitravatinib administered to patients at 120 mg daily free base capsule formulation or 100 mg 
daily malate capsule formulation should achieve the plasma exposure required for inhibition of 
VEGF and TAM receptors, necessary to achieve antitumor efficacy in the combination setting. 
2. 
STUDY OBJECTIVES 
2.1. 
Objectives 
2.1.1. 
Primary Objective 
To compare OS in patients with non-squamous NSCLC who have experienced disease 
progression on or after platinum-based chemotherapy and CIT, treated with sitravatinib and 
nivolumab versus docetaxel. 
2.1.2. 
Secondary Objectives 
• To evaluate the safety of sitravatinib with nivolumab in the study population. 
• To evaluate the relative tolerability of sitravatinib and nivolumab versus docetaxel. 
• To evaluate secondary efficacy endpoints in the study population. 
• To evaluate the PK of sitravatinib (MGCD516) administered in combination with 
nivolumab. 
• To evaluate health-related quality of life and lung cancer-specific symptoms in the 
study population. 
2.1.3. 
Exploratory Objective 
• To assess correlations between baseline tumor immune biomarkers and gene 
mutations and treatment-related outcomes. 

 
 
 
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• To evaluate efficacy endpoints using exploratory disease response criteria. 
• To characterize the immunogenicity of nivolumab in combination with sitravatinib. 
2.1.4. 
Primary Endpoint 
Overall Survival (OS). 
2.1.5. 
Secondary Endpoints 
• Safety characterized by type, incidence, severity, timing, seriousness and relationship 
to study treatment of adverse events, laboratory abnormalities, and number of patients 
discontinuing study treatment due to an adverse event. 
• Secondary efficacy endpoints: 
− ORR as defined by RECIST 1.1. 
− DOR; 
− CBR; 
− PFS; and 
− 1-Year Survival Rate. 
• Blood plasma concentrations of MGCD516. 
• PROs: 
− Lung Cancer Symptom Scale (LCSS); and 
− EQ-5D-5L. 
2.1.6. 
Exploratory Endpoints 
• Tumor PD-L1 expression. 
• Tumor gene alterations. 
• Circulating tumor ctDNA. 
• Efficacy parameters as evaluated per iRECIST. 
• Nivolumab anti-drug antibody (ADA) 
3. 
STUDY DESIGN 
Study 516-005 is an open-label, randomized (1:1), multicenter, Phase 3 clinical trial evaluating 
the efficacy and safety of nivolumab in combination with the investigational agent sitravatinib 
compared to docetaxel in patients with advanced non-squamous NSCLC who have previously 
experienced radiographic disease progression on or after treatment with platinum-based 

 
 
 
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chemotherapy and CIT. The primary objective is to compare OS in the two treatment arms. 
Secondary objectives include evaluation of safety and tolerability, secondary efficacy endpoints, 
PK of sitravatinib, and patient reported outcomes. Correlative science endpoints include tumor 
PD-L1 expression, tumor gene mutations, nivolumab ADA and ctDNA. The Schedule of 
Assessments to be performed in the study is presented in Table 1. 
Patient eligibility for study enrollment based on radiographic disease progression on or after 
treatment with CIT, either in combination with platinum-based chemotherapy or following 
platinum-based chemotherapy, will be evaluated by the Investigator. Data entered into the CRF 
are to include the date of at least one radiographic evaluation prior to the occurrence of disease 
progression on most recent CIT and the date the radiographic evaluation demonstrating disease 
progression, as well as specifics about organ systems (e.g., lung, liver, lymph node, bone and/or 
brain) having tumors that increase in size or are new. 
Patient randomization will be stratified based on: 
1. prior treatment regimens in the advanced setting (1 versus 2): 
One prior therapy: platinum-based chemotherapy in combination with CIT 
Two prior therapies: platinum-based chemotherapy  disease progression  CIT, 
2. ECOG Performance Status at baseline (0 versus 1), and 
3. presence of brain metastasis at baseline (presence versus absence). 
Patients randomized to the experimental arm will receive treatment with nivolumab in 
combination with sitravatinib, delivered in 28-day cycles. Nivolumab will be administered as an 
infusion over approximately 30 minutes (± 5 minutes) at 240 mg every 2 weeks or 480 mg every 
4 weeks, at the discretion of the Investigator. Sitravatinib malate capsules will be administered 
orally at 100 mg QD. Sitravatinib free base capsules will be administered orally at 120 mg QD 
(for patients who started on free base capsules, USA only). Patients enrolled in the USA who 
began treatment with the sitravatinib free base capsule formulation will remain on the free base 
capsule formulation throughout the duration of the study. 
Patients randomized to the comparator arm will receive treatment with docetaxel, delivered in 
21-day cycles. Docetaxel will be administered by intravenous infusion at 75 mg/m2 over 1 hour 
every 3 weeks. 
Disease assessments and patient-reported outcomes questionnaires must be performed as 
scheduled according to the calendar to prevent the introduction of bias based on toxicity into the 
assessment of efficacy. Disease response and progression per RECIST 1.1 as documented by the 
Investigator in the CRF will be the basis for patient management and supportive statistical 
analyses of radiology-based study endpoints. 
Central radiology review for disease response and progression will be conducted. Timely and 
complete disease assessments and transfer of radiographic documentation to the Central 
Radiology Laboratory is critical to the integrity of this clinical trial. 

 
 
 
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Patients will receive study treatment as assigned at randomization until disease progression, 
unacceptable adverse events, investigator decision, patient refusal or death. Patients experiencing 
clinical benefit in the judgment of the Investigator may continue study treatment beyond disease 
progression as defined by RECIST 1.1 if the progression is not rapid, symptomatic, or requiring 
urgent medical intervention. Patients considering continuation of study treatment beyond 
RECIST 1.1 defined disease progression must be provided with and sign an informed consent 
detailing any available therapies and potential clinical benefit that the patient may be foregoing 
by continuing study treatment. Patients remaining on study treatment beyond RECIST 1.1. 
defined progression will continue to undergo disease assessments until study treatment is 
discontinued. Post-treatment disease assessment will continue until objective disease progression 
or start of subsequent anti-cancer therapy, whichever is sooner. PRO assessments will continue 
until start of subsequent anti-cancer therapy. No crossover to the alternative treatment 
assignment is provided in this study. 
End of trial in a Member State of the European Union is defined as the time at which it is 
deemed that sufficient patients have been recruited and completed the study as stated in the 
regulatory application (ie, Clinical Trial Application [CTA]) and ethics application in the 
Member State (Section 14.1). End of Trial in all other participating countries 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 (Section 14.2). 
The study will employ a group sequential design with one planned interim analysis and one final 
analysis for OS. The interim analysis will be performed after approximately 242 OS events (65% 
of total OS events) have occurred, with the possibility of stopping the trial for efficacy or futility. 
The efficacy boundary is constructed using the O’Brien-Fleming boundary implemented by Lan-
DeMets alpha spending function. A non-binding futility boundary based on 2% conditional 
power (CP) is also constructed at the time of the interim analysis. The study may be declared 
futile if the estimated HR at interim > 0.92. The exact alpha spent and the futility boundary will 
be adjusted based on the observed number of events. 
4. 
SUBJECT SELECTION AND ENROLLMENT 
Patient eligibility must be reviewed and documented by an appropriately qualified member of the 
Investigator’s study team before patients are randomized into the study. No exceptions to the 
patient eligibility requirements will be granted by the Sponsor. 
4.1. 
Inclusion Criteria 
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the 
study. 
1. Histologically or cytologically confirmed non-squamous NSCLC with metastatic (Stage 
IV) or unresectable, locally advanced (Stage IIIB/IIIC) disease, not amenable to 
treatment with curative intent including concurrent chemoradiotherapy. 

 
 
 
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2. Receipt of at least one but not more than two prior treatment regimens in the advanced 
disease setting to include: 
• Treatment with a CIT (ie, anti-PD-1/PD-L1) and a platinum-based chemotherapy, 
which may have been in combination or in sequence (ie, platinum-based 
chemotherapy followed by CIT) 
− Prior treatment may have included maintenance therapy with a chemotherapy 
agent (eg, pemetrexed) and/or a CIT 
• Most recent treatment regimen must have included a CIT with radiographic disease 
progression on or after treatment, for example: 
− 1 prior treatment regimen: platinum-based chemotherapy in combination with 
CIT  radiographic disease progression, or 
− 2 prior treatment regimens: platinum-based chemotherapy  disease progression 
 CIT  radiographic disease progression 
NOTE: Platinum-based adjuvant, neoadjuvant, or definitive chemoradiation therapy given 
for locally advanced disease followed by recurrent or metastatic disease within 6 months of 
completing chemotherapy may be considered treatment in the advanced disease setting. 
3. Duration of at least 4 months (120 days) from first dose of most recent CIT to date of 
radiographic disease progression. 
4. Availability of source documents for historical disease evaluations to allow Investigator 
certification of disease progression on or after most recent CIT. 
5. Most recent prior therapy (eg, chemotherapy, CIT, or radiation therapy) discontinued at 
minimum of 2 weeks before the date of randomization; palliative radiation therapy to 
skeletal metastases and stereotactic radiation for brain metastases allowed if discontinued 
at least 7 days before the date of randomization. 
6. Candidacy to receive treatment with docetaxel as the next line of therapy if randomized 
to the comparator arm. 
7. Recovery from adverse effects of prior therapy to baseline or Grade 1 (excluding 
alopecia). 
8. ≥ 18 years of age. 
9. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. 
10. Life expectancy of at least 3 months. 
11. Adequate bone marrow and organ function demonstrated by: 
a. Absolute neutrophil count ≥ 1,500/mm3 (≥ 1.5 × 109/L). 
b. Hemoglobin ≥ 9.0 g/dL not dependent on transfusion support. 
c. Platelet count ≥ 100 × 109/L (≥ 100,000 per mm3). 

 
 
 
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d. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 1.5 × ULN 
without liver metastases; < 5.0 x ULN if documented liver metastases; if alkaline 
phosphatase > 2.5 × ULN then ALT and AST must be ≤ 1.5 × ULN with or without 
liver metastases. 
e. Serum bilirubin ≤ 1.0 x ULN. 
f. Calculated creatinine clearance ≥ 40 mL/min, using the Cockcroft-Gault formula. 
12. 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. 
13. Completed informed consent process, including signing IRB/EC-approved informed 
consent form. 
14. Willing to comply with clinical trial instructions and requirements. 
4.2. 
Exclusion Criteria 
Patients presenting with any of the following will not be included in the study: 
1. Discontinuation of prior treatment with CIT more than 90 days prior to the date of 
randomization. 
2. Receipt of systemic cancer therapy since discontinuation of CIT, with the exception of 
maintenance chemotherapy. 
3. Active brain metastases. Patients are eligible if brain metastases are adequately treated 
and patients are neurologically stable (except for residual signs or symptoms related to 
the central nervous system (CNS) treatment) for at least 2 weeks prior to randomization 
without the use of anticonvulsants and without the use of corticosteroids (or are on a 
stable or decreasing dose of ≤10 mg daily prednisone or equivalent). 
4. Carcinomatous meningitis. 
5. Known history of tumors that test positive for EGFR, ROS1, ALK mutations, or ALK 
fusions. 
6. Prior therapies: 
• Immunotherapies not previously specified, including anti-OX40 and anti–CD137; 
prior anti-CTLA-4 is permitted. 
• Cancer therapy having the same mechanism of action as sitravatinib (eg, tyrosine 
kinase inhibitor with a similar target profile or bevacizumab). 
7. Known toxicity on prior checkpoint inhibitor treatment: 
a. ≥ Grade 3 immune-related AE related to checkpoint inhibitor. 
b. Grade 2 immune-related AE associated with checkpoint inhibitor unless the AE 
resolved or was well controlled by withholding the checkpoint inhibitor and/or 

 
 
 
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treatment with steroids, with the exception of prior colitis, myocarditis, and 
pneumonitis, which are exclusionary. 
c. CNS or ocular AE of any grade related to checkpoint inhibitor. 
NOTE: Patients with a prior endocrine AE are permitted to enroll if they are stably 
maintained on appropriate replacement therapy and are asymptomatic. 
8. Active or prior documented autoimmune disease: 
a. Inflammatory bowel disease (eg, Crohn’s disease, ulcerative colitis). 
b. History of interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis 
which required steroid treatment, or any evidence of clinically active ILD. 
c. Active or prior documented autoimmune disease within the past 2 years. NOTE: 
Patients with Type 1 diabetes, vitiligo, Graves’ disease, residual hypothyroidism due 
to an autoimmune condition only requiring hormone replacement, or psoriasis not 
requiring systemic treatment (within the past 2 years) are not excluded. 
9. Active or prior immunocompromising conditions: 
a. Current or prior use of immunosuppressive medication within 28 days before the date 
of randomization, with the exceptions of topical, ocular, intranasal and inhaled 
corticosteroids (with minimal systemic absorption) or systemic corticosteroids at 
physiological doses, which are not to exceed 10 mg/day of prednisone, or an 
equivalent corticosteroid. A brief course (≤ 3 days) of systemic corticosteroids 
> 10 mg/day of prednisone (or equivalent corticosteroid) for prophylaxis (eg, contrast 
dye allergy) or for treatment of non-immune conditions (eg, delayed-type 
hypersensitivity reaction caused by a contact allergen) is permitted within the 
28 days. 
b. Known acute or chronic human immunodeficiency virus (HIV); 
− Sites in Germany and Switzerland only: HIV infection at screening (positive HIV 
test). 
c. History of primary immunodeficiency. 
d. History of allogeneic transplant. 
10. History of severe hypersensitivity reaction to any monoclonal antibody or polysorbate 80. 
11. Criterion #11 removed, but numbering maintained. 
12. Use of live vaccines against infectious disease (eg varicella) within 28 days of the date of 
randomization (note: killed vaccinations (eg influenza) are allowed at any appropriate 
time before and during the study). 
13. Known acute or chronic hepatitis B or hepatitis C. Patients treated for hepatitis C with no 
detectable viral load are permitted. 
• Sites in Germany and Switzerland (testing required during screening): positive 
hepatitis B surface antigen [HBsAg] or positive hepatitis C virus [HCV] antibody;  

 
 
 
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− patients with past or resolved hepatitis B virus (HBV) infection (defined as the 
presence of hepatitis B core antibody [HBcAb] and absence of HBsAg) are 
eligible only if HBV DNA is negative 
− patients treated for hepatitis C with no detectable viral load (HCV RNA negative) 
are permitted 
14. History of hypersensitivity to study treatment excipient. 
15. History of stroke or transient ischemic attack within the previous 6 months. 
16. Any of the following cardiac abnormalities: 
a. Unstable angina pectoris within the past 6 months. 
b. Symptomatic or uncontrolled atrial fibrillation within the past 6 months. 
c. Congestive heart failure ≥ NYHA Class 3 within the past 6 months. 
d. Prolonged QTc on electrocardiogram > 480 milliseconds. 
e. Left ventricular ejection fraction (LVEF) < 40%. 
17. Ongoing need for treatment with concomitant medication known to cause prolonged 
QTc. Such medication may be discontinued or changed to a different medication prior to 
enrollment. 
18. Uncontrolled arterial hypertension (> 150 mm Hg systolic or > 100 mm Hg diastolic) on 
multiple observations despite standard of care treatment. 
19. Major surgery within 4 weeks of the date of randomization. 
20. History of significant hemoptysis or hemorrhage within 4 weeks of the date of 
randomization. 
21. Known or suspected presence of another malignancy that could be mistaken for the 
malignancy under study during disease assessments. 
22. Pregnancy. WOCBP must have a negative serum or urine pregnancy test documented 
within the screening period prior to the date of randomization. 
23. Breast-feeding or planning to breast-feed during the study or within 30 days following 
the last dose of docetaxel or sitravatinib and within 5 months following the last dose of 
nivolumab. 
24. Any serious illness, uncontrolled inter-current illness, psychiatric illness, active or 
uncontrolled infection, or other medical condition or history, including laboratory results, 
which, in the Investigator’s opinion, interferes with the patient’s capacity to provide 
informed consent, or would be likely to interfere with the patient’s participation in the 
study, or with the interpretation of the results. 

 
 
 
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4.3. 
Life Style Guidelines 
Patients, including men whose partner is a WOCBP, 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 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 abstinencea 
a 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 (ie, 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 spermicidea 
3. Cap, diaphragm or sponge with spermicide 
a A combination of male condom with either cap, diaphragm or sponge with spermicide 
(double barrier methods) are also considered acceptable, but not highly effective, birth 
control methods. 
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 (eg, 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. 

 
 
 
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4.4. 
Randomization 
Following completion of the study-specific informed consent process, patients will be assigned a 
patient number, automatically generated, by a centralized Interactive Web Response System 
(IWRS) via the “screening” function. The patient number must be used on all documentation and 
correspondence with the Sponsor, Contract Research Organization (CRO) and laboratory 
vendors. Following review of all screening procedures, patient eligibility will be confirmed by 
appropriately qualified staff at the investigational site. Patients will be randomized in a 1:1 ratio 
using IWRS to receive treatment assignment to either sitravatinib and nivolumab or docetaxel. 
Study treatment should begin within 3 business days of randomization. 
5. 
STUDY TREATMENTS 
Investigational Product 
An investigational product, also known as an investigational medicinal product in some regions, 
is defined as a pharmaceutical from of an active substance or placebo being tested or used as a 
reference in a clinical study, including products already with a marketing authorization but used 
or assembled (formulated or packaged) differently than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form. 
Investigational products must be dispensed only from official study sites by authorized personnel 
according to local regulations. 
In this protocol, investigational products are:  
• Sitravatinib (MGCD516)  
• Nivolumab (OPDIVO) 
• Docetaxel 
Non-Investigational Product 
Medications used as support or escape medication for preventative, diagnostic, or therapeutic 
reasons, as components of the standard of care for a given diagnosis may be considered as non-
investigational products. These non-investigational products will be sourced by the investigative 
sites if available and permitted by local regulations. 
In this protocol, non-investigational product(s) is/are: 
• Any pre-medications associated with the comparator arm (eg, dexamethasone, or 
institutional equivalent, given as premedication for docetaxel) and medications used 
to treat chemotherapy infusion-related reactions. 
• Any medications used to treat nivolumab infusion-related reactions (eg, steroids). 

 
 
 
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5.1. 
Sitravatinib 
5.1.1. 
Sitravatinib Formulation, Packaging and Storage 
This study began patient treatment in the USA with the sitravatinib free base capsule formulation 
used in previous clinical trials. Transition to use of an alternative formulation, sitravatinib malate 
capsule formulation, is being implemented with this protocol amendment. Newly randomized 
patients will be administered the sitravatinib malate capsule formulation. Patients in the USA on 
study treatment with the free base capsule formulation at the time the sitravatinib malate capsule 
formulation is introduced will remain on the free base capsule formulation until treatment 
discontinuation. The formulations are described below. 
• (USA only) The composition of the drug product used in previous clinical trials 
consists of a blend of sitravatinib (MGCD516) free base drug substance, 
microcrystalline cellulose, polysorbate 80, and colloidal silicon dioxide. The blend is 
filled into hard gelatin capsules. To help differentiate between the products, the free 
base formulation will be labeled with the drug product code “MGCD516”. 
• The sitravatinib malate capsule product consists of a blend of sitravatinib malate drug 
substance, microcrystalline cellulose, mannitol, croscarmellose sodium, colloidal 
silicon dioxide, and magnesium stearate; the blend is filled into hard gelatin capsules. 
To help differentiate between the products, the malate formulation will be labeled 
with the drug product name “Sitravatinib”. 
The strength of all sitravatinib capsule formulations are expressed based on MGCD516 free base 
weight. Dose strengths of sitravatinib will be provided in the Pharmacy Study Manual. 
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 and all countries in 
which the clinical trial material will be used and will be printed in the languages required in the 
countries in which the study is conducted. 
Investigational clinical trial material should be stored in an area that is secure, with limited 
access and monitored for temperature using a calibrated thermostat or thermometer. Sitravatinib 
capsules should be stored under the conditions stated on the container labels and the Pharmacy 
Study Manual. 
Refer to the Pharmacy Study Manual for details. 
5.1.2. 
Sitravatinib Preparation, Dispensing, and Accountability 
Only 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 
chemotherapeutic agents. 

 
 
 
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Study site personnel will dispense bottles containing sitravatinib capsules on Day 1 of each dose 
cycle. Sufficient supply will be provided for each cycle and extra capsules may be provided to 
cover an additional 2 days in case of delayed clinic visits or lost capsules. 
All sitravatinib study treatment supplies will be accounted for in the drug accountability 
inventory forms supplied by the Sponsor or using locally approved forms that include all 
required information. The drug accountability inventory forms must identify the study drug, 
including batch or lot numbers and account for its disposition on a patient-by- patient basis, 
including specific dates and quantities. The forms must be signed by the individual who 
dispensed the drug. 
Patients will be asked to record their daily dosing on Sponsor provided diary cards and report 
any missed doses or lost doses at the next clinic visit. On the back of each Sponsor provided 
diary card, written dosing instructions for sitravatinib capsules are provided (eg, fasting 
instructions, take with water, etc). Patients should be told to bring study treatment bottle(s) 
(empty or not) and completed dosing diaries with them to the clinic visit for a compliance check 
and capsule count. Study site personnel will retain the bottle(s) until a monitor has completed 
reconciliation and retain dosing diaries with site study files. 
At the end of the study, all unused sitravatinib drug supplies must be destroyed in accordance 
with local Standard Operating Procedure provided to the Sponsor for the Trial Master File, or 
returned to the Sponsor or its appointed agent, as directed by the Sponsor. 
5.1.3. 
Sitravatinib Administration 
Sitravatinib capsules will be administered orally, QD, in a continuous regimen expressed in 28-
day cycles. 
• The starting dose of sitravatinib using the malate capsule formulation is 100 mg QD. 
• The starting dose of sitravatinib using the free base capsule formulation (for patients 
who started on free base capsule formulation, USA only) is 120 mg QD. 
Depending on safety observations, the sitravatinib dose during subsequent cycles of treatment 
may be reduced in accordance with Table 3 for patients administered the free base capsule 
formulation and in accordance with Table 4 for patients administered the malate capsule 
formulation. 
The dose selected for the malate capsule formulation is based on delivering sitravatinib exposure 
comparable to that achieved using the free base capsules at 120 mg QD. Study 516-006 (interim 
report) demonstrated bioequivalence between the 100 mg sitravatinib malate and 120 mg 
sitravatinib free base capsule formulations (see Section 1.3.3.4). 
The following guidelines should be followed for sitravatinib administration: 
• Dosing in the morning is preferred. 

 
 
 
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• 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. This requirement may be eliminated based on the outcome of the study 
described in Section 1.3.3.5. Any change in fasting will be implemented by 
Administrative Letter to Investigators and reiterated in the next protocol amendment 
required within the study. 
• Capsules should be taken with at least 200 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. 
On days when sitravatinib and nivolumab dosing are both scheduled, the daily dose of 
sitravatinib should precede nivolumab infusion for logistical reasons. This order of dosing is of 
most interest on days when blood sampling is scheduled for sitravatinib PK. 
5.1.4. 
Sitravatinib Dose Modification or Discontinuation 
This protocol section provides guidance for dose modification of sitravatinib (ie, interruption, 
dose reduction or discontinuation) for AEs attributed to sitravatinib. For AEs attributed to 
nivolumab, see the current OPDIVO approved product label (USPI, SmPC). 
Available dose modification levels for each of the sitravatinib formulations are outlined in 
Table 3 and Table 4. Dose modifications for the sitravatinib free base capsule formulation 
(Table 3) follow guidelines from Study MRTX-500. Dose modifications guidelines for the 
sitravatinib malate capsule formulation (Table 4) follow comparable dose reduction proportions 
used for the sitravatinib free base capsule formulation. Guidelines for sitravatinib dose 
modifications to be implemented to manage AEs are described in Sections 5.4.1 and 5.4.3. Once 
the dose has been reduced, re-escalation is generally not recommended but may be considered on 
a case-by-case basis. 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. 
The starting dose for sitravatinib using the free base capsule formulation is 120 mg administered 
once daily (for patients who started on free base capsules formulation, USA only). 
Table 3: 
Sitravatinib Sequential Dose Reductions for Individual Patients on Free Base 
Capsule Formulation 
120 mg once daily 
80 mg once daily 
60 mg once daily 
 

 
 
 
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Dose reduction below 60 mg QD to 40 mg QD for the free base capsule formulation may be 
undertaken after discussion with the Sponsor. 
The starting dose for sitravatinib using the malate capsule formulation is 100 mg administered 
once daily. 
Table 4: 
Sitravatinib Sequential Dose Reductions for Individual Patients on Malate 
Capsule Formulation 
100 mg once daily 
70 mg once daily 
50 mg once daily 
 
Dose reduction below 50 mg QD to 35 mg QD for the malate capsule formulation may be 
undertaken after discussion with the Sponsor. 
In the event of sitravatinib-related AE, dose reduction with continuous treatment is preferred 
over repeated dose interruption. If treatment with sitravatinib is delayed for ≥ 14 days, then 
resumption at a reduced dose should be considered. If treatment with sitravatinib is withheld for 
≥ 28 consecutive days, then permanent discontinuation from sitravatinib should be considered. If 
one study drug is interrupted or discontinued, administration of the other study drug may 
continue at the discretion of the Investigator. 
5.2. 
Nivolumab Study Drug 
Nivolumab will be provided by the Sponsor. All administration information, including adverse 
event management should be in accordance with the current OPDIVO approved product label 
(USPI, SmPC). The following reports information and guidance included in the OPDIVO USPI 
dated September 2021. Refer to the current OPDIVO approved product label (USPI, SmPC) 
provided by the manufacturer for updates during the conduct of this clinical trial. 
5.2.1. 
Nivolumab Formulation and Packaging 
OPDIVO is a sterile, preservative-free, non-pyrogenic liquid. OPDIVO injection for intravenous 
infusion is supplied in single-dose vials. Each mL of OPDIVO solution contains nivolumab 
10 mg. Refer to the current OPDIVO approved product label (USPI, SmPC) for further details. 
5.2.2. 
Nivolumab Preparation and Dispensing 
Visually inspect drug product solution for particulate matter and discoloration prior to 
administration. OPDIVO is a clear to opalescent, colorless to pale-yellow solution. 
Discard the vial if the solution is cloudy, discolored, or contains extraneous particulate matter 
other than a few translucent-to-white, proteinaceous particles. Do not shake the vial. 

 
 
 
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• Withdraw the required volume of OPDIVO and transfer into an intravenous 
container. 
• Dilute OPDIVO with either 0.9% Sodium Chloride Injection, United States 
Pharmacopeia (USP) or equivalent or 5% Dextrose Injection, USP or equivalent to 
prepare an infusion with a final concentration ranging from 1 mg/mL to 10 mg/mL. 
The total volume of infusion must not exceed 160 mL. 
• For patients with body weights less than 40 kg, the total volume of infusion must not 
exceed 4 mL/kg of body weight. 
• Mix diluted solution by gentle inversion. Do not shake. 
• Discard partially used vials or empty vials of OPDIVO. 
The product does not contain a preservative. After preparation, store the OPDIVO infusion 
either: 
• at room temperature for no more than 8 hours from the time of preparation. This 
includes room temperature storage of the infusion in the intravenous (IV) container 
and time for administration of the infusion, or 
• under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from the 
time of preparation to end of infusion. 
Do not freeze OPDIVO solutions. 
5.2.3. 
Nivolumab Administration 
Nivolumab (OPDIVO) will be administered in this study as an infusion over approximately 
30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator 
and in accordance with the current OPDIVO approved product label (USPI, SmPC). Sitravatinib 
dosing should precede nivolumab infusion. Nivolumab infusion can be administered any time 
after the oral dose of sitravatinib is administered, except on C1D1 where the 30 min post 
sitravatinib dose PK sample has to be collected before nivolumab infusion. 
Administer the OPDIVO infusion through an intravenous line containing a sterile, non- 
pyrogenic, low protein binding in-line filter (pore size of 0.2 micrometer to 1.2 micrometer). 
Flush the intravenous line at end of infusion. 
5.2.4. 
Nivolumab Dose Modification or Discontinuation 
Required dose modifications (ie, interruption or discontinuation) for nivolumab should be 
performed per the current OPDIVO approved product label (USPI, SmPC), in addition to 
potential dose modifications for sitravatinib in accordance to protocol Section 5.4.1. 
If one agent is interrupted or discontinued, administration of the other agent may continue at the 
discretion of the Investigator and patient. 

 
 
 
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5.3. 
Docetaxel Study Drug 
Docetaxel will be obtained from commercial sources or provided by the Sponsor depending on 
local country requirements and managed in accordance with the current TAXOTERE approved 
product label. 
TAXOTERE or generic equivalent (docetaxel) are acceptable for use in this study. 
The following reports information and guidance included in the TAXOTERE USPI dated  May 
2021. Refer to the current TAXOTERE approved product label (USPI, SmPC) provided by the 
manufacturer for updates during the conduct of this clinical trial. 
5.3.1. 
Docetaxel Formulation and Packaging 
TAXOTERE (docetaxel) Injection Concentrate, Intravenous Infusion (IV), is a sterile, non-
pyrogenic, non-aqueous solution. TAXOTERE is supplied in single use vials, 20 mg/mL and 
80 mg/4mL, 50/50 (volume/volume) ratio polysorbate 80/dehydrated alcohol. Refer to the 
current TAXOTERE approved product label (USPI, SmPC) for further detail. 
5.3.2. 
Docetaxel Preparation and Dispensing 
Only 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 
chemotherapeutic agents. 
TAXOTERE Injection Concentrate requires no prior dilution with a diluent and is ready to add 
to the infusion solution. Use only a 21-gauge needle to withdraw TAXOTERE from the vial 
because larger bore needles (eg, 18 and 19 gauge) may result in stopper coring and rubber 
particulates. Add drug concentrate into a 250 mL infusion bag or bottle of either 0.9% Sodium 
Chloride solution or 5% Dextrose solution to produce a final concentration of 0.3 mg/mL to 
0.74 mg/mL. If a dose greater than 200 mg of TAXOTERE is required, use a larger volume of 
the infusion vehicle so that a concentration of 0.74 mg/mL TAXOTERE is not exceeded. 
Thoroughly mix the infusion by gentle manual rotation and inspect visually for particulate matter 
or discoloration prior to administration whenever the solution and container permit. 
5.3.3. 
Docetaxel Administration 
• TAXOTERE should be administered in a facility equipped to manage possible 
complication (eg, anaphylaxis). 
• Patients should be premedicated with oral corticosteroids such as dexamethasone 
16 mg per day (eg, 8 mg twice daily) for 3 days starting 1 day prior to TAXOTERE 
administration, unless contraindicated, in order to reduce the incidence and severity 
of fluid retention as well as the severity of hypersensitivity reactions. 

 
 
 
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• For treatment of NSCLC after failure of prior platinum-based chemotherapy, the 
TAXOTERE recommended dose is 75 mg/m2 administered intravenously over 1 hour 
every 3 weeks. 
Before each cycle of docetaxel, 
• LFTs should be reviewed, and docetaxel should not be given if bilirubin > ULN, or if 
AST and/or ALT > 1.5 × ULN concomitant with alkaline phosphatase > 2.5 × ULN. 
• Blood counts should be reviewed, and docetaxel should not be given if neutrophil 
counts are < 1500 cells/mm3. 
During this study, institutional or regional standard practice for administration of pre- 
medications and docetaxel may be followed with the exception of the initial (Cycle 1) dose 
which should remain 75 mg/m2. 
5.3.4. 
Docetaxel Dose Modification 
The following is guidance provided in the TAXOTERE USPI dated May 2021. Refer to the 
current TAXOTERE approved product label (USPI, SmPC); a generic equivalent product may 
be used in the study. Patients who are dosed initially at 75 mg/m2 and who experience either 
febrile neutropenia, neutrophils < 500 cells/mm3 for more than one week, severe or cumulative 
cutaneous reactions, or other Grade 3/4 non-hematological toxicities during TAXOTERE 
treatment should have treatment withheld until resolution of the toxicity and then resumed at 
55 mg/m2. Patients who develop ≥ Grade 3 peripheral neuropathy should have TAXOTERE 
treatment discontinued entirely. 
During this study, local standard practice for docetaxel administration, with the exception of the 
initial (Cycle 1) dose which should remain 75 mg/m2, may be used. Patients requiring more than 
two dose reductions of docetaxel due to adverse events should discontinue treatment with 
docetaxel. 
5.4. 
Management of Adverse Events 
5.4.1. 
Sitravatinib-Related Adverse Events 
5.4.1.1. 
General Management of Non-Hematological Toxicities 
A complete review of adverse events should be conducted at each clinic visit. Symptomatic 
Grade 2 sitravatinib-related non-hematological adverse events occurring any time on study, 
particularly early in treatment (eg, Cycle 1 Day 15 or Cycle 2 Day 1), are recommended to be 
managed using dose reduction to the next lower dose level, per the reduction schedule outlined in 
Table 3 (free base capsule formulation) and Table 4 (malate capsule formulation), rather than 
continued dosing until interruption becomes necessary. 
Non-hematological toxicities ≥ Grade 3 and considered to be related to sitravatinib treatment 
should be managed with sitravatinib interruption, with or without dose reduction, until resolution 

 
 
 
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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 5. Treatment with sitravatinib may continue without 
dose modification (eg, interruption or reduction) in cases of asymptomatic amylase and/or lipase 
increases in the absence of other clinical evidence of pancreatitis (eg, symptoms, electrolyte 
abnormalities, radiographic changes) at the investigator’s discretion. Recurrence of a toxicity 
may be managed similarly. If treatment is interrupted for ≥ 28 days, permanent discontinuation 
of sitravatinib should be considered. 
Table 5: 
Sitravatinib Dose Modifications – Non-Hematological Drug- Related 
Toxicities1 
Toxicity 
Treatment Delay 
Dose Modification 
Grade 1 
Continue treatment unchanged 
Grade 2 Asymptomatic 
May be implemented based on Investigator discretion2 
Grade 2 Symptomatic 
May be implemented based on Investigator or patient discretion2 
Early dose reduction to the next lower dose level is recommended over 
treatment interruption. 
Grade 3 or 4 
Hold until ≤ Grade 1 or return to 
baseline2 
Resume at dose one or more levels 
below that inducing the toxicity. 
Exceptions presented in footnotes2,3 
1 Management of selected adverse events for sitravatinib are presented in Section 5.4.1.3. 
2 The current OPDIVO approved product label (USPI, SmPC) must be consulted to determine appropriate dose 
modifications for nivolumab. 
3 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; 
b. Grade 3 amylase or lipase elevation that is not associated with symptoms or other clinical (eg, electrolyte 
abnormalities, radiographic changes) manifestations of pancreatitis. 
 
5.4.1.2. 
General Management of 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 should be 
implemented in the following cases: 
• Grade 3 or 4 febrile neutropenia; 
• Grade 4 neutropenia persisting for ≥ 8 days; or 

 
 
 
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• Grade 4 thrombocytopenia of any duration or Grade 3 thrombocytopenia with 
bleeding. 
5.4.1.3. 
Management of Selected Adverse Event 
The following are guidelines for management of potential AEs more specific to treatment with 
sitravatinib or agents in the same class of cancer treatment. 
5.4.1.3.1. Hypertension 
Hypertension, including Grade 4 events, has been reported with sitravatinib. Dihydropyridine 
calcium channel blockers such as nifedipine, amlodipine, and nicardipine may be considered if 
anti-hypertensive therapy is required and should be considered for patients with Grade 3 
hypertension without clinically significant increases in blood pressure (BP) (Table 6). On the 
other hand, in cases of Grade 3 hypertension with clinically significant increases in blood 
pressure (Table 6), temporary suspension of sitravatinib dosing is recommended until blood 
pressure is controlled. Treatment with sitravatinib may resume at the same or a lower dose at the 
discretion of the Investigator. 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 Investigator. In the event of Grade 4 hypertension, sitravatinib 
should be permanently discontinued (Table 6). 
Table 6: 
Sitravatinib Dose Modification for Increased Blood Pressure 
Toxicity 
Interruption 
Reduction 
Grade 1 or 2 hypertension 
May be implemented based on Investigator and 
patient discretion 
Grade 3 hypertension without clinically significant 
increases in BP as defined below 
Investigator discretion. Consider anti- hypertensives 
per Section 5.4.1.3.1 
Grade 3 hypertension with clinically significant 
increases in BP 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 
Hold until ≤ Grade 2 or 
return to baseline 
Investigator discretion 
Grade 4 hypertension 
Discontinue sitravatinib 
Discontinue sitravatinib 
 
5.4.1.3.2. Palmar-Plantar Erythrodysesthesia 
Palmar plantar erythrodysesthesia (PPE) has been reported as a DLT 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 

 
 
 
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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. 
5.4.1.3.3. Diarrhea 
Diarrhea should be evaluated to determine whether it may be immune-mediated colitis due to 
nivolumab (see Section 5.4.3.1), related to sitravatinib, or due to another cause. 
Diarrhea has been reported with sitravatinib treatment, though the mechanism remains unclear, 
as with other small molecule RTK inhibitors. 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 developing dehydration or clinically significant 
electrolyte abnormalities due to sitravatinib should interrupt sitravatinib treatment, but treatment 
may be restarted once diarrhea is controlled. 
5.4.1.3.4. Hemorrhagic Events 
The risk of hemorrhagic events with sitravatinib is unknown; 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. 
5.4.1.3.5. Thrombotic Events 
Though thrombotic events (eg, pulmonary embolism) have been reported with sitravatinib and 
with inhibitors of VEGFR, the risk of such events with sitravatinib is unknown. Precautions 
should be taken in patients with recent, clinically significant thrombotic events, and treatment 
should be discontinued in patients who develop clinically significant thromboembolic 
complications such as acute myocardial infarction or severe pulmonary embolism. 
5.4.1.3.6. 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 at the Investigator’s 
discretion. 
5.4.1.3.7. 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 <50% and >20% below baseline. Discontinuation 

 
 
 
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should be considered for patients requiring acute hospitalization for treatment of congestive heart 
failure (CHF). 
5.4.1.3.8. Proteinuria 
Although the risk with sitravatinib is unknown, proteinuria has been described with other 
inhibitors of the VEGFR pathway. Patients 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 restart when protein 
levels decrease to less than 2 grams/24 hours. Patients who develop nephrotic syndrome should 
be withdrawn from treatment with sitravatinib. 
5.4.2. 
Nivolumab Adverse Event Management Guidelines 
Refer to the local current OPDIVO approved product label (USPI, SmPC) for guidance 
concerning management of AEs, including irAEs, during treatment with nivolumab. 
5.4.3. 
Management of Immune-Related Adverse Events 
Single agent sitravatinib has not been associated with irAEs. However, the potential exists for 
irAEs associated with nivolumab treatment or for sitravatinib to contribute to irAEs associated 
with nivolumab treatment. In the event of a Grade 2 irAE during study treatment, administration 
of sitravatinib and nivolumab should be interrupted until the event stabilizes to Grade 
≤ 1 (consistent with guidance provided in the current OPDIVO approved product label 
[USPI, SmPC]). At the time of resumption of sitravatinib dosing, a dose reduction may be 
implemented at the discretion of the Investigator. 
Management of Grade 3 and 4 irAEs should be performed in accordance with the current 
OPDIVO approved product label (USPI, SmPC). However, recurrent Grade 3, or any Grade 4, 
irAEs should generally be managed with permanent discontinuation of nivolumab, and 
temporary or permanent interruption of sitravatinib. Sitravatinib may be resumed at the same or 
lower dose at the discretion of the Investigator once the event stabilizes to Grade ≤ 1. 
5.4.3.1. 
Diarrhea/Colitis 
The management of diarrhea should be guided by clinical judgment and an assessment of the 
most likely causative etiology, with special consideration given to the potential for immune-
related colitis. The presence of abdominal pain, mucus or blood in the stool or peritoneal signs 
should raise the index of suspicion for immune-related colitis, as these features are generally not 
observed with sitravatinib treatment-associated diarrhea. The diarrhea observed with sitravatinib 
generally improves within several days of interrupting study medication, with close observation 
may help establish the most likely causality. 
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-

 
 
 
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related colitis, all study medications should be withheld and treatment with immuno-suppressive 
therapy initiated as detailed in the current OPDIVO approved product label (USPI, SmPC). 
5.4.3.2. 
Increased Transaminases 
The management of increases in AST and ALT should be guided by the clinical judgment of the 
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. 
For cases where transaminase increases are not likely to be immune-related, treatment 
management decisions should be made using Investigator discretion in consideration of clinical 
factors. Recommended treatment modifications for sitravatinib are provided in Table 7. 
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 should be withheld and treatment with immuno-
suppressive therapy initiated as detailed in the current OPDIVO approved product label 
(USPI, SmPC). 
Table 7: 
Sitravatinib Dose Modification for Increased Hepatic Transaminase 
Toxicity 
Treatment Delay 
Dose Modification 
Grade 1 (> ULN to 3.0 × ULN) 
May be implemented based on Investigator and patient discretion 
Grade 2 (> 3.0 to 5.0 × ULN) 
Not required1 
Decrease by 1 dose level1 
Grade 3/4 (> 5.0 × ULN) 
Hold until ≤ Grade 1 or return to 
baseline1 
If resolution occurs within 29 days, 
decrease by 1 dose level1 
If no resolution within 29 days, 
discontinue sitravatinib1 
1 The current OPDIVO approved product label (USPI, SmPC), and Section 5.4.3, in case the event is deemed to be 
an irAE, must be consulted to determine appropriate dose modifications for nivolumab. 
 
5.4.4. 
Management of Hy’s Law Cases 
In the event a patient develops concurrent increase in AST and/or ALT ≥ 3 × ULN, bilirubin 
≥ 2 × ULN but without concurrent increases in alkaline phosphatase (ie, alkaline phosphatase 
< 2 × ULN), that is not attributable to other causes (eg, liver metastases, biliary obstruction, viral 
hepatitis, concomitant medication, etc), sitravatinib and nivolumab should be permanently 
discontinued and steroids administered. Hy’s Law cases should be reported as SAEs 
(Section 8.2.1). 

 
 
 
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5.4.5. 
Docetaxel Adverse Event Management Guidelines 
Refer to local current TAXOTERE approved product label (USPI, SmPC) for guidance 
concerning management of AEs during treatment with docetaxel. In addition to local product 
information and the administration guidelines described in Section 5.3, please specifically note: 
Severe hypersensitivity reactions require immediate discontinuation of the docetaxel infusion 
and aggressive therapy. Patients with a history of severe hypersensitivity reactions should not be 
re-challenged with docetaxel. 
5.5. 
Medication Error 
Medication errors may involve patient exposure to a wrong study drug, at a wrong dosing 
frequency, or at a wrong dose level (eg, a dose that is not planned in the study). 
Medication errors occurring during the conduct of this study will be documented as AEs 
(regardless of whether clinical signs or symptoms are observed) and if serious consequences are 
observed, will be reported on SAE forms. In all cases of medication error, the Sponsor should be 
notified immediately. 
There is currently no specific treatment in the event of an overdose of sitravatinib or nivolumab. 
The Investigator will use clinical judgment to treat any overdose. 
5.6. 
Concomitant Therapies 
5.6.1. 
Concomitant Medication(s) 
Prior medications, including chronically administered medication, used within the 28-day period 
preceding Day 1 of the trial, will be reviewed and recorded. Anti-cancer treatment for NSCLC 
will not be recorded as a prior medication but will be listed separately. 
Concomitant medications must be locally approved and used at doses and regimens that are 
considered standard-of-care for the treated indication. Treatment for co-morbidities, disease 
signs and symptoms and treatment emergent adverse events should be provided as necessary in 
the judgment of the Investigator. Patients may continue to use any ongoing medications not 
prohibited by the inclusion/exclusion criteria or treatment plan. Medications to be used with 
caution or avoided are listed for sitravatinib in Appendix 2 and for docetaxel in Appendix 3. 
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. Recommended anti-
emetic agents include granisetron 1 mg as premedication, and then granisetron and/or 
prochlorperazine as needed. 
Medications with QTc Prolonging Activity with Sitravatinib: The risk of QTc prolongation in 
patients receiving sitravatinib has not been characterized. Use of medications known to prolong 

 
 
 
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QTc and pose risk of Torsades de Pointes (examples listed in Appendix 2) is to be avoided 
during sitravatinib treatment. Use of medications with conditional risk of Torsades de Pointes 
should be used with caution during sitravatinib treatment (examples listed in Appendix 2). 
P-gp and BCRP substrates with Sitravatinib: Sitravatinib is a strong inhibitor of P-gp and 
BCRP transporters (Section 1.3.2). Concomitant medications that are sensitive substrates or 
substrates with narrow therapeutic index for these transporters (examples listed in Appendix 2) 
should be used with caution during sitravatinib treatment.  
P-gp Inhibitors and Inducers with Sitravatinib: Sitravatinib is a substrate of P-gp in vitro. 
Inhibitors of P-gp (eg, clarithromycin, itraconazole, propafenone, quinidine, ranolazine, 
ritonavir, verapamil) may increase sitravatinib exposure while inducers of P-gp (eg, rifampin) 
may decrease sitravatinib exposure. Caution should therefore be used when administering 
sitravatinib to patients taking medications that inhibit or induce P-gp. 
CYP3A4 Substrates with Sitravatinib: In vitro data imply that sitravatinib is a strong direct 
inhibitor of CYP3A4 (Section 1.3.2). Concomitant medications that are sensitive substrates or 
substrates with narrow therapeutic index for CYP3A4 (examples listed in Appendix 2) should be 
used with caution during sitravatinib treatment. 
Strong and Moderate CYP3A4 Inhibitors with Docetaxel: Docetaxel is a CYP3A4 substrate. 
In vivo studies showed that the exposure of docetaxel increased 2.2-fold when it was co-
administered with ketoconazole, a potent inhibitor of CYP3A4 (TAXOTERE USPI). 
Concomitant use of docetaxel and medications that are strong or moderate inhibitors of CYP3A4 
may increase exposure to docetaxel and should be avoided (examples listed in Appendix 3). 
These medications should be used with caution if they cannot be avoided; close monitoring for 
toxicity and docetaxel dose reduction should be considered. 
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. 
Transfusions: Patients may receive transfusions as necessary. 
Antibiotics: Antibiotics should be used as needed. Patients with neutropenic fever or infection 
should be treated promptly. 
Supportive Care/Palliative Care: Supportive and palliative care for disease related symptoms* 
may be administered at the Investigator’s discretion, including the use of analgesics. 
*Bisphosphonates (eg, zoledronic acid) and RANK-L inhibitors (eg, denosumab) should be 
initiated prior to first dose of study therapy. 
Growth Factors: Therapeutic colony-stimulating factors should be used in accordance with 
American Society of Clinical Oncology (ASCO) guidelines. 

 
 
 
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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. 
Vaccines: Live attenuated vaccines within 100 days of nivolumab dosing are to be avoided. 
Inactivated vaccines, such as the injectable influenza vaccine, are permitted. 
5.6.2. 
Concomitant Surgery or Radiation Therapy 
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. For patients with bone 
involvement, any foreseeable need for palliative radiotherapy should be addressed before study 
entry, if possible and clinically appropriate (eg, bone lesions at risk for spontaneous micro-
fractures or painful lesions). However, these treatments may be used in cases where it is 
medically necessary. If radiotherapy is required, the Sponsor will provide guidance on duration 
of sitravatinib interruption. 
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. 
5.6.3. 
Other Anticancer or Experimental Therapy 
Use of approved or investigational anticancer treatment will not be permitted during the study 
treatment period, including ramucirumab, chemotherapy, 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 trial is not allowed. 
* Certain ongoing hormonal therapies taken to prevent recurrence of a malignancy not under 
study (eg, tamoxifen/aromatase inhibitor for breast cancer) may be permitted after discussion 
with and agreement of the Sponsor’s Medical Monitor. 
6. 
STUDY ASSESSMENTS 
6.1. 
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. 

 
 
 
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6.2. 
Study Period 
For details on procedures during the study period, see Schedule of Assessments as shown in 
Table 1 and procedure descriptions in Section 7. 
6.3. 
End of Treatment Assessment 
All patients will be followed for non-irAEs for at least 28 days after the last dose of study 
treatment and followed for irAEs for at least 100 days after the last dose of nivolumab or until 
subsequent immunotherapy is administered, whichever is earlier. See the Schedule of 
Assessments (Table 1) for evaluations to be performed at the End of Treatment visit. 
Assessments completed in the previous 4 weeks do not need to be repeated with the exception of 
assessment of AEs, hematology and chemistry. 
6.4. 
Initial Follow-up 
Initial follow up after discontinuation of study treatment will include the following as outlined in 
Table 1: 
• patients discontinuing treatment for reasons other than objective disease progression 
(eg, due to an adverse event or delivery of maximal number of cycles per local 
standard-of-care) will be followed by radiographic evaluation at the intervals 
established for disease assessment until objective disease progression or start of 
subsequent anti-cancer therapy, whichever is sooner; 
• patients randomized to sitravatinib/nivolumab will undergo blood sampling for ADA 
assessment at least 80 days after last dose of nivolumab or immediately before the 
start of subsequent therapy, whichever occurs earlier; and 
• all patients will undergo PRO assessments until start of subsequent anti-cancer 
therapy 
• survival status and start of subsequent therapy will be collected. 
6.5. 
Long-Term Follow-up 
Survival status and subsequent therapies will be collected during long term follow-up as outlined 
in the Schedule of Assessments (Table 1) until death or lost 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. 
6.6. 
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 Investigator or Sponsor 
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. 

 
 
 
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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 Investigator); 
• Global deterioration of health status requiring discontinuation; 
• Adverse event; 
• Significant protocol violation; 
• Lost to follow-up; 
• Refusal for further treatment; 
• Study termination by Sponsor; 
• Pregnancy; 
• Death. 
Reasons for discontinuation from study follow-up may include: 
• Study terminated by Sponsor; 
• 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 may retain and continue to use any data collected before such refusal for 
further follow-up. 
7. 
PROCEDURES 
Every effort should be made to ensure that the protocol required tests and procedures are 
completed as described. However, it is anticipated that there may be circumstances outside of the 
control of the Investigator that may make it infeasible to perform a protocol-specified 

 
 
 
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assessment. In these cases, the Investigator will take all steps necessary to ensure the safety and 
well-being of the patient. When a protocol required test cannot be performed, the Investigator 
will document in the source document and CRF the reason and any corrective and preventive 
actions which he/she has taken to ensure that normal processes are adhered to as soon as 
possible. The study team will be informed of these incidents in a timely fashion. 
7.1. 
Documentation of Disease Progression On or After Prior 
Chemotherapy and Checkpoint Inhibitor Therapy 
Patient eligibility for study enrollment based on radiographic disease progression on or after 
treatment with CIT, either in combination with platinum-based chemotherapy or following 
platinum-based chemotherapy, will be evaluated by the Investigator. Data entered into the CRF 
are to include the date of at least one radiographic evaluation prior to the occurrence of disease 
progression on most recent CIT treatment and the date of the radiographic evaluation 
demonstrating disease progression, as well as specifics about organ systems (eg, lung, liver, 
lymph node, bone and/or brain) having tumors that increase in size or are new. 
Radiology reports coinciding with evaluations interpreted by the Investigator as indicating 
radiographic disease progression on the most recent CIT containing regimen will be appended to 
the CRF in countries where this is permitted by applicable laws and regulations. 
7.2. 
Efficacy 
7.2.1. 
Overall Survival 
Overall survival is the primary efficacy endpoint for this study. Survival status and information 
concerning subsequent therapies will be collected during initial and long-term follow-up as 
outlined in the Schedule of Assessments (Table 1). Long term follow-up may be performed by 
telephone contact or email. In the event a patient discontinues treatment due to loss to follow-up 
or withdraws consent for use data from medical records, surveillance of public sources of death 
information (eg, published obituaries) should be undertaken and reported date of death recorded 
in the CRF. 
7.2.2. 
Radiographic Disease Assessment 
All patients enrolled in the study are to undergo disease evaluations as outlined in the Schedule 
of Assessments (Table 1). On-study disease assessments must be performed as scheduled 
according to the calendar to prevent the introduction of bias based on toxicity into the assessment 
of efficacy. 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. Patients continuing study treatment beyond 
RECIST 1.1 defined progression will continue radiographic disease evaluations until 
discontinuation of study treatment. 

 
 
 
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The Investigator’s assessment of disease response and progression per RECIST 1.1 will be the 
basis for patient management and supportive statistical analyses of radiology-based study 
endpoints. Central radiology review for disease response and progression will be conducted. 
Early central radiology review of screening/baseline assessments for each patient will inform 
Investigators of the minimum evaluation methods required during on-study assessments to 
support review by the Central Radiology Laboratory. Timely and complete disease assessments 
and transfer of radiographic documentation to the Central Radiology Laboratory is critical to the 
integrity of this clinical trial. 
Disease response will be assessed in accordance with RECIST 1.1 (Eisenhauer, 2009). 
Appendix 4 provides guidance in using the response criteria. In addition, the Central Radiology 
Laboratory will evaluate disease response and progression in accordance with the exploratory 
method iRECIST (Seymour, 2017). 
Screening/baseline tumor assessments should include CT with contrast of the chest, CT or MRI 
of the abdomen and pelvis, whole body bone scan (or PET, PET/CT if local standard for clinical 
trials), CT with contrast or MRI of the brain with and without gadolinium and, evaluation of any 
superficial lesions. For patients having effusions or ascites, cytological proof of malignancy 
should be obtained prior to selection of the effusion as a non-target lesion. New effusions that 
have not been evaluated using cytology or were found to be non-malignant should not be 
considered to be cancer lesions. The allowable windows for screening/baseline assessments is 
28 days prior to randomization. 
Disease assessments performed on-study will include CT of the chest, CT or MRI of the 
abdomen and assessment of all known and suspected sites of disease and any additional sites, if 
any, specified for each patient by the Central Radiology Laboratory. Assessments will be 
performed at 8-week intervals, based on a calendar beginning from randomization, until 
approximately 1-year and then every 16 weeks; bone scans may be performed half as often as 
other radiology evaluations (ie, every 16 weeks) and should be performed during assessment for 
confirmation of disease response. The allowable windows for on-study assessments is ± 10 days. 
Assessments will be performed until objective disease progression is documented by the 
Investigator, or subsequent anti-cancer therapy is begun. 
CT scans should be performed with contrast agents unless contraindicated for medical reasons. If 
intravenous contrast is medically contraindicated, the imaging modality to be used (either CT 
without contrast or MRI) should be the modality which best evaluates the disease, and the choice 
should be determined by the Investigator in conjunction with the local radiologist. Depending on 
the adequacy for evaluation of disease, a combination of CT without contrast and MRI should 
most often be used. CT without contrast is preferred for evaluation of lesions in lung 
parenchyma. MRI is not adequate for evaluation of lung parenchyma but should also be 
performed to evaluate all other aspects of the chest. MRI of the abdomen and pelvis should 
substitute for CT with contrast unless the method does not adequately depict the individual’s 
disease, in which case CT without contrast is preferred. New fluid collections identified on-study 

 
 
 
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and existing non-malignant fluid collections that change in character require cytological proof of 
malignancy in order to be reported as a new lesion. 
Patients experiencing tumor response (Partial Response [PR] or Complete Response [CR]) 
should undergo confirmatory assessment no earlier than 4 weeks after initial documentation; it is 
acceptable to perform confirmatory assessments at the next appointed evaluation per protocol (ie, 
8 weeks after the observation of tumor response). In patients for whom bone lesions were 
identified at the baseline, bone scan is required as an element of the confirmation of PR or CR. 
Patients experiencing early radiographic progression accompanied by deteriorating health status 
should be evaluated for the possibility of hyperprogression (Kurman, 2018). Patients 
experiencing rapid clinical and radiographic progression of disease should be discontinued from 
study treatment. 
Materials to be forwarded for independent central radiology review will include all imaging 
studies performed at screening/baseline and on-study, preferably in digital format, using an 
electronic transfer through a portal to the review vendor or transfer on compact disc or optical 
disc. All digital media must be in DICOM format. Films may be forwarded for review if 
necessary; all films must be originals (second original films acceptable) rather than copies of 
films. Further information on materials to be forwarded for independent review is provided in the 
Independent Radiology Study Manual. 
The Sponsor will inform investigators when collection of materials for central radiology review 
is no longer required in this study. 
7.3. 
Safety Assessments 
7.3.1. 
Medical History 
Medical history, including clinically significant past and present medical conditions, will be 
recorded. Lung cancer history will be recorded separately. Signs and symptoms of the patient’s 
cancer diagnosis and/or comorbidities present on Day 1 of study treatment and throughout 
treatment will be recorded in the CRF as AEs. The actual date of onset should be recorded in all 
cases. Thus, for signs and symptoms present on Day 1, the date of onset may pre-date the start of 
study treatment. 
7.3.2. 
Physical Examination and Vital Signs 
A physical examination including all major body systems is mandated at Screening and End of 
Treatment Visits only. Height will be recorded at screening only. During study treatment, 
symptom directed physical examinations will be performed. 
Vital signs to be assessed include weight, body temperature, blood pressure, and pulse rate. On 
days when both vital signs and PK sampling are scheduled, the vital signs should be assessed 
prior to blood sampling. 

 
 
 
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Clinically significant findings noted during screening will be reflected on the medical history 
CRF, while those noted on Day 1 of study treatment and throughout study treatment will be 
collected on the AE CRFs. 
7.3.3. 
Laboratory Safety Assessments 
Laboratory safety assessments for which data will be collected in this study will include 
hematology, thyroid tests, urinalysis and chemistry parameters presented in Table 8. 
Laboratory tests will be drawn at the time points described in the Schedule of Assessments 
(Table 1) and analyzed at local laboratories. Additional laboratory tests may be performed per 
standard of care, at the Investigator's discretion for the purpose of planning treatment 
administration, dose modification, following adverse events, or as clinically indicated. 
Table 8: 
Laboratory Safety Parameters 
Hematology Panel 
Blood Chemistry Panel 
Hemoglobin 
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 
Lipase 
 
Amylase 
Urinalysis (dip stick) 
Sodium 
Blood 
Potassium 
Protein 
Chloride 
 
Bicarbonate or carbon dioxide (CO2) 
Thyroid Function Test 
Blood urea nitrogen (BUN) or urea 
Thyroid-stimulating hormone 
Creatinine 
 
Albumin 
 
Total Calcium 
 
Magnesium 
 
Uric acid 
 
Pregnancy Testing: For patients of childbearing potential, a serum or urine pregnancy test will be 
performed by the local laboratory at screening. Pregnancy testing will also be performed at the 
beginning of every treatment cycle and the same frequency, approximately monthly, will be 

 
 
 
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maintained for at least 1 month after the last dose of sitravatinib, 5 months after the last dose of 
nivolumab and for 1 month after the last dose of docetaxel. Pregnancy tests will also be done 
whenever pregnancy is suspected during the study. Additional pregnancy testing may be 
necessary if required by local practices or regulations. 
Sites in Germany and Switzerland only: Patients must be tested for human immunodeficiency 
virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV) infection (all tests performed 
by local laboratory) at screening. Testing for HIV infection is by local standards. Hepatitis B 
serology to include the following: hepatitis B surface antigen (HBsAg), hepatitis B surface 
antibody (HBsAb/anti-HBs), and hepatitis B core antibody (HBcAb/anti-HBc); HBV DNA 
performed only if HBcAb positive and HBsAg negative. Hepatitis C serology: HCV antibody 
(anti-HCV); HCV RNA performed only if anti-HCV is positive. 
7.3.4. 
Electrocardiograms 
Single and triplicate ECGs are to be performed as outlined in the Schedule of Assessments 
(Table 1 and Table 2). It is preferable that the machine used has a capacity to calculate the 
standard intervals automatically. Assessments reported by automated read as prolongation of 
QTc should be over-read by a cardiologist to ensure accuracy of interpretation. 
7.3.5. 
Echocardiogram or Multigated Acquisition Scan 
Echocardiogram (preferred) or MUGA will be performed at screening (MUGA option is not 
available for sites in Germany), and thereafter as in the Schedule of Assessments (Table 1). 
Additional assessments of LVEF may be performed as clinically indicated at the Investigator’s 
discretion if there are signs or symptoms of cardiotoxicity. 
7.4. 
Laboratory Studies 
Full details on sample collection, processing, storage and shipment are presented in the Study 
Laboratory Manual. 
7.4.1. 
Pharmacokinetic Evaluation 
In patients randomized to the sitravatinib/nivolumab treatment arm the PK of sitravatinib will be 
determined using blood samples collected at specified time points prior to and following study 
treatment dosing. Every effort will be made to collect these PK samples at the exact nominal 
times relative to dosing. A variation window is allowed for each time point as outlined in 
Table 2. The actual time of each sample collection will be recorded on the source document and 
CRF. 
All plasma samples will be stored frozen and shipped on dry ice according to instructions 
provided. Analysis of samples will be performed using specific validated bioanalytical methods 
and irrespective of dose of nivolumab. Full details on sample collection, processing, storage and 
shipment will be provided in the Study Laboratory Manual. 

 
 
 
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7.4.2. 
Nivolumab Anti-Drug Antibody Evaluation 
In patients randomized to the sitravatinib/nivolumab treatment arm, the development of ADA to 
nivolumab will be evaluated using blood samples collected prior to, during and following study 
treatment as specified in Table 1. All serum samples will be stored frozen and shipped on dry ice 
according to instructions provided. Analysis of samples will be performed using specific 
validated bioanalytical methods and irrespective of dose of sitravatinib. Full details on sample 
collection, processing, storage and shipment will be provided in the Study Laboratory Manual. 
7.4.3. 
Molecular Marker Evaluation 
Molecular markers prior to treatment to be investigated include PD-L1 expression and tumor 
gene alterations in tumor tissue and tumor gene alterations in ctDNA. Full details on sample 
collection, processing, storage and shipment will be provided in the Study Laboratory Manual. 
7.4.3.1. 
Circulating Tumor DNA 
Optional blood samples for ctDNA analysis will be collected at baseline/screening as outlined in 
Table 1. Blood samples will be collected into two 10 mL Streck brand Cell-Free DNA Blood 
Collection tubes allowing shipping and stability at ambient temperatures. Tumor gene alterations 
in ctDNA samples will be determined using NGS performed by a central laboratory. Collection 
of ctDNA blood samples is not mandatory for study participation. 
7.4.3.2. 
Markers in Tumor Tissue 
Freshly biopsied tumor tissue collections at pre-treatment for analysis of PD-L1 expression and 
evaluation of tumor gene alterations are highly desirable; however, tumor biopsies having 
significant risk should not be performed and tumor lesions evaluated on-treatment as measurable 
lesions per RECIST 1.1 should not be disturbed for study biopsies. Samples should be collected 
via a core needle of 18 gauge or larger or be collected by an incisional or excisional tumor 
biopsy. Where institutional practice uses a smaller gauge needle, samples should be evaluated for 
tumor cell quantity (ie, > 100 tumor cells) to allow for adequate PD-L1 immunohistochemistry 
analyses. Samples should be formalin fixed and embedded in paraffin. Samples from fine needle 
aspirates (FNA) or decalcified bone are not appropriate for study evaluations. Archival samples 
may be submitted if more recent tumor specimens or fresh biopsies cannot be obtained. 
Submission of pre-study tumor samples is not mandatory for study participation. 
Tumor PD-L1 expression in freshly biopsied tumor tissue will be determined by the PD-L1 
(28-8) companion diagnostics assay completed through the central laboratory. If tumor tissue 
from a patient has previously undergone PD-L1 testing, results to be collected in the CRF 
include the type of assay employed, percent tumor and/or immune cell staining (if available) and, 
categorization of high- versus low-PD-L1 expression. 
Tumor gene alterations in freshly biopsied tumor samples will be determined using NGS 
performed by a central laboratory. For patients in whom tumor tissue has previously been tested 
using NGS, presence of tumor gene mutations and estimation of total tumor mutation burden 

 
 
 
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(TMB) will be collected in the CRF. In addition, a copy of the prior report will be appended to 
the CRF in countries where this is permitted by applicable laws and regulations. 
7.5. 
Patient Reported Outcomes 
Patient reported outcomes (PROs) of health-related quality of life and lung cancer-specific 
symptoms will be evaluated using two tools: the European Quality of Life Five Dimensions 
Questionnaire (EQ-5D-5L) and the Lung Cancer Symptom Scale (LCSS). 
The EQ-5D-5L questionnaire includes two components – the EQ-5D-5L descriptive assessment 
of five dimensions (including mobility, self-care, usual function status, pain and/or discomfort, 
and anxiety and/or depression) using 5 levels, and the EQ VAS for the patient’s self-rated health 
using a 20 cm vertical visual analogue scale. The data from this instrument will be used in 
economic models and analyses. 
The LCSS is a lung cancer specific measure of quality of life and includes 9 questions, including 
patient-reported ratings of six symptoms (appetite loss, fatigue, cough, dyspnea, hemoptysis, 
pain) and three summary items (symptom distress, activity level, overall quality of life) using 
100-mm visual analogue scales. This instrument will be used in the assessment of health-related 
quality of life. 
PRO assessments will be collected at C1D1 and then coincide with disease evaluations as 
outlined in Table 1. EQ-5D-5L questionnaires should always be completed before LCSS. 
Assessments should continue until start of other anti-cancer therapy. 
8. 
ADVERSE EVENT REPORTING 
8.1. 
Sponsor Medical Monitor Personnel 
The contact information for the Sponsor's Medical Monitor personnel for this trial is available in 
the study contact list located in the Study Manual. 
8.2. 
Adverse Events 
An 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. 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. A treatment emergent AE 
(TEAE) is an AE that occurs after the first dose of any study treatment or any preexisting 
condition that increases in severity after the first dose of study treatment. 
All observed or volunteered AEs will be recorded in source documents and reported in the CRF. 
The best available medical terminology should be used to describe AEs in source documents and 
CRFs. Terms describing the diagnosis are preferred over individual signs and symptoms of the 

 
 
 
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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. Examples of AEs include but are not limited to: 
• Signs or symptoms of co-morbidity, illness, or toxicity of study treatment; 
• Signs or symptoms of worsening malignancy under study (disease progression 
assessed by measurement of malignant lesions should not be reported as an AE); 
• Laboratory abnormalities (see Section 8.2.1 for guidance for reporting in CRF); 
• Hypersensitivity; 
• Drug abuse, dependency, overdose, withdrawal or misuse; 
• Signs or symptoms of drug interactions; 
• Extravasation; 
• Exposure during pregnancy or via breastfeeding; 
• Medication error; or 
• Occupational exposure. 
8.2.1. 
Laboratory Abnormalities 
An abnormal laboratory test result should be reported as an AE in the CRF only if it is associated 
with one or more of the following: 
• Clinical symptoms; 
• Requires additional tests (beyond repeats), treatment or intervention; 
• Results in change in study treatment dosing; 
• Requires discontinuation from study treatment; and/or 
• Considered by the Investigator or Sponsor to be an AE. 
Hy’s Law 
Hepatic function abnormality defined by an increase in AST and/or ALT to ≥ 3 × ULN 
concurrent with an increase in total bilirubin to ≥ 2 × ULN but without increase in alkaline 
phosphatase (ie, alkaline phosphatase < 2 × ULN) meets the criteria for Hy’s Law and raises the 
concern for drug-induced liver injury when no other cause of the abnormal laboratory results is 
identified. Follow-up investigations and inquiries will be initiated promptly by the 
investigational site to determine whether the findings are reproducible and/or whether there is 
objective evidence that clearly supports causation by a disease (eg, cholelithiasis and bile duct 
obstruction with distended gallbladder) or an agent other than the investigational product. 

 
 
 
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Cases meeting Hy’s Law should be reported as SAEs. Study drug should be permanently 
discontinued for a Hy’s Law case (see Section 5.4.4). 
8.2.2. 
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. 
8.2.3. 
Causality 
For each AE, the Investigator should determine and document whether there exists a reasonable 
possibility that the study treatment caused or contributed to the AE. 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. 
Collection of causal relationship for AEs associated with study procedures (eg, tumor biopsy) is 
provided for separately in the CRF. 
8.3. 
Serious Adverse Events 
8.3.1. 
Definition of a Serious Adverse Events 
An SAE is any event that meets any of the following criteria: 
• 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; 

 
 
 
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− Development of drug dependency or drug abuse; 
Progression of the malignancy under study, including any signs or symptoms of progression that 
may require hospitalization, should not be reported as an SAE unless the outcome is fatal within 
the safety reporting period. 
Definition of Terms 
Life-threatening: An AE is life threatening if the patient was at immediate risk of death from the 
event as it occurred; ie, it does not include a reaction that if it had occurred in a more serious 
form might have caused death. For example, drug-induced hepatitis that resolved without 
evidence of hepatic failure would not be considered life-threatening even though drug-induced 
hepatitis can be fatal. 
Hospitalization: In general, hospitalization signifies that the patient has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation and/or 
treatment that would not have been appropriate in the physician's office or outpatient setting. 
When in doubt as to whether 'hospitalization' occurred or was necessary, the AE should be 
considered serious. Hospitalization for elective surgery or routine clinical procedures that are not 
the result of AE (eg, elective surgery for a preexisting condition that has not worsened) need not 
be considered AEs or SAEs. If anything untoward is reported during the procedure, that 
occurrence must be reported as an AE, either 'serious' or 'non-serious' according to the usual 
criteria. 
Disability/permanent damage: An AE is disabling or caused permanent damage if it resulted in a 
substantial disruption of a person’s ability to conduct normal life functions, eg, a significant, 
persistent or permanent change, impairment, damage or disruption in body function/structure, 
physical activities and/or quality of life. 
Adverse Event of Special Interest (AESI): AESIs are of scientific and medical interest specific to 
understanding of the investigational product and may require close monitoring and rapid 
communication by the Investigator to the Sponsor. An AESI may be serious or non-serious. The 
rapid reporting of AESIs allows ongoing surveillance of these events in order to characterize and 
understand them in association with the use of this investigational product. 
Immune-related Adverse Events (irAE): An irAE is defined as an AE that is associated with drug 
exposure and is consistent with an immune-mediated mechanism of action and where there is no 
clear alternative etiology. Serologic, immunologic, and histologic (biopsy) data, as appropriate, 
should be used to support an irAE diagnosis. Appropriate efforts should be made to rule out 
neoplastic, infectious, metabolic, toxin, or other etiologic causes of the AE. 
8.3.2. 
Exposure During Pregnancy 
Exposure during pregnancy (ie, exposure in-utero [EIU]) may occur in a female study 
participant, the female partner of a male study participant or study site personnel working with 
the investigational product (eg, occupational exposure) if: 

 
 
 
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• 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 Investigator must submit an SAE form and an EIU Supplemental Form within 
24 hours of awareness of the exposure, regardless of whether an AE or SAE has occurred. 
In the event of pregnancy in a female study participant, if the pregnancy is continued, study 
treatment will be immediately discontinued. 
In the event of exposure of the pregnant partner of a male study participant, the study participant 
should be asked to deliver an EIU Pregnant Partner Release of Information Form to his partner. 
The Investigator must document on the EIU Form that the patient was given this letter to provide 
to his partner. 
Follow-up to obtain pregnancy outcome information is to be conducted for all EIU reports. In the 
case of a live birth, the health of the neonate should be assessed at the time of birth and for up to 
3 months after birth. Further follow-up of birth outcomes will be handled on a case-by-case basis 
(eg, follow-up on preterm infants to identify developmental delays). In the event the pregnancy is 
terminated, the reason(s) for termination should be reported and, if clinically possible, the 
structural integrity of the terminated fetus should be assessed by gross visual inspection. 
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly), an SAE 
report should be submitted to the Sponsor. 
8.4. 
Reporting of SAEs and AEs 
8.4.1. 
Reporting Period 
The active reporting period for SAEs begins from the time that the patient provides informed 
consent (ie, prior to undergoing any study-specific procedure or assessment) and continues until 
at least 28 days* after last administration of study treatment. All SAEs ongoing on Day 28 after 
the last dose 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. Death must be reported if it occurs 
within at least 28 days after the last administration of study treatment, regardless of whether a 
subsequent anticancer therapy is administered. Serious adverse events occurring to a patient after 
the active reporting period has ended should be reported to the Sponsor if the Investigator 
becomes aware of them and if the Investigator assesses at least a reasonable possibility of being 
related to study drug. These SAEs should be followed until resolved or stabilized to a chronic 
condition. 

 
 
 
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The reporting period for non-serious AEs begins from the day of first dose of study treatment 
and continues until at least 28 days after last administration of study treatment. If a patient begins 
a subsequent anticancer therapy, the AE reporting period ends at the time the new treatment is 
started. 
*The reporting period for serious and non-serious irAEs will continue until at least 100 days 
after the last administration of nivolumab or until subsequent immunotherapy is administered, 
whichever is earlier. 
8.4.2. 
Reporting Requirements 
All SAEs must be reported within 24 hours of Investigator/site knowledge of the event, 
irrespective of the extent of available AE information, by faxing the SAE report to the Sponsor’s 
pharmacovigilance representative designated in the Study Manual. The 24-hour timeframe also 
applies to additional new information (follow-up) on previously forwarded SAE reports and to 
the initial and follow-up reporting of exposure during pregnancy and exposure via breastfeeding. 
The need for an expedited report to regulatory authorities will be determined by the Sponsor and 
necessary reporting will be performed by the Sponsor. The Sponsor will notify study 
Investigators of all Suspected, Unexpected (as judged against the Investigator Brochure) Serious 
Adverse Reaction (SUSAR) reports. The Investigator is responsible for reporting all SUSARs to 
the IRB/EC. 
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. 
9. 
STATISTICS 
Detailed methodology for summary and statistical analyses of the data collected in this study will 
be documented in a Statistical Analysis Plan (SAP), which will be maintained by the Sponsor. 
The SAP may modify the plans outlined in the protocol; however, any major modifications of the 
primary endpoint definition and/or its analysis will also be reflected in a protocol amendment. 
The control of the overall type 1 error between the primary endpoint and key preidentified 
secondary efficacy endpoints will be performed using a gatekeeper strategy. The order of testing 
will be detailed in the SAP. 
9.1. 
Hypotheses and Sample Size 
9.1.1. 
Primary Efficacy Hypothesis 
Overall survival (OS) is the primary efficacy endpoint of this study. The study hypotheses are: 

 
 
 
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• H0: Hazard Ratio (HR) for OS with sitravatinib/nivolumab versus OS with docetaxel 
= 1.0, versus 
• H1a: HR for OS with sitravatinib/nivolumab versus OS with docetaxel = 0.73 
9.1.1.1. 
 Sample Size Determination 
The following assumptions were used in the sample size determination: 
• Median OS in the control group (docetaxel) is 9.5 months. 
Median OS in the experimental group (sitravatinib in combination with nivolumab) is 
13.0 months (HR of 0.73). Approximately 372 total OS events will be required to detect the 
assumed HR at a 2-sided alpha 0.05 and a power of 85%. Assuming an enrollment duration of 
approximately 25 months and an additional 13 months of follow-up, a sample size of 
approximately 532 patients is planned to achieve the required number of events. An interim 
analysis and final analysis are planned for this study. 
9.2. 
Data Handling 
Listings of all patient data will be prepared. Data summaries will be presented in tabular and/or 
graphical format and summarized descriptively, where appropriate. Further details of planned 
analyses will be described in the SAP. 
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 with specific rules defined in the SAP. 
9.3. 
Analysis Populations 
9.3.1. 
Intent-to-Treat Population 
The Intent-to-Treat (ITT) population is defined as all patients who are randomized into this 
study. The ITT population will be used to describe demographics and in the analyses for the 
PRO and efficacy endpoints. 
9.3.2. 
Safety Population 
The Safety population is defined as all patients who received any dose of study treatment 
(ie, sitravatinib, nivolumab or docetaxel). The Safety population will be used for all safety 
analyses. 
9.3.3. 
Pharmacokinetic Evaluable Population 
The Pharmacokinetic evaluable population will consist of all patients who received treatment 
with sitravatinib and had sufficient concentration-time data to permit calculation of PK 

 
 
 
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parameters for sitravatinib. For patients who were noncompliant with respect to administration of 
sitravatinib, or for patients with incomplete data, a decision as to their inclusion in the analysis 
will be made on a case-by-case basis. 
9.3.4. 
Molecular Marker Evaluable Population 
The molecular marker evaluable population will consist of all patients who receive at least one 
dose of either sitravatinib or nivolumab for whom PD-L1 expression or tumor gene alteration 
results are available. 
9.4. 
Efficacy Endpoint Definitions and Analyses 
9.4.1. 
Overall Survival 
Overall survival is defined as the time from date of randomization to death due to any cause. 
Censoring for the survival endpoint will be assigned on the date of the last on-study follow-up 
that the patient is reported to be alive. 
The Kaplan-Meier method and the unstratified log-rank test will be used to estimate the median 
OS and to compare the times to death between the two treatment arms. 
Moreover, 1-year Survival Rate and the 95% CI of the 1-year survival rate will also be reported. 
A Cox proportional hazard model with Efron's method of tie handling will be used to assess the 
magnitude of the treatment difference (ie, the hazard ratio). The hazard ratio and its 95% 
confidence interval from the stratified Cox model with a single treatment covariate will be 
reported. 
The stratified log-rank test will be used to compare OS between the two treatment arms as 
sensitivity analysis. The stratification factors used for randomization (see Section 3) will be 
applied to both the stratified log rank test and the stratified Cox model. Patients enrolled under 
Protocol version 1.0 (with a randomization stratification factor of the duration of previous CIT) 
will not be included in the analysis due to the different stratification factors after protocol 
amendment. 
Additional sensitivity analyses to test and account for possible non-proportional hazards effect 
will be described in the SAP. 
9.4.2. 
Objective Response Rate 
Objective disease response will be categorized in accordance with RECIST v1.1 (Appendix 4). 
Objective Response Rate (ORR) is defined as the percent of patients documented to have a 
confirmed CR or PR. 
Descriptive statistics (frequency and percentage) for ORR will be presented. The 95% CI of the 
response rate will be calculated using Clopper-Pearson method. A Chi-square test test will be 
used to compare response rates between the two treatment arms. 

 
 
 
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A Cochran Mantel Haenszel (CMH) test will be used, controlling for the stratification variables 
to compare response rates between the two treatment arms as sensitivity analysis. Patients 
enrolled under Protocol version 1.0 (with a randomization stratification factor of the duration of 
previous CIT) will not be included in the analysis due to the different stratification factors after 
protocol amendment. 
 
9.4.3. 
Clinical Benefit Rate 
Clinical Benefit Rate 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 8 weeks on study. 
An approach similar to that described for ORR in Section 9.4.2 will be used to compare CBR for 
the two treatment arms. 
9.4.4. 
Duration of Response 
Duration of Response is defined as the time from date of the first documentation of objective 
tumor response (CR or PR) to the first documentation of Objective Progression of Disease (PD) 
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 in the ITT population with a confirmed objective response in 
order to obtain the estimate of median DOR. Censoring for the DOR 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 while on study. Patients who start a new anti-cancer therapy prior to 
documented PD or death will be censored at the date of the last tumor assessment prior to the 
start of the new therapy. Patients who discontinue from study will be censored on the date of last 
evaluable tumor assessment. 
Descriptive statistics will be provided for the DOR in responding patients (ie, median duration of 
response and 95% CIs) by treatment arm, including the associated Kaplan-Meier curves. A 
stratified log-rank test will be used to compare the duration of response between the two 
treatment arms. 
9.4.5. 
Progression Free Survival 
Progression-free survival is defined as the time from randomization to first PD or death due to 
any cause in the absence of documented PD. Censoring for the PFS endpoint will be assigned on 
the date of the last tumor assessment if no assessment of tumor progression is identified and the 
patient does not die while on study. Patients lacking an evaluation of disease after first study 
treatment will have their PFS time censored on the date of randomization with duration of 1 day. 
Patients who start a new anti-cancer therapy prior to documented PD will have the endpoint 
censored at the date of the last tumor assessment prior to the start of the new therapy. The 
Kaplan-Meier method and the stratified log-rank test will be used to obtain the estimate of 
median PFS time and to compare time to progression between the two treatment arms. 

 
 
 
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Additional sensitivity analyses (eg, Cox proportional hazard model or different censoring rules) 
will be performed and described in the SAP. 
9.4.6. 
Subgroup Analyses 
Treatment effect on OS will be evaluated in subgroup analyses of the following baseline 
characteristics where there are sufficient subjects: 
• Age (< 65 years, ≥ 65 years) 
• Gender (Female, Male) 
• Prior treatment regimens in the advanced setting (1 vs 2) 
• ECOG Performance Status (0, 1) 
• Brain metastases (yes, no) 
• Geographic regions: USA, Non-USA 
• Smoking status (never, former/current) 
• Receipt of maintenance chemotherapy (yes, no) 
• Time elapsed since last chemotherapy (cut-off to be determined based on the 
distribution of the observed data) 
• Time from last treatment with prior checkpoint inhibitor (≤ 30 days, > 30 days) 
• Most recent tumor PD-L1 expression test result (high, low) 
• Most recent TMB test result (high TMB, low TMB). 
Subgroup analyses will be further described in the SAP but will utilize Cox proportional hazard 
models with treatment and baseline characteristic-by-treatment interaction to present HR and 
95% confidence intervals within each subgroup of interest. 
9.5. 
Safety Data Presentations and Summaries 
9.5.1. 
Adverse Events 
Adverse events will be classified using the medical dictionary for regulatory activities 
(MedDRA) classification system. Listings will include the verbatim term, preferred term, and 
system organ class (SOC). The number of patients with treatment emergent AEs and the 
incidence of TEAEs by SOC and preferred term will be summarized. TEAEs (defined as those 
occurring from the date of the first dose until 28 days after the last dose of study treatment for 
non-irAEs and those occurring from the date of the first dose until 100 days after the last dose of 
nivolumab for irAEs) will be summarized by maximum intensity and relationship to study 
therapy. Separate summaries will be provided for TEAEs, TESAEs, treatment-related AEs, 

 
 
 
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AESI, treatment-related SAEs, and other significant AEs (eg, AEs leading to study 
discontinuation). 
9.5.2. 
Prior and Concomitant Medications 
Collected prior and concomitant medications will be coded using the World Health Organization 
(WHO) medical dictionary; patients who received these medications will be listed and 
summarized. 
9.5.3. 
Clinical and Laboratory Assessments 
Clinical and laboratory assessments include clinical laboratory tests (hematology, urinalysis, 
thyroid function tests and chemistry), vital signs, ECHO or MUGA scans and 12-lead ECGs. 
Clinical laboratory results will be listed by patient and, as appropriate, summarized descriptively, 
which will include a display of change from baseline. Selected parameters will be presented in 
shift tables of baseline against worst grade test result. Laboratory values outside of the normal 
ranges will be identified. Laboratory values that meet Grade 3 or 4 criteria according to NCI 
CTCAE v.5.0 will be listed and summarized. 
Electrocardiogram assessments will be evaluated for change of QTc from baseline to the highest 
on-study value. The Investigator’s interpretation of QTc will be used in the clinical management 
of patients. The study analysis will use Fridericia’s formula applied programmatically to the 
ECG data collected in CRFs using the QT interval and either the RR interval or the heart rate if 
the RR interval is not reported. 
Vital signs, ECHO or MUGA scans and ECG measurements will be listed for each patient at 
each visit. Descriptive statistics of observed values and changes from baseline will be 
summarized by treatment group. 
9.5.4. 
Patient Demographics, Baseline Characteristics and Disposition 
Presentations of patient characteristics will include a summary of the following for all patients 
randomized into the study: 
• Demographics 
• Baseline disease characteristics 
• Pre-existing conditions/concurrent illness 
• Prior therapies/surgeries 
A summary of patient disposition will include reasons for study discontinuation. 

 
 
 
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9.5.5. 
Analysis of Study Treatment Dosing 
Study treatment administration will be described in terms of the duration of treatment, total study 
drug administered, dose intensity, compliance and reasons for the deviations from planned 
therapy for each agent separately and for the combination. 
9.6. 
Other Study Endpoints 
9.6.1. 
Pharmacokinetic Analysis 
The PK sparse exposure data from this study may be used in the development of population PK 
and PK/PD models. Pharmacokinetic plasma levels and parameters will be determined, listed, 
and summarized for the PK evaluable population in the Pharmacokinetic Analysis Plan (PKAP). 
Only samples with acceptable PK (as defined in the PKAP) will be included in the summary 
statistics and a listing of individual data points or patients excluded from the analysis will be 
presented. Plasma concentrations will be listed by patient for the PK Population. Summary 
statistics of sitravatinib concentrations will be reported by dose level, formulation, Day and 
Cycle. The exposure levels as well as the PK parameters of sitravatinib reported in earlier studies 
will be compared to the current study PK exposure and parameters to evaluate the potential 
effect of the study population, and concomitant administration of nivolumab on sitravatinib PK. 
Details of this analysis will be provided in the PKAP. Possible relationships between PK 
parameters, PD variables, safety, and efficacy may be examined. 
9.6.2. 
Patient Reported Outcomes Analysis 
For the EQ-5D-5L, the change from baseline in health state utility values and the visual analogue 
scale will be compared between treatment arms at each visit using a mixed effect model repeated 
measurement (MMRM) analysis, which adjusts for the same factors as the primary analysis and 
also the baseline health state utility value/visual analogue scale as appropriate. Adjusted mean 
differences between treatments and 95% CIs from these analyses will be presented. Descriptive 
statistics will be reported for health state domain (eg, proportion in each domain) and the visual 
analogue scale by visit, as well as the change in the visual analogue scale value and the derived 
utility index value from baseline. 
The LCSS three summary items (symptom distress, activity level, overall quality of life) will be 
analyzed using a MMRM analysis as described above. Descriptive statistics will also be reported 
for all scores and change-from-baseline scores. 
Further detail of analyses to be performed using the PRO endpoints will be provided in the SAP. 
9.7. 
Interim Analysis 
An interim analysis based on OS is planned when approximately 65% of the events 
(~242 events) are observed. The efficacy boundary is constructed using the O’Brien-Fleming 
boundary as implemented by Lan-DeMets alpha spending method. The alpha spend at interim 
and final analysis is 0.0109 and 0.0381. A non-binding futility analysis is also planned at the 

 
 
 
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time of the interim analysis. The futility boundary is constructed based on 2% conditional power 
(CP) and the study may be declared futile if the estimated HR at interim> 0.92. The exact alpha 
spent and the futility boundary will be adjusted based on the observed number of events. 
The IDMC will review the safety and efficacy data and may make a recommendation to: 
• stop the study for safety or futility, 
• continue the study as planned, or 
• stop the study for efficacy and may recommend submitting interim results for full 
marketing approval. 
If the study continues as planned, the final analysis will include approximately 372 OS events 
and is expected to occur approximately 38 months after the start of enrollment. 
9.8. 
Data Monitoring Committee 
An Independent Data Monitoring Committee (IDMC) will oversee the conduct of the study as 
outlined in the IDMC Charter. The IDMC will have access to open-label trial data and will 
perform the following functions: 
• Review the conduct of the study and accruing safety data at 6-month intervals and on 
an ad hoc basis as safety questions arise. 
• Review the interim analysis and recommend the appropriate course of action as 
outlined in Section 9.7. 
10. 
ETHICS AND RESPONSIBILITIES 
10.1. 
Ethical Conduct of the Study 
This study will be conducted in accordance with 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). 
Specifically, this study is based on adequately performed laboratory and animal experimentation; 
the study will be conducted under a protocol reviewed and approved by an IRB/EC; 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. 

 
 
 
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10.2. 
Obligations of Investigators 
The Investigator is responsible for complying with the protocol and all applicable regulations 
and guidelines governing clinical research. Additionally, he/she is responsible for ensuring that 
all participating staff members are adequately trained and competent to perform his/her assigned 
tasks. 
All Investigators must provide the Sponsor with a current curriculum vitae. Only Investigators 
and designated Sub-Investigators are permitted to sign CRFs and examination findings 
(eg, laboratory results or ECGs). 
The Investigator or designee is responsible for informing the patient of all available information 
relevant to his/her safety and obtaining signed, written consent from all participating patients. 
Additionally, the Investigator is responsible for monitoring patient safety and providing periodic 
and requested reports to the IRB/EC/Research Ethics Board (REB). 
The Investigator is responsible for the accuracy and completeness of all study records including 
CRFs, source documents, and the Site Trial Master File. The Investigator will allow the Site 
Monitor, Sponsor, auditor, regulatory agencies, and IRB/EC/REB full access to the study and 
source documents. 
10.3. 
Institutional Review Board/Ethics Committee/Research Ethics Board 
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/EC/REB for written 
approval. The Investigator will provide the Sponsor with a copy of the IRB/EC/REB’s written 
approval, as well as the membership list or a compliance statement from the IRB/EC/REB. The 
Investigator is responsible for notifying the IRB/EC/REB of any Sponsor-approved amendments 
to the protocol or ICF, SAEs occurring in patients treated at the study site in accordance with 
local IRB/EC/REB practice, and all expedited safety reports from SAEs occurring at other study 
sites participating in the drug development program. 
10.4. 
Informed Consent Form 
The ICF must contain all elements required by the FDA under 21 Code of Federal Regulations 
(CFR) Part 50 and the ICH GCP guidelines (ICH E6, 4.8) in addition to any other elements 
required by applicable national, state, provincial, and local regulations, or institutional policies. 
All patients who choose to participate in the study must provide written consent after having had 
adequate time to consider whether they will participate in the study. The written consent must be 
obtained prior to any protocol-related procedures that are not part of the patient’s normal medical 
care. The patient must be advised of his/her right to withdraw from the study at any time. 

 
 
 
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Written documentation of consent must be recorded in the patient’s source documents, study 
records and CRF indicating the date the consent was signed. The patient should receive a signed 
copy of the consent form according to GCP guidelines. 
10.5. 
Confidentiality and Privacy Protection 
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 involved 
with the study without the Sponsor’s prior written consent or in accordance with applicable law 
or regulations. Persons or entities involved with the study who may have access to the 
information will be subject to contractual confidentiality requirements. However, authorized 
regulatory officials, such as IRB/EC/REB, the Sponsor and its authorized representatives (as and 
to the extent authorized in the patient’s ICF) are allowed access to the records. 
Identification of patients in CRFs shall be by study assigned patient numbers only. If required, 
the patient's full name may be made known to authorized third-parties, to the extent permitted by 
applicable laws and regulations and mentioned in the ICF. 
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, to the extent permitted in the 
ICF. In either way, the patient name will not be used in publicly available documents. 
Records and documents which identify the individual patient will be stored securely for the 
length of time required by applicable clinical research, health information and data privacy laws, 
as described in Section 11.2 and in the ICF. 
Regarding Privacy and Data Protection, the Sponsor ensures that personal data is collected and 
processed in accordance with all the applicable laws and regulations. 
Ethnic factors could influence the effects (safety and efficacy) of medicines and the risk/benefit 
assessment in different populations. Race and Ethnicity data are collected in CDISC SDTM 
(SDTM Implementation Guide v3.2), in accordance with ICH guidance (ICH E5) adopted by the 
EMA and FDA, to support population pharmacokinetic (PK) analysis, which is a well-
established, quantitative method that can quantify and explain the variability in drug 
concentrations among patients. Variability can be attributed to intrinsic factors (eg, body weight, 
age, gender, race/ethnicity), or to extrinsic factors (eg, concomitant medications). In some cases, 
intrinsic or extrinsic factors lead to clinically relevant changes in drug concentrations that require 
a change in the dose or dosing regimen. Results from population PK analyses will be 
incorporated into drug product labeling to provide guidance on the dose or dosing regimen 
including any potential dose adjustment in some subpopulations (eg, race or ethnic 
group).  Therefore, collecting race/ethnicity data in the study is essential to understand whether 
race/ethnicity could influence the PK, safety and/or efficacy. 
Detailed description of the conditions for the collection and processing of personal data is made 
available to the patient in the ICF and, if applicable, the relating Data Protection Privacy Policy. 

 
 
 
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The Sponsor, as data controller, collects and processes personal data related to (i) patient identity 
and health in order to conduct the study, and (ii) financial data and identification data for 
administrative tasks, under the conditions set forth in the ICF. 
In accordance with all applicable data protection rules, the patient will have the right to access, 
rectify, delete, limit or oppose the processing of its personal data, the right to define guidelines 
for the storage, deletion and communication of the data after its death and the right to the 
portability of its personal data. The investigator is in charge of the exercising of the rights. The 
Sponsor may also have appointed a Data Protection Officer to whom it will be permitted access 
to directly identifying personal data when necessary to answer a patient’s request. 
The Sponsor has implemented appropriate protocols and mechanisms in case of a breach of 
confidentiality. 
10.6. 
Reporting of Serious Breaches of the Protocol or ICH GCP 
In the event of any prohibition or restriction (ie, clinical hold) imposed by an applicable 
Regulatory Authority, or if the Investigator is aware of any new information which might 
influence the evaluation of the benefits and risks of the investigational product, the Sponsor must 
be informed immediately. In addition, the Investigator will inform the Sponsor immediately of 
any serious breaches of this protocol or of ICH GCP of which the Investigator becomes aware. 
11. 
RECORDS MANAGEMENT 
11.1. 
Source Documentation 
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. 
11.2. 
Study Files and Records Retention 
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 
Principal Investigator has responsibility for ensuring the authenticity, accuracy, completeness 
and timeliness of all data collected in the CRF. CRFs must be signed by the Principal 
Investigator or by an authorized Sub-Investigator to attest that the information included is true. 
Each study site will maintain a Site Trial Master File in accordance with GCPs. The Investigator 
shall retain all records for the longest of the following periods: (i) 15 years; (ii) the period of time 
that conforms to ICH GCP guidelines; (iii) the period of time required by applicable law or 
regulations, or (iv) the period of time specified in the Clinical Research Agreement. 

 
 
 
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12. 
QUALITY CONTROL AND QUALITY ASSURANCE 
12.1. 
Monitoring Procedures 
Sponsor appointed Site Monitor(s) must be allowed access to all study records, original source 
documents, and investigational products throughout the duration of the study. 
These personnel are responsible to assess compliance with the protocol, appropriate health 
authority regulations, ICH GCP guidelines, and Sponsor requirements. 
The Site Monitor is responsible for complying with the monitoring guidelines established by the 
Sponsor for the study, assessing the site’s needs, and liaising with the assigned Sponsor staff. 
If the Investigator withdraws from the study and relinquishes his/her responsibility for the 
maintenance and retention of records, he/she must notify the Sponsor in writing so arrangements 
can be made to properly store the study materials. 
12.2. 
Auditing and Inspection Procedures 
The Sponsor’s Quality Assurance representatives, IRB/EC/REB reviewers, or inspectors from 
regulatory agencies may perform an audit or inspection at any time during or after completion of 
the clinical study. All study-related documentation must be made available to the designated 
auditor. In addition, representatives of applicable regulatory health authorities may choose to 
inspect a study. A Sponsor representative will be available to assist in the preparation for such an 
inspection. 
13. 
CHANGES IN STUDY CONDUCT 
13.1. 
Protocol Amendments 
Changes to the study protocol, except those intended to reduce immediate risk to study patients, 
may be made only by the Sponsor. A protocol change intended to eliminate an apparent 
immediate hazard to patients may be implemented immediately, provided the IRB/EC/REB 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. 
Any permanent change to the protocol must be handled as a protocol amendment. The change 
will be documented in writing by the Sponsor, as an Administrative Letter or amended protocol. 
The written Administrative Letter or amendment must be submitted to the IRB/EC/REB and the 
Investigator must await approval before implementing the changes. The Sponsor will be 
responsible for submitting protocol amendments to the appropriate regulatory authorities for 
approval. 
If in the judgment of the IRB/EC/REB, the Investigator, and/or the Sponsor, the amendment to 
the protocol substantially changes the study design and/or increases the potential risk to the 

 
 
 
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patient and/or has an impact on the patient's involvement as a study participant, the currently 
approved written informed consent form will require similar modification. In such cases, 
informed consents (revised as appropriate to address protocol amendments) will be obtained for 
patients enrolled in the study before continued participation. 
13.2. 
Protocol Deviations 
Prospective permission to deviate from the eligibility criteria for this protocol will not be 
provided by the Sponsor. Study specified assessments should not be omitted and the study 
treatment regimen should not deviate from protocol specifications. Minor, occasional 
adjustments in the clinic visit schedule may be necessary for logistical reasons (eg, due to 
weather conditions) but must not become routine or systematically alter the study schedule. The 
IRB/EC/REB should be informed of any deviations that may affect a patient’s treatment or 
informed consent, especially those increasing potential risks, which must receive prior written 
approval by the IRB/EC/REB. 
14. 
END OF TRIAL 
14.1. 
End of Trial in a European Union Member State 
In accordance with Regulation EU No 536/2014, the End of Trial in a Member State of the 
European Union is defined as the last visit of the last patient included in a member state, or at a 
later point in time defined in the protocol. 
14.2. 
End of Trial in all other Participating Countries 
End of Trial in all other participating countries 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. 
14.3. 
Premature Termination 
Premature termination of this study may occur at any time because of a regulatory authority 
decision, change in opinion of the IRB/EC/REB, drug safety concerns, or at the discretion of the 
Sponsor. In addition, the Sponsor retains the right to discontinue development of sitravatinib at 
any time. If termination becomes necessary, the Sponsor will inform the appropriate regulatory 
authorities of the termination and the reason. The Principal Investigator will inform the 
IRB/EC/REB of the same. In terminating the study, the Sponsor and the Principal Investigator 
will assure that adequate consideration is given to the protection of the patients’ interests. 

 
 
 
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15. 
STUDY REPORT AND PUBLICATION POLICY 
The Sponsor is responsible for preparing and providing the appropriate regulatory authorities 
with clinical study reports according to the applicable regulatory requirements. 
The publication of study results will be governed by the applicable Clinical Research Agreement 
between the Sponsor and the Study Site and Investigator (as applicable). 

 
 
 
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16. 
REFERENCES 
16.1. 
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Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous 
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Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus Docetaxel in Advanced Squamous-
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Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: 
GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries 
[published correction appears in CA Cancer J Clin. 2020 Jul;70(4):313]. CA Cancer J Clin. 
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Camenisch TD, Koller BH, Earp HS, Matsushima GK. A novel receptor tyrosine kinase, Mer, 
inhibits TNF-alpha production and lipopolysaccharide-induced endotoxic shock. J Immunol. 
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Chen PM, Liu KJ, Hsu PJ, et al. Induction of immunomodulatory monocytes by human 
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Committee for Medicinal Products for Human Use (CHMP). Guideline on the Investigation of 
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Costantini A, Corny J, Fallet V, et al. Efficacy of next treatment received after nivolumab 
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2000;18(12):2354-2362. doi:10.1200/JCO.2000.18.12.2354 
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doi:10.1056/NEJMoa1801005 
Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non-small-cell lung 
cancer. N Engl J Med. 2015;372(21):2018-2028. doi:10.1056/NEJMoa1501824 

 
 
 
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Hanna N, Shepherd FA, Fossella FV, et al. Randomized phase III trial of pemetrexed versus 
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2011;480(7378):480-489. Published 2011 Dec 21. doi:10.1038/nature10673 
Mu CY, Huang JA, Chen Y, Chen C, Zhang XG. High expression of PD-L1 in lung cancer may 
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NSCLC Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis 
using updated data on individual patients from 52 randomised clinical trials. Non-small Cell 
Lung Cancer Collaborative Group. BMJ. 1995;311(7010):899-909. 
Okunishi K, Dohi M, Nakagome K, et al. A novel role of hepatocyte growth factor as an immune 
regulator through suppressing dendritic cell function. J Immunol. 2005;175(7):4745-4753. 
doi:10.4049/jimmunol.175.7.4745 
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therapies. Cancer Res. 2009;69(6):2514-2522. doi:10.1158/0008-5472.CAN-08-4709 
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Park SE, Lee SH, Ahn JS, Ahn MJ, Park K, Sun JM. Increased Response Rates to Salvage 
Chemotherapy Administered after PD-1/PD-L1 Inhibitors in Patients with Non-Small Cell Lung 
Cancer. J Thorac Oncol. 2018;13(1):106-111. doi:10.1016/j.jtho.2017.10.011 
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Oncol. 2019 May;30(5):863-870]. Ann Oncol. 2018;29(Suppl 4):iv192-iv237. 
doi:10.1093/annonc/mdy275 
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advanced non-small-cell lung cancer. N Engl J Med. 2002;346(2):92-98. 
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16.2. 
Approved Labels 
European Medicines Agency. Opdivo (Nivolumab) Product Information. Website: 
https://www.ema.europa.eu/en/medicines/human/EPAR/opdivo#product-information-section. 
Accessed October 2021. 
European Medicines Agency. Taxotere (Docetaxel) Product Information. Website: 
https://www.ema.europa.eu/en/medicines/human/EPAR/taxotere#product-information-section. 
Accessed October 2021. 
OPDIVO (nivolumab) injection, for intravenous use [package insert]. Princeton, NJ: Bristol-
Myers Squibb Company; 2021. https://packageinserts.bms.com/pi/pi_opdivo.pdf. 
Taxotere® (Docetaxel) [package insert]. Bridgewater, NJ: Sanofi-Aventis U.S. LLC; 2021. 
http://products.sanofi.us/Taxotere/taxotere.html 
 

 
 
 
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APPENDIX 1. ECOG PERFORMANCE STATUS 
ECOG PERFORMANCE STATUS 
Grade 
ECOG 
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, eg, light house work, office work 
2 
Ambulatory and capable of all self care but unable to carry out any work activities. Up and about more 
than 50% of waking hours 
3 
Capable of only limited self care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any self care. Totally confined to bed or chair 
5 
Dead 
 

 
 
 
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APPENDIX 2. MEDICATIONS OR SUBSTANCES TO BE AVOIDED OR 
USED WITH CAUTION DURING TREATMENT WITH 
SITRAVATINIB 
Examples of Drugs with a Known Risk of Torsades de Pointes1 
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 

 
 
 
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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 

 
 
 
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Generic Name 
Brand Names (Partial List) 
Drug Class 
Therapeutic Use 
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 
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 

 
 
 
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Generic Name 
Brand Names (Partial List) 
Drug Class 
Therapeutic Use 
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) 
1 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. 
 
Examples of Drugs with Conditional Risk of Torsades de Pointes1 
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 
Amitriptyline 
Elavil (Discontinued 6/13), 
Tryptomer, Tryptizol, Laroxyl, 
Saroten, Sarotex Lentizol, Endep 
Antidepressant, 
Tricyclic 
Depression 

 
 
 
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Generic Name 
Brand Names (Partial List) 
Drug Class 
Therapeutic Use 
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 

 
 
 
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Generic Name 
Brand Names (Partial List) 
Drug Class 
Therapeutic Use 
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, Metozolv, 
Plasil, Pramin, Primperan, 
Perinorm 
Antiemetic 
Nausea, vomiting 
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 

 
 
 
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Generic Name 
Brand Names (Partial List) 
Drug Class 
Therapeutic Use 
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 
1 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. 
 
Examples of 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 
 

 
 
 
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Examples of 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 
 

 
 
 
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APPENDIX 3. EXAMPLES OF STRONG AND MODERATE CYP3A4 
INHIBITORS 
Strong 
CYP3A4 
Inhibitors 
Boceprevir, clarithromycin, cobicistat, conivaptan, danoprevir/ritonavir, 
diltiazem, elvitegravir/ritonavir, grapefruit juice, idelalisib, indinavir/ritonavir, 
itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, 
paritaprevir/ritonavir/ombitasvir plus dasabuvir, posaconazole, ritonavir, 
saquinavir/ritonavir, telaprevir, tipranavir/ritonavir, troleandomycin, 
voriconazole. 
Moderate 
CYP3A4 
Inhibitors 
Aprepitant, cimetidine, ciprofloxacin, clotrimazole, crizotinib, cyclosporine, 
dronedarone, erythromycin, fluconazole, fluvoxamine, imatinib, tofisopam, 
verapamil. 
 

 
 
 
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APPENDIX 4. ABBREVIATED PRESENTATION OF RECIST VERSION 
1.1 GUIDELINES 
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. 
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. 

 
 
 
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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 (eg, ‘multiple liver metastases’). 
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. 

 
 
 
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• 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 (eg, 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. 
• 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. 

 
 
 
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Supplemental Investigations 
If CR determination depends on a residual lesion that decreased in size but did not disappear 
completely, it is recommended the residual lesion be investigated with biopsy or fine needle 
aspirate. If no disease is identified, objective status is CR. 
Best Objective Response 
Target Lesions 
Non-Target Lesions 
New Lesion 
Point in Time 
Response 
Best Response 
CR 
CR 
No 
CR 
CR and PR require 
confirmation at least 4 weeks 
after first observation 
CR 
Non-CR/Non-PD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
SD requires an on-study 
assessment after at least 6 
weeks on study. 
Unconfirmed PR or CR are 
reported as SD. 
PD 
Any 
Yes or No 
PD 
 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
Subjective Progression 
Patients requiring discontinuation of treatment due to worsening health status attributable to 
advancement of the malignancy under study but without objective evidence of disease 
progression should not be reported as PD on tumor assessment CRFs. This should be indicated 
on the end of treatment CRF as off treatment due to Global Deterioration of Health Status. 

 
 
 
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APPENDIX 5. COVID-19 PANDEMIC CHANGES TO STUDY CONDUCT 
The table below summarizes temporary changes to specific protocol assessments and procedures 
that are allowable during the COVID-19 pandemic (FDA, 2020), (EMA, 2020); these changes 
will not be recorded as protocol deviations unless otherwise specified. This Appendix should be 
considered in effect until notification from Mirati is provided via Protocol Administrative Letter. 
Upon such notification, this Appendix will no longer be applicable, and study conduct in 
accordance with the language in the body of the protocol will resume. 
Assessment/Procedure 
Change During COVID-19 Pandemic 
Visit Window 
Visit widows of up to ± 5 days are allowed for Day 1 (beyond Cycle 1) 
and Day 15 clinic visits for patients in the combination arm. 
Visit windows of ± 3 days are allowed for Day 8 clinic visits for patients 
in the docetaxel arm. 
Clinic Visits 
Clinic visits may be conducted remotely by telephone/video conference; 
any missed assessments or procedures (eg, tumor assessment, laboratory 
assessments, vital signs, study drug administration, etc) should be 
documented as Protocol Deviations. 
Clinic Visits 
Clinic visits may be conducted at the patient’s residence by qualified 
home health care professionals; any missed assessments or procedures (eg, 
laboratory assessments, vital signs, study drug administration, etc) should 
be documented as Protocol Deviations. 
Safety Laboratory Assessments 
Safety laboratory assessments may be performed at the patients nearest 
CAP or CLIA certified local laboratory if a remote visit is being 
conducted, whenever feasible.