Conditions: Urothelial Carcinoma Urothelial Carcinoma Bladder Urothelial Carcinoma Ureter Urothelial Carcinoma of the Renal Pelvis and Ureter Urothelial Carcinoma Urethra
Keywords: MGCD516 Antineoplastic Agents Immunologic Factors Nivolumab Tyrosine Kinase Inhibitor VEGFR TAM RTKs PD-1 PD-L1 Pembrolizumab Enfortumab vedotin Checkpoint Inhibitors Antibody Drug Conjugates ADC
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 260
Healthy volunteers: no

Brief summary:
The study will evaluate the clinical activity of PD-(L)1 Checkpoint Inhibitor regimens in combination with the investigational agent sitravatinib in patients with advanced or metastatic urothelial carcinoma.

Detailed description:
Sitravatinib is an orally-available, small molecule inhibitor of a closely related spectrum of receptor tyrosine kinases (RTKs) including MET, Axl, MERTK, VEGFR family, PDGFR family, KIT, FLT3, Trk family, RET, DDR2 and selected Eph family members. Nivolumab is a human IgG monoclonal antibody that binds to the programmed cell death-1(PD-1) receptor and blocks its interaction with programmed cell death ligand-1 (PD-L1) and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response including anti-tumor immune response. Combining an immunotherapeutic 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. 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 checkpoint inhibitor therapy.

Pembrolizumab is a humanized 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 response. Enfortumab vedotin (enfortumab) is an investigational ADC that is comprised of a fully human anti-Nectin-4 IgG1 monoclonal antibody conjugated to MMAE via a protease-cleavable linker. Enfortumab binds to cells that express Nectin-4 with high affinity, triggering the internalization and release of MMAE in target cells, inducing cell cycle arrest and apoptotic cell death. Early efficacy results from enfortumab in combination with pembrolizumab in frontline cisplatin-ineligible urothelial carcinoma in the ongoing EV-103 study have demonstrated encouraging activity with a safety profile that appears manageable and tolerable. Addition of sitravatinib to this combination might further augment clinical activity by selectively inhibiting key molecular and cellular pathways strongly implicated in checkpoint inhibitor resistance.

Arms:
arm 1: Patients previously treated with checkpoint inhibitor and platinum-based chemotherapy. Nivolumab over 30 min IV infusion (240 mg IV every 2 weeks or 480 mg every 4 weeks) and sitravatinib 120 mg orally once per day continuously in 28-day cycles. arm 2: Patients previously treated with checkpoint inhibitor, but ineligible for platinum-based chemotherapy. Nivolumab over 30 min IV infusion (240 mg IV every 2 weeks or 480 mg every 4 weeks) and sitravatinib 120 mg orally once per day continuously in 28-day cycles. arm 3: Patients previously treated with selected immunotherapies and platinum-based chemotherapy. Nivolumab over 30 min IV infusion (240 mg IV every 2 weeks or 480 mg every 4 weeks) and sitravatinib 120 mg orally once per day continuously in 28-day cycles. arm 4: Patients previously treated with with selected immunotherapies, but ineligible for platinum-based chemotherapy. Nivolumab over 30 min IV infusion (240 mg IV every 2 weeks or 480 mg every 4 weeks) and sitravatinib 120 mg orally once per day continuously in 28-day cycles. arm 5: Patients previously treated with platinum-based chemotherapy, but never treated with checkpoint inhibitor. Nivolumab over 30 min IV infusion (240 mg IV every 2 weeks or 480 mg every 4 weeks) and sitravatinib 120 mg orally once per day continuously in 28-day cycles. arm 6: Patients ineligible for treatment with platinum-based chemotherapy and never treated with checkpoint inhibitor. Nivolumab over 30 min IV infusion (240 mg IV every 2 weeks or 480 mg every 4 weeks) and sitravatinib 120 mg orally once per day continuously in 28-day cycles. arm 7: Patients previously treated with antibody-drug conjugate, checkpoint inhibitor and platinum-based chemotherapy. Nivolumab over 30 min IV infusion (240 mg IV every 2 weeks or 480 mg every 4 weeks) and sitravatinib 120 mg orally once per day continuously in 28-day cycles. arm 8: Patients previously treated with antibody-drug conjugate and checkpoint inhibitor, but ineligible for platinum-based chemotherapy. Nivolumab over 30 min IV infusion (240 mg IV every 2 weeks or 480 mg every 4 weeks) and sitravatinib 120 mg orally once per day continuously in 28-day cycles. arm 9: Patients previously treated with checkpoint inhibitor and platinum-based chemotherapy. There are 2 parts to this Cohort - a lead-in dose escalation portion and a dose expansion portion. In the dose escalation portion, treatment with up to 3 dose levels of sitravatinib in combination with up to 2 dose levels of pembrolizumab and enfortumab combination regimen to determine the recommended doses to be used in the combination treatment regimen and those doses will be further studied in the dose expansion portion. Pembrolizumab 200 mg over 30 min IV infusion every 3 weeks, sitravatinib orally once per day continuously in 21-day cycles (at 35 mg, 50 mg, 70 mg, or 100 mg) and enfortumab vedotin over 30 min IV infusion on Day 1 and Day 8 in 21-day cycles (at 1 mg/kg or 1.25 mg/kg).

Interventions: intervention 1: Sitravatinib intervention 2: Nivolumab intervention 3: Pembrolizumab intervention 4: Enfortumab vedotin
Intervention descriptions: intervention 1: Sitravatinib is a small molecule inhibitor of receptor tyrosine kinases intervention 2: Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody intervention 3: Pembrolizumab is a programmed death receptor-1 (PD-1) blocking antibody intervention 4: Enfortumab is a Nectin-4 directed antibody-drug conjugate (ADC) comprised of a monoclonal antibody conjugated to the small molecule microtubule disrupting agent, monomethyl auristatin E (MMAE)

Protocol document:
Prot_000.pdf: 
Protocol Number: 516-003  
 
 
Official Title: A Phase 2 Study of Sitravatinib in Combination with PD-(L)1 Checkpoint 
Inhibitor Regimens in Patients with Advanced or Metastatic Urothelial Carcinoma  
 
NCT Number: NCT03606174  
 
 
Document Date: 22 June 2020


 
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Mirati Therapeutics, Inc. 
 
 
 
 
 
 
 
 
 
CLINICAL RESEARCH PROTOCOL 
 
DRUG(S): 
Sitravatinib (MGCD516) 
Nivolumab (OPDIVO®) 
Pembrolizumab (KEYTRUDA®) 
Enfortumab vedotin-ejfv (PADCEV™) 
STUDY NUMBER: 
516-003 
PROTOCOL TITLE: 
A Phase 2 Study of Sitravatinib in Combination 
with PD-(L)1 Checkpoint Inhibitor Regimens in 
Patients with Advanced or Metastatic Urothelial 
Carcinoma 
IND NUMBER: 
138337 
SPONSOR: 
Mirati Therapeutics, Inc. 
9393 Towne Centre Drive, Suite 200 
San Diego, California, 92121, USA 
ORIGINAL PROTOCOL 
DATE: 
09 March 2018 
VERSION NUMBER: 
V4.0 
VERSION DATE: 
22 June 2020 
 
 
 
CONFIDENTIALITY STATEMENT 
This is a Mirati Therapeutics, Inc. document that contains confidential information.  It is intended solely 
for the use of the clinical Investigator(s) and other individuals involved in the study of sitravatinib in 
combination with PD-(L)1 checkpoint inhibitor regimens.  This document is not to be reproduced, 
abstracted, or quoted without written authorization from Mirati Therapeutics, Inc. 
 


 
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DOCUMENT HISTORY 
Document 
Version Date 
Summary of Changes 
Original Protocol, 
Version 1.0 
09 March 
2018 
NA 
Amendment #1, 
Version 2.0 
19 April 2018 
• 
At the request of US Food and Drug Administration during 
IND review, the following changes were made. 
o Added limitations on continuation of study treatment in 
the event of RECIST-defined disease progression and the 
requirement for written informed consent to continue 
study treatment. 
o Specified that if one study treatment is interrupted or 
discontinued to manage adverse events, the other study 
treatment may continue in accordance with the protocol 
and OPDIVO Product Information. 
o Added details to sitravatinib dose modification to 
manage hematological and non-hematological adverse 
events, hypertension (added Table 9), decreased LVEF, 
and increase hepatic transaminases. 
o Added that if sitravatinib dosing is interrupted for 
≥ 14 days, dose reduction should be considered. 
o Emphasized that OPDIVO Product Information must be 
consulted to ensure correct action is taken for nivolumab 
dose modification in the management of adverse events. 
• 
Removed absolute requirement for tumor tissue tests from 
Table 1, footnote #2. 
• 
Rearranged Section 5 subsections to address management of 
adverse events under one heading (Section 5.5) for clarity. 
• 
Addressed clerical errors and made minor clarifications. 
Amendment #2,  
Version 3.0 
13 September 
2019 
Study Design: 
• 
Added Appendix 8 – a contingent cohort study in 
patients previously treated with an antibody-drug 
conjugate, in response to emerging treatment options for 
the study population.  
• 
Updated the number of patients expected to participate 
in the study. 
Schedule of Assessments (Table 1 and Table 2): 
• 
Clarified visit windows for: 
o 
Day 1 of Cycles 2 and 3, and 
o 
ECHO or MUGA examinations. 
• 
Clarified that beyond treatment Cycle 3, Day 15 clinic 
visits (i.e., abbreviated physical examination and vital 
signs) are required only when the nivolumab Q2W 
dosing schedule is used. 


 
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Document 
Version Date 
Summary of Changes 
• 
Added flexibility in scheduling of tumor biopsies 
around C2D15. 
• 
Added requirement for a urinalysis to be performed 
prior to study-related biopsies of tumors involving the 
genitourinary tract. 
• 
Adjusted time of PK and ECG assessments in main 
study to later in the clinic day (from hour 4 to hour 7 
after dosing) to improve PK parameter estimations and 
in response to US FDA request. 
Entry Criteria: 
• 
Inclusion criterion 4: updated to allow enrollment of 
patients having selected unresolved AEs of prior 
therapy including alopecia, and ≤ grade 2 dysgeusia or 
peripheral neuropathy. 
• 
Exclusion criteria 
o 
4a: clarified that ≥ grade 3 immune-related 
AEs during prior treatment with CIT are of 
interest for enrollment exclusion, rather than all 
≥ grade 3 related AEs. 
o 
4b: aligned with product labeling by removal 
of hepatitis from the list of immune-related 
AEs. 
o 
4c: deleted criterion excluding patients having 
prior Grade 1 immune-related AEs during CIT 
treatment. 
o 
5c: clarified that medically-important 
autoimmune diseases are to be considered and 
added Sjögren’s syndrome.  
o 
17: added approximate 2-week washout 
window for prior systemic therapy.  
Study Treatment: 
• 
Corrected sitravatinib dispensing to every cycle beyond 
Cycle 12 rather than allowing dispensing every 2 cycles. 
• 
Added allowance for use of nivolumab regimen 480 mg 
administered every 4 weeks, per revised product 
labeling. 
• 
Updated guidance for sitravatinib management in the 
event of Grade 2 symptomatic toxicities early in 
treatment (Section 5.5.1.1).  Study sites were informed 
of this change by Administrative Letter dated 15 May 
2019.  
Clarified the reporting period for patient deaths to include at least 
28 days after the last administration of study treatment, 
regardless of start of subsequent therapy. 


 
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Document 
Version Date 
Summary of Changes 
Appendix 2 Calculation of Glomerular Filtration Rate and Renal 
Impairment Scale: clarified use of individual patient BSA rather 
than standardized BSA in calculation of eGFR. 
Appendix 5 Contingent Cohort Study in Patients Previously 
Treated with Immunotherapies: clarified that eligible prior 
immunotherapies are not limited to those listed, in response to 
emerging treatment options for the study population.  In addition, 
clarified several enrollment criteria in relation to the main 
protocol. 
Appendix 6 Contingent Cohort Study in CIT-Naïve Populations: 
clarified several enrollment criteria in relation to the main 
protocol. 
Appendix 7 Renal Impairment Evaluation: added evaluation of 
sitravatinib PK in patients having normal renal function to 
strengthen interpretation of PK observed in patients having mild 
or moderate renal impairment.  
Addressed clerical errors and made minor clarifications. 
Amendment #3,  
Version 4.0 
22 June 2020 
Executive summary of main changes in Amendment #3: 
• 
Introduction of a new regimen of sitravatinib in 
combination with a PD-(L)1 checkpoint inhibitor 
(sitravatinib, pembrolizumab and enfortumab in Cohorts 
9 and 10), in addition to the existing regimen 
(sitravatinib and nivolumab in Cohorts 1 through 8).  
Relevant background information has been updated 
throughout the protocol as a result.  Information 
regarding a lead-in dose escalation evaluation with the 
new regimen is also provided. 
• 
Addition of sitravatinib malate capsule formulation.  
[Note that the free base capsule formulation will remain 
available for new patients in Cohorts 1 through 6, and 
for patients who start the study under a previous 
protocol version on the free base capsule formulation 
who 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. 
• 
Consolidation of all entry criteria in Section 4.1 and 
Section 4.2 for clarity (previously changes to entry 
criteria for contingent cohorts were mentioned in 
corresponding appendices). 
• 
Added status of all cohorts as of protocol version 4.0 for 
clarity. 
• 
Clarified temporary changes to specific protocol 
assessments and procedures that are allowable only 
during the COVID-19 pandemic. 
A detailed description of changes follows. 


 
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Document 
Version Date 
Summary of Changes 
Cover Page:  
• 
Updated Drugs to include drugs to be used as part of 
treatment regimen in Cohorts 9 and 10. 
• 
Updated Title to specify class of drug to be given in 
regimens with sitravatinib to reflect the new regimen to 
be used in Cohorts 9 and 10. 
Study Summary: 
• 
Added the rationale for using antibody-drug conjugates 
(ADCs) in combination with checkpoint inhibitors to 
treat cancer. 
• 
Added background information regarding 
pembrolizumab and enfortumab since they are 
components of the treatment regimen for Cohorts 9 and 
10. 
• 
Updated the number in trial (with the increased sample 
size of Cohorts 7 and 8, and the proposed total 
enrollment in Cohorts 9 and 10) and added the status of 
contingent cohorts as of protocol version 4.0. 
• 
Primary objective updated to specify class of drug to be 
given in regimens with sitravatinib to be inclusive of the 
new regimen to be used in Cohorts 9 and 10. 
• 
Revised secondary objectives updated to “combination 
regimens” to be inclusive of the new regimen to be used 
in Cohorts 9 and 10. 
• 
Added secondary objectives for new Cohort 9 to identify 
the recommended phase 2 combinational doses 
(RP2Ds). 
• 
Added secondary endpoint of dose-limiting toxicities for 
new Cohort 9. 
• 
Study Design updated to reflect status of all cohorts as 
of protocol version 4.0, and added details regarding 
Cohorts 3-8 (that were previously only included in the 
appendices) and the new Cohorts 9 and 10 (sitravatinib 
in combination with pembrolizumab and enfortumab). 
• 
Study Schema was updated to include all 10 cohorts that 
are now included in the protocol. 
• 
Study Treatments was updated with the new sitravatinib, 
pembrolizumab and enfortumab regimen that is given 
every 3 weeks.  
Schedule of Assessments (Table 1):  
• 
Clarified that table applies to Cohorts 1 through 8 
(sitravatinib and nivolumab). 
• 
Footnote #11: added disease evaluations for patients 
who discontinue study treatment due to reasons other 


 
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Summary of Changes 
than objective disease progression at same frequency 
until progression,  new cancer therapy or death. 
• 
Footnote #13: Added option to perform long-term 
follow-up by email in addition to telephone contact. 
• 
Footnote #14: Clarified timing of the End of Treatment 
Visit as within 7-14 days after decision to permanently 
discontinue study treatments. 
Schedule of PK, PD and ECG assessments (Table 2): 
• 
Clarified that table applies to Cohorts 1 through 8. 
• 
Footnote #1: Clarified PK collections in cases of 
sitravatinib dose interruptions. 
Schedule of Assessments (Table 3):  
• 
Added table for new Cohorts 9 and 10 (sitravatinib, 
pembrolizumab and enfortumab).  
Schedule of PK, PD and ECG assessments (Table 4): 
• 
Added table for new Cohorts 9 and 10.  
Section 1.1.3 Checkpoint Inhibitor Therapy in UC: 
• 
Added background pembrolizumab information. 
Section 1.1.4 Antibody-Drug Conjugates (ADCs): 
• 
Added definition of ADCs. 
Section 1.1.5 ADC Targeted Therapy in UC: 
• 
Added background ADCs information (emphasis on 
enfortumab) and provided rationale for the sitravatinib, 
pembrolizumab and enfortumab combination regimen. 
Section 1.2.2 Sitravatinib in Combination with a Checkpoint 
Inhibitor and an ADC: 
• 
Added preclinical and clinical data as background to 
support the rationale for the sitravatinib, pembrolizumab 
and enfortumab combination regimen. 
• 
Specified hypothesis that adding sitravatinib, may 
complement the therapies in mounting an anti-tumor 
immune response and further augment the antitumor 
efficacy observed with enfortumab and pembrolizumab 
combination. 
Section 1.3.1 Sitravatinib Drug Substance: 
• 
Added malate salt formulation of sitravatinib and 
clarified the initial formulation was “free base”. 
Sections 1.3.2 Nonclinical Data, 1.3.3 Sitravatinib Clinical 
Experience: 
• 
Added guidance, throughout, that the current IB should 
be referenced for current data. 
Section 1.3.3 Sitravatinib Clinical Experience: 


 
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Document 
Version Date 
Summary of Changes 
• 
Added 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: 
• 
Updated the results for relevant studies contributing to 
sitravatinib’s clinical safety data (516-003, 516-001, and 
MRTX500) and the cumulative safety data based upon 
the current IB. 
Section 1.3.3.3 Sitravatinib Clinical Efficacy: 
• 
Added preliminary clinical activity results for relevant 
studies (516-003 and MRTX-500).  
Section 1.3.3.4 Sitravatinib Capsule Formulation Study: 
• 
Added interim results from Study 516-006, a healthy 
volunteer study evaluating the bioavailability and PK of 
sitravatinib free base and sitravatinib malate capsule 
formulations.  
Sections 1.4 Nivolumab, 1.5 Pembrolizumab and 
1.6 Enfortumab: 
• 
Added pembrolizumab and enfortumab sections. 
• 
Added guidance, throughout protocol, that the current 
OPDIVO, KEYTRUDA and PADCEV USPIs should be 
referenced for current data. 
Sections 1.4.3 Nivolumab, 1.5.3 Pembrolizumab and 
1.6.3 Enfortumab Clinical Data: 
• 
Updated OPDIVO information based on OPDIVO USPI 
dated June 2020. 
• 
Added KEYTRUDA information based on 
KEYTRUDA USPI dated April 2020. 
• 
Added PADVCEV information based on PADVCEV 
USPI dated December 2019. 
Section 1.7.1.2 Potential for Drug-Drug Interactions (DDIs) with 
Sitravatinib, Pembrolizumab and Enfortumab: 
• 
Added DDI information and a mitigation strategy for the 
dose escalation portion of new Cohort 9 where 
sitravatinib administered in combination pembrolizumab 
and enfortumab.  
Section 1.7.2.1 Potential for Increased Toxicity with the 
Combination of Sitravatinib and a PD-(L)1 Checkpoint Inhibitor: 
• 
Added relevant pembrolizumab information since it is 
part of the regimen in new Cohorts 9 and 10. 
Section 1.7.2.2 Potential for Increased Toxicity with the 
Combination of Sitravatinib, Pembrolizumab and Enfortumab: 
• 
Added information regarding the potential for 
commonly observed AEs of the agents included in the 


 
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regimen for Cohorts 9 and 10 to be observed with 
increased severity or frequency when administered as 
combination regimen and the well-precedented 
management of those AEs in patients receiving cancer 
therapy to support the addition of new Cohorts 9 and 10. 
Section 1.8 Study Rationale: 
• 
Added explanation that the newly enrolled patients in 
Cohorts 1-6 will continue to be treated with the free base 
formulation at a starting dose of 120 mg QD, while 
Cohorts 7-10 new patients will be treated at the 
equivalent starting dose of 100 mg QD with the malate 
capsule formulation. 
• 
Added rationale for combination regimen of sitravatinib, 
pembrolizumab and enfortumab in Cohorts 9 and 10, 
and strategy for a lead-in dose escalation evaluation 
followed by evaluation of clinical activity at the 
recommended dose. 
• 
Added rationale for the starting doses of sitravatinib, 
pembrolizumab and enfortumab to be studied in the 
lead-in dose escalation evaluation. 
Section 2.1.2 Secondary Objectives and 2.2.2 Secondary 
Endpoints 
• 
Added a secondary objective for new Cohort 9 to 
identify the RP2Ds with DLTs as its endpoint. 
Section 3 Study Design: 
• 
Updated to reflect status of all cohorts as of protocol 
version 4.0, and added details regarding Cohorts 3-8 
(that were previously only included in the appendices) 
and the new Cohorts 9 and 10 (sitravatinib in 
combination with pembrolizumab and enfortumab). 
• 
Added explanation that the newly enrolled patients in 
Cohorts 1-6 will continue to be treated with the free base 
formulation at a starting dose of 120 mg QD, while 
Cohorts 7-10 new patients will be treated at the 
equivalent starting dose of 100 mg QD with the malate 
capsule formulation. 
Section 4.1 Inclusion Criteria: 
• 
Inclusion Criterion #2: Updated with the cohort-specific 
requirements, Cohorts 1 through 10.  
• 
Inclusion Criterion #3: Updated with the cohort-specific 
requirements, Cohorts 1 through 9.  
• 
Inclusion Criterion #4: Updated with the cohort-specific 
modification for preexisting sensory or motor 
neuropathy, and resolution of toxicities from prior 
therapy, Cohorts 9 and 10.  


 
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Version Date 
Summary of Changes 
• 
Inclusion Criterion #6: Updated with the cohort-specific 
modification to allow ECOG 2, Cohort 10.  
• 
Inclusion Criterion #7: Updated with the cohort-specific 
modifications and requirements, Cohorts 9 and 10.  
Section 4.2 Exclusion Criteria: 
• 
Exclusion Criterion #3: Updated with the Cohort-
specific requirements, Cohorts 1, 2, 5 and 6. 
• 
Exclusion Criterion #22-#26: Added as cohort-specific 
exclusionary criteria to ensure safety for patients 
enrolling in Cohorts 9-10 due to the unique safety 
profile of enfortumab. 
Section 5.1.1 Formulation, Packaging and Storage  
• 
Added information regarding the sitravatinib malate 
capsule product. 
• 
Added explanation that the newly enrolled patients in 
Cohorts 1-6 will continue to be treated with the free base 
formulation at a starting dose of 120 mg QD, while 
Cohorts 7-10 new patients will be treated at the 
equivalent starting dose of 100 mg QD with the malate 
capsule formulation. 
• 
Clarified patients on study treatment with the free base 
capsule formulation at the time the malate capsule 
formulation is introduced will remain on the free base 
capsule formulation until treatment discontinuation. 
Section 5.1.2 Preparation, Dispensing, Administration and 
Accountability: 
• 
Added explanation that the newly enrolled patients in 
Cohorts 1-6 will continue to be treated with the free base 
formulation at a starting dose of 120 mg QD, while 
Cohorts 7-10 new patients will be treated at the 
equivalent starting dose of 100 mg QD with the malate 
capsule formulation. 
• 
Added starting dose of malate capsule formulation for 
Cohort 9 as 35 mg QD. 
• 
Added clarification that there is an ongoing food-effect 
study that may eliminate the fasting requirement for 
taking sitravatinib and that any change in the fasting 
requirement will be communicated in an Administrative 
Letter.  
Section 5.1.3 Sitravatinib Dose Modification or Discontinuation: 
• 
Removed outdated information regarding starting dose 
of 120 mg QD for the free base formulation. 
• 
Deleted requirement for Investigator to contact the 
Sponsor to reduce a patient’s dose below 60 mg once 
daily due to sitravatinib-related AEs. 


 
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• 
Clarified that continuous treatment with dose reductions 
is preferred over repeated dose interruptions.  
• 
Added starting dose for malate capsule formulation. 
Table 5 Sitravatinib Sequential Dose Reductions for Individual 
Patients on Free Base Capsule Formulation: 
• 
Added formulation to title name for clarity to 
differentiate from the malate capsule formulation. 
• 
Added 40 mg once daily as a dose level.  
Table 6 Sitravatinib Sequential Dose Reductions for Individual 
Patients on Malate Capsule Formulation: 
• 
Added table due to new formulation that will be used for 
patients enrolling into Cohorts 7-10. 
Section 5.2 Nivolumab Study Drug: 
• 
Added guidance, throughout protocol, that the current 
OPDIVO USPI should be referenced for current data. 
Section 5.2.1 Formulation and Packaging: 
• 
Removed details regarding nivolumab formulation and 
packaging and stated that current OPDIVO USPI should 
be referenced for description of formulation and 
packaging. 
Section 5.2.2 Preparation and Dispensing: 
• 
Removed instructions for preparing nivolumab and 
when to dispense nivolumab and stated that current 
OPDIVO USPI should be referenced for how to prepare 
and dispense nivolumab. 
Section 5.2.3 Administration: 
• 
Clarified the window of +/- 5 minutes around infusion 
time of nivolumab. 
• 
Removed instructions for administering nivolumab and 
stated that current OPDIVO USPI should be referenced 
for how to administer nivolumab. 
Section 5.3 Pembrolizumab Study Drug: 
• 
Added as part of combination regimen to be used in new 
Cohorts 9 and 10.  
• 
Clarified that pembrolizumab will be obtained from 
commercial sources. 
• 
Advised that the current KEYTRUDA USPI should be 
referenced for formulation, packaging, preparation, 
dispensing, administration and dose modifications. 
Section 5.4 Enfortumab Study Drug: 
• 
Added as part of combination regimen to be used in new 
Cohorts 9 and 10.  


 
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• 
Clarified that enfortumab will be obtained from 
commercial sources. 
• 
Advised that the current PADCEV USPI should be 
referenced for formulation, packaging, preparation, 
dispensing, administration and dose modifications. 
Table 7 Enfortumab Sequential Dose Reductions for Individual 
Patients: 
• 
Added table due to new combination regimen to be used 
in new Cohorts 9 and 10. 
Section 5.5.1.1 General Management of Non-Hematological 
Toxicities:  
• 
Added reference to Table 6 for patients requiring a dose 
reduction who are receiving the sitravatinib malate 
capsule formulation. 
Table 8 Sitravatinib Dose Modifications – Non-Hematological 
Drug-Related Toxicities: 
• 
Footnote #2: Added reference to USPIs for 
KEYTRUDA and PADCEV. 
Section 5.5.1.3.3 Diarrhea: 
• 
Due to different checkpoint inhibitor (pembrolizumab) 
to be used in Cohorts 9 and 10, added clarification that 
diarrhea should be evaluated to determine whether it 
may be immune-mediated colitis due to nivolumab or 
pembrolizumab, related to sitravatinib, or due to another 
cause. 
Sections 5.5.3 Pembrolizumab and 5.5.4 Pembrolizumab Adverse 
Event Management Guidelines: 
• 
Added sections since these agents are included in the 
regimen for new Cohorts 9 and 10. 
Section 5.5.5 Management of Immune-Related Adverse Events: 
• 
Updated with the sitravatinib, pembrolizumab and 
enfortumab combination regimen. 
• 
Added references to the KEYTRUDA USPI and the 
PADCEV USPI throughout the section. 
Section 5.5.6 Management of Hy’s Law Cases: 
• 
Expanded the list of other causes that should be 
excluded when evaluating liver function tests that meet 
Hy’s Law criterion. 
• 
Clarified actions to take with all on-study checkpoint 
inhibitor combination regimens due to new regimen 
(sitravatinib, pembrolizumab and enfortumab) added in 
Cohorts 9 and 10. 
• 
Clarified that Hy’s Law cases need to be reported as 
SAEs. 


 
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Document 
Version Date 
Summary of Changes 
Section 5.6 Medication Error: 
• 
Updated with the sitravatinib, pembrolizumab and 
enfortumab combination regimen. 
Section 5.7.1 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 antacid and/or H2 antagonist administration in 
relation to sitravatinib dosing. 
• 
Medications with QTc Prolonging Activity: Added 
cautionary advice that medications with conditional risk 
of Torsades de Pointes should be used with caution 
during sitravatinib treatment. 
• 
Clarified that P-gp and BCRP transporters and CYP3A4 
substrates should be used with caution during treatment 
with sitravatinib in alignment with Appendix 3. 
• 
Added that use of P-gp inhibitors/inducers and strong 
CYP3A4 inhibitors are prohibited during treatment with 
enfortumab in alignment with Appendix 10.   
• 
Added reference to Cohort 9 restrictions for transfusions 
and growth factors. 
Section 5.7.2 Concomitant Medication(s) Restrictions in Cycle 1 
of Lead-In Dose Escalation Evaluation (Cohort 9) for Patients 
Undergoing a DLT Assessment: 
• 
Added for new Cohort 9 to ensure accurate assessment 
of safety and DLTs of the combination regimen. 
Section 5.7.4 Other Anticancer or Experimental Therapy: 
• 
Added language indicating that certain ongoing 
hormonal therapies taken to prevent recurrence of a 
malignancy not under study may be permitted after 
discussion with and agreement of Sponsor. 
Section 6.4 Long-Term Follow-up and End of Study Assessment: 
• 
Added option to contact patients by email for the long-
term follow-up. 
Section 7.1 Efficacy: 
• 
Added possibility of future central radiological review 
for patients enrolled into Cohorts 7-10 and requested 
that sites ensure copies of scans are retained.  An 
Administrative Letter or protocol amendment will be 
issued if a central radiological review is implemented. 
Section 7.2.3 Eye Examination (Only for Cohorts 9 and 10): 
• 
Added to further assess potential risks associated with 
enfortumab treatment. 
Table 11 Laboratory Safety Parameters: 


 
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Document 
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• 
Added glucose test for Cohorts 9 and 10 only, as it is a 
requirement to determine if the dose of enfortumab may 
be given at each scheduled administration. 
Section 8.2.1 Laboratory Abnormalities: 
• 
Clarified actions to take with all on-study checkpoint 
inhibitor combination regimens due to new regimen 
(sitravatinib, pembrolizumab and enfortumab) added in 
Cohorts 9 and 10. 
Section 9.1 Hypothesis and Sample Size: 
• 
Added summary of the study design, hypothesis and 
statistical considerations by cohort, for Cohorts 1 
through 10 (previously only mentioned in appendices). 
Section 9.3.1 Full Analysis Population: 
• 
Changed name of modified intent-to-treat (mITT) 
population to a full analysis population (FAP) and 
defined FAP, as it is a more accurate nomenclature. 
• 
Clarified decisions that will be based on the FAP. 
Section 9.3.2 Clinical Activity Evaluable Population: 
• 
Clarified that the clinical activity evaluable population 
will be summarized based upon the Predictive 
Probability Design for Cohorts 1 through 6, and based 
upon the Simon 2-stage optimal design for Cohorts 9 
(dose expansion portion) and 10. 
Section 9.3.7 DLT Evaluable Population: 
• 
Added for new Cohort 9 to be used to make dose 
escalation decisions during the lead-in dose escalation 
evaluation. 
Section 9.4.2 Clinical Benefit Rate: 
• 
Revised definition of clinical benefit rate to align with 
RECIST 1.1. guidance on Stable Disease. 
Section 9.4.6 Subgroup Analyses: 
• 
Added clarification as to which cohorts would be 
included in the subgroup analysis of the outcome of 
prior treatment with checkpoint inhibitor therapy. 
Section 10.5 Confidentiality: 
• 
Revised based upon updated protocol template. 
Section 16 References: 
• 
Updated accordingly based on changes throughout the 
protocol. 
Appendix 3 Medications 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. 


 
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Document 
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• 
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 5 Contingent Study Cohorts in Patients Previously 
Receiving Treatment with Selected Immunotherapies: 
• 
Removed details that had been moved to the applicable 
sections of the main protocol to reduce redundancy. 
Appendix 6 Contingent Study Cohorts in Checkpoint Inhibitor 
Therapy Naïve Populations: 
• 
Removed details that had been moved to the applicable 
sections of the main protocol to reduce redundancy. 
Appendix 7 Evaluation of the Pharmacokinetics of Sitravatinib in 
Patients with Renal Impairment: 
• 
Clarified that the specified PK evaluation will only 
include patients who were treated with the sitravatinib 
and nivolumab combination regimen (Cohorts 1 through 
8). 
Appendix 8 Contingent Study Cohorts in Patients Previously 
Receiving Treatment with an Antibody-Drug Conjugate: 
• 
Removed details that had been moved to the applicable 
sections of the main protocol to reduce redundancy. 
• 
Changed the study design from Predictive Probability 
Designs to confidence interval method, revised the 
hypothesis and sample size, and included an interim 
futility analysis.  Clarified that the maximum sample 
size of each cohort increased to 55 evaluable patients. 
Appendix 9 Contingent Study Cohorts Evaluating Sitravatinib 
Combination with a Checkpoint Inhibitor and an Antibody-Drug 
Conjugate: 
• 
Added to describe Cohorts 9 and 10 in detail. 
Appendix 10 Examples of Prohibited P-GP Inhibitors and Strong 
CYP3A4 Inhibitors During Treatment with Enfortumab: 
• 
Added to help prevent prohibited medications from 
being taken while patients in Cohorts 9 and 10 are 
treated with enfortumab. 
Appendix 11 Dose De-Escalation Decision Table Using the 
mTPI Method: 
• 
Added to guide decision making with regards to dose 
escalations in subsequent patients during the lead-in 
dose escalation portion of Cohort 9. 
Appendix 12 COVID-19 Pandemic Changes to Study Conduct: 
• 
Added appendix allowing temporary changes to specific 
protocol assessments and procedures that are allowable 
only during the COVID-19 pandemic. 


 
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Document 
Version Date 
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Addressed clerical errors and made minor clarifications 
throughout the protocol. 
 
 


 
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STUDY SUMMARY 
Title:  
A Phase 2 Study of Sitravatinib in Combination with PD-(L)1 
Checkpoint Inhibitor Regimens in Patients with Advanced or 
Metastatic Urothelial Carcinoma 
Rationale:  
Combining an immunotherapeutic Programmed Cell Death 1 (PD-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).  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 and MERTK may 
complement PD-(L)1 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 


 
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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 (i.e., 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 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.  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 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.  The TKI profile of sitravatinib 
suggests the potential for synergistic anti-tumor effect when 
administered in combination with a checkpoint inhibitor.   
Until recently, there were no established treatment options for patients 
with platinum-refractory urothelial carcinoma.  Indeed, second-line 
chemotherapy was associated with modest efficacy, and survival times 
of approximately 7 months underscored the need for alternate 
treatment approaches.  Since 2016, treatment options for platinum-
refractory or platinum-ineligible advanced urothelial carcinoma have 
been expanded to include agents targeting programmed death protein-
1 and its ligand, and there are now 5 FDA-approved immunotherapies 
in this setting.  While overall survival benefits of immunotherapy have 
been demonstrated in a large-scale randomized controlled trial, 
response rates are relatively low and not all patients benefit from 


 
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therapy.  Consequently, there is a need for new treatment options in 
the post-platinum and post-immunotherapy settings. 
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 
response.  Nivolumab has been approved for the treatment of patients 
with advanced or metastatic urothelial carcinoma who have disease 
progression during or following platinum-containing chemotherapy.   
Combining an immunotherapeutic PD-(L)1 checkpoint inhibitor with 
an agent that has both immune modulatory and antitumor properties 
could augment the antitumor efficacy observed with either agent 
alone.  This study will evaluate the clinical activity of nivolumab in 
combination with sitravatinib in patients with advanced or metastatic 
urothelial carcinoma. 
The antitumor activity of antibody drug conjugates (ADCs) that are 
linked to the microtubule-inhibitor monomethyl auristatin E (MMAE) 
has been extensively studied and characterized as resulting primarily 
from the intracellular payload release, leading to mitotic arrest and 
apoptotic cell death.  Emerging data indicates a potential immune 
modulatory activity with these ADCs by inducing immunogenic cell 
death (ICD) that enhances innate and adaptive antitumor immunity in 
vitro and in vivo, in addition to other Fc-mediated effector 
mechanisms including antibody-dependent cellular phagocytosis and 
cytotoxicity involvement.  In vivo administration of these ADCs leads 
to proinflammatory immune responses directed against the tumor and 
this activity is further potentiated by PD-1 checkpoint inhibitor 
therapy as demonstrated by accelerated tumor regressions and greater 
antitumor activity than either agent alone, demonstrating 
complementary modes of action for these agents and providing a 
rationale for exploring therapeutic strategies that combine ADCs with 
other immune stimulatory regimens.  Multiple clinical trials are 
ongoing to evaluate the efficacy of similar combinations. 
Pembrolizumab is a humanized 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 response.  
Pembrolizumab has been approved for the treatment of patients with 
advanced or metastatic urothelial carcinoma who have disease 
progression during or following platinum-based chemotherapy. 


 
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Enfortumab vedotin (enfortumab) is an investigational ADC that is 
comprised of a fully human anti-Nectin-4 IgG1 monoclonal antibody 
conjugated to MMAE via a protease-cleavable linker.  Nectin-4, also 
known as poliovirus receptor-related protein 4 (PVRL4), is an 
adhesion protein located on the surface of cells, with weak to 
moderate expression in normal skin.  Copy number gain of the PVRL4 
gene is a frequent event in carcinogenesis and promotes 
epithelial-to-mesenchymal transition, invasion and metastasis, 
resulting in high expression of Nectin-4 in several solid tumors, 
particularly urothelial carcinomas.  Enfortumab binds to cells that 
express Nectin-4 with high affinity, triggering the internalization and 
release of MMAE in target cells, inducing cell cycle arrest and 
apoptotic cell death.  Enfortumab has been approved under 
accelerated approval based on tumor response rate for the treatment of 
adult patients with locally advanced or metastatic urothelial cancer 
who have previously received a PD-(L)1 checkpoint inhibitor, and a 
platinum-based chemotherapy in the neoadjuvant/adjuvant, locally 
advanced or metastatic setting. 
Early efficacy results from enfortumab in combination with 
pembrolizumab in frontline cisplatin-ineligible urothelial carcinoma in 
the ongoing EV-103 study have demonstrated encouraging activity 
with a safety profile that appears manageable and tolerable.  Addition 
of sitravatinib to this combination might further augment clinical 
activity by selectively inhibiting key molecular and cellular pathways 
strongly implicated in checkpoint inhibitor resistance.  This study may 
evaluate the safety of sitravatinib administered in combination with 
pembrolizumab and enfortumab starting with a lead-in dose finding 
evaluation in patients with locally advanced or metastatic urothelial 
carcinoma who have previously received a PD(L1)-1 inhibitor and a 
platinum-based chemotherapy.  If a tolerable dose is identified for 
sitravatinib in combination with pembrolizumab and enfortumab the 
clinical activity of this combination may be further explored in 
patients with metastatic urothelial carcinoma. 
Target 
Population: 
Patients eligible for this study will have advanced or metastatic 
urothelial carcinoma.  Initial cohorts will enroll patients with 
documented disease progression on or after checkpoint inhibitor 
therapy.  In the event results in the initial cohorts are of high interest 
for efficacy, patients naïve to checkpoint inhibitor therapy may be 
enrolled in additional study cohorts described in the protocol.  
Number in 
Trial:  
Initial patient cohorts (Cohorts 1 and 2): as many as 80 patients. 


 
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Patient cohorts to be implemented in the event of high interest for 
efficacy: 
• Contingent cohorts implemented and active as of this protocol 
version 4.0 (Cohorts 3 through 9): as many as 345 patients. 
• Contingent cohort not yet implemented as of this protocol 
version 4.0 (Cohort 10): as many as 49 patients. 
Primary 
Objective:  
To evaluate the clinical activity of sitravatinib in combination with 
PD-(L)1 checkpoint inhibitor regimens in patients with advanced or 
metastatic urothelial carcinoma. 
Secondary 
Objectives: 
• To evaluate the safety and tolerability of the combination 
regimens in the selected population. 
• To evaluate secondary efficacy endpoints of the combination 
regimens in the selected population. 
• To evaluate the pharmacokinetics (PK) of sitravatinib 
administered in combination regimens. 
• To evaluate the PK of sitravatinib in patients with renal 
impairment, to be implemented in selected study sites contingent 
upon early results in the study or sitravatinib program. 
• Cohort 9 only: To identify recommended Phase 2 combinatorial 
doses (RP2Ds) of sitravatinib, pembrolizumab and enfortumab 
combination treatment. 
Exploratory 
Objectives: 
• To assess the effect of the combination regimens on circulating 
PD-L1, immune cell populations and cytokines. 
• To assess the effect of the combination regimens on tumor cell 
PD-L1 expression, tumor infiltrating immune cell populations 
and gene expression signatures. 
• To assess the correlation of tumor PD-L1 protein expression and 
gene alterations in circulation and in tumor tissue with treatment 
outcome. 
Primary 
Endpoints: 
Objective Response Rate (ORR) as defined by Response Evaluation 
Criteria in Solid Tumors version 1.1 (RECIST 1.1). 


 
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Secondary 
Endpoints: 
• Safety characterized by type, incidence, severity, timing, 
seriousness and relationship to study treatment of adverse events 
and laboratory abnormalities. 
• Secondary efficacy endpoints: 
− 
Duration of Response (DOR); 
− 
Clinical Benefit Rate (CBR); 
− 
Progression-Free Survival (PFS); 
− 
1-Year Survival Rate; and 
− 
Overall Survival (OS). 
• Blood plasma concentrations of sitravatinib. 
• Cohort 9 only: Dose-limiting toxicities (DLTs). 
Exploratory 
Endpoints: 
• Circulating PD-L1 concentration. 
• Circulating immune cell populations. 
• Circulating cytokine concentrations. 
• Circulating tumor deoxyribonucleic acid (ctDNA). 
• T-Cell Receptor sequencing. 
• Tumor PD-L1 expression. 
• Immune cell populations in the tumor. 
• Gene expression signatures in the tumor. 
• Tumor gene alterations. 
Study Design: 
Study 516-003 is an open-label, Phase 2 evaluation of the 
investigational agent sitravatinib in combination with PD-(L)1 
checkpoint inhibitor regimens in patients with locally advanced or 
metastatic urothelial carcinoma.  Initially, the study will include 
patients who experienced progression of disease on or after treatment 
with a checkpoint inhibitor as the most recent treatment.  In the event 
that results in the initial cohorts are of high interest for efficacy, 


 
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contingency plans are described in the protocol to add new cohorts to 
include patients who previously received treatment with selected 
systemic therapies or who are treatment-naïve.  Details, including the 
composition of the combination regimens (either sitravatinib in 
combination with nivolumab, or sitravatinib in combination with 
pembrolizumab and enfortumab), are provided in Section 3 of the 
protocol and associated appendices. 
The primary objective is to evaluate the clinical activity of the 
combination regimens using ORR in accordance with RECIST 1.1.  
Secondary objectives include evaluation of safety, secondary efficacy 
endpoints, and PK of sitravatinib.  The Schedule of Assessments to be 
performed in the study is presented in Table 1 and Table 3.  The 
schedule for collection of PK and pharmacodynamic samples and 
ECG assessment time points are presented in Table 2 and Table 4. 
The initial study population will include patients with documented 
disease progression on or after checkpoint inhibitor therapy as the 
most recent treatment [anti-PD-(L)1 refractory cohorts], stratified into 
2 cohorts based on whether patients were previously treated with or 
ineligible for platinum-based chemotherapy, as depicted in Figure 1.  
As of this protocol version 4.0, enrollment into Cohort 1 is complete. 
• Cohort 1: Patients with documented disease progression on or 
after previous anti-PD-(L)1 as most recent treatment, and who 
were previously treated with a platinum-based chemotherapy.   
• Cohort 2: Patients with documented disease progression on or 
after previous anti-PD-(L)1 as most recent treatment, and 
considered ineligible for platinum-based chemotherapy.  
Stage 1 of enrollment will include a minimum of 9 evaluable patients 
in each cohort.  Patients included in the evaluable population will have 
received treatment with both sitravatinib and nivolumab and have at 
least one on-study disease assessment prior to discontinuation.  With 
exactly 9 evaluable patients at Stage 1, if at least 1 patient has an 
Objective Response, 8 additional evaluable patients will be enrolled in 
the treatment cohort, for a total sample size of 17 evaluable patients.  
If at least 3 Objective Responses are observed in a treatment cohort, 
further investigation may be warranted.  If Stage 2 results in a cohort 
are of high interest for efficacy (in terms of examining the risk benefit 
ratio and not only in terms of ORR), enrollment may be expanded to 
as many as 40 patients total in that cohort to narrow the 95% 
Confidence Interval (CI) around the ORR point estimate and to further 
characterize the durability of disease control. 


 
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In the event that results in the initial cohorts are of high interest for 
efficacy, contingency plans are described in Appendix 5, Appendix 6, 
Appendix 8 and Appendix 9 to add one or more study cohorts. 
Appendix 5 describes addition of Cohort 3 and Cohort 4 (cohorts 
which allow other prior selected immunotherapy in addition to anti-
PD-(L)1, including but not limited to anti-CTLA-4, anti-OX40 or 
anti-CD137).  The statistical design for these cohorts will be the same 
as applied to Cohorts 1 and 2.  These contingent cohorts described 
below were implemented by Administrative Letter and still enrolling, 
as depicted in Figure 1. 
• Cohort 3: Patients with documented disease progression on or 
after a previous anti-PD-(L)1 as most recent treatment, who 
previously received (in combination or separately) other selected 
immunotherapies, and who were previously treated with a 
platinum-based chemotherapy.  
• Cohort 4: Patients with documented disease progression on or 
after a previous anti-PD-(L)1 as most recent treatment, who 
previously received (in combination or separately) other selected 
immunotherapies, and considered ineligible for platinum-based 
chemotherapy.  
Appendix 6 describes addition of Cohort 5 and Cohort 6 [anti-PD-(L)1 
naïve cohorts].  The statistical design for these cohorts is described in 
the appendix.  These contingent cohorts described below were 
implemented by Administrative Letter and still enrolling, as depicted 
in Figure 1. 
• Cohort 5: Patients who have not previously received an 
anti-PD-(L)1, and who were previously treated with a 
platinum-based chemotherapy.  
• Cohort 6: Patients who have not previously received an 
anti-PD-(L)1, and considered ineligible for platinum-based 
chemotherapy. 
Appendix 8 describes addition of Cohort 7 and Cohort 8 [post-ADC 
(antibody-drug conjugate) cohorts].  The statistical design for these 
new cohorts is described in the appendix.  These contingent cohorts 
described below were implemented by Administrative Letter and still 
enrolling, as depicted in Figure 1. 


 
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• Cohort 7: Patients with documented disease progression on or 
after a previous anti-PD-(L)1 and ADC (in combination or 
separately, and in any order), and who were previously treated 
with a platinum-based chemotherapy.  
• Cohort 8: Patients with documented disease progression on or 
after a previous anti-PD-(L)1 and ADC (in combination or 
separately, and in any order), and considered ineligible for 
platinum-based chemotherapy. 
Appendix 9 describes addition of Cohort 9 and Cohort 10 to evaluate 
sitravatinib in combination with pembrolizumab and enfortumab.  The 
appendix describes the initial lead-in dose escalation followed by 
further evaluation of clinical activity in 2 populations if a tolerable 
dose regimen is identified.  Cohort 9 is introduced and implemented 
with this protocol Version 4.0, whereas Cohort 10 is introduced in this 
protocol Version 4.0 and may be implemented by Administrative 
Letter, as described below and depicted in Figure 1. 
• Cohort 9 (including lead-in dose escalation and dose expansion 
portions): Patients who have previously received a PD-(L)1 
checkpoint inhibitor and a platinum-based chemotherapy. 
• Cohort 10: Patients with previously untreated unresectable, 
locally advanced or metastatic urothelial cancer. 
Figure 1: 
Study Schema 
 
The evaluation of the pharmacokinetics (PK) of sitravatinib in patients with renal impairment was implemented by an 
Administrative Letter dated December 2018 and applies to Cohorts 1 through 8.  This evaluation is active and ongoing. 


 
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Disease response and progression as documented by the 
Investigator in the Case Report Form (CRF) will be the basis for 
patient management and study expansion decision making.  
Unconfirmed objective responses recorded in the CRF may be used 
as the initial basis for expansion of study enrollment; however, 
follow-up evaluations on patients with unconfirmed responses must 
continue to support the decision to continue to the full number of 
patients to be included in the next stage. 
Study 
Treatments: 
Throughout the study, treatment will be delivered in 21-day or 28-
day cycles based on study cohort.  Nivolumab will be administered 
by intravenous infusion, 240 mg every 2 weeks (Q2W) or 480 mg 
every 4 weeks (Q4W), in accordance with approved labeling.  
Pembrolizumab will be administered by intravenous infusion, 200 
mg Q3W, in accordance with approved labeling.  Enfortumab will 
be administered by intravenous infusion, with a starting dose of 
1.25mg/kg on days 1 and 8 of Q3W (a lower dose may be evaluated 
if necessary). 
Sitravatinib capsules will be administered orally, once daily (QD), 
continuously.  Guidelines for study drug formulation, 
administration and dose reduction in the event of toxicity are 
provided in Sections 5.1.2 and 5.1.3. 
Patients will continue to receive study treatment at the discretion of 
the Investigator until disease progression, unacceptable adverse 
events, 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.  
Patients discontinuing treatment will be followed for receipt of 
subsequent anti-cancer therapies and survival.  
Statistical 
Considerations: 
This Phase 2 study will use Predictive Probability Designs 
(Lee-2008) for initial cohorts.  In creating the statistical designs, the 
Type 1 error (α) is constrained to <0.05 and Power (1-β) is 
constrained to ≥0.90.  Statistical designs of the contingent cohorts 
are provided in Section 9 of the protocol and associated appendices. 
The ORR using nivolumab in the population of patients with 
advanced/metastatic urothelial carcinoma who experienced disease 
progression on or after treatment with a checkpoint inhibitor is 
assumed to be 5% (p0); thus, this rate is considered uninteresting.  
The target ORR using sitravatinib in combination with nivolumab 
in this study population is 30% (p1).  Stage 1 of enrollment will 


 
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include a minimum of 9 evaluable patients in each cohort.  Patients 
included in the evaluable population will have at least one on-study 
disease assessment prior to discontinuation; patients who 
discontinue treatment due to adverse events or withdrawal of 
consent prior to the first on-study disease assessment will not be 
included in the evaluable population.  With exactly 9 evaluable 
patients at Stage 1, if at least 1 patient has an Objective Response, 
8 additional evaluable patients will be enrolled in the treatment 
cohort, for a total sample size of 17 evaluable patients.  If at least 
3 Objective Responses are observed in a treatment cohort, further 
investigation may be warranted.  If the true ORR is 5% (null 
hypothesis), the probability of early termination during the study is 
0.63; the Type 1 error is equal to 0.0466 and the power is equal to 
0.9045.  
The exact stopping rules for each cohort will be calculated based on 
the Predictive Probability Design, once the exact number of 
patients evaluable at Stage 1 is known.  The aim is to include a 
minimum of 9 evaluable patients at Stage 1.  If Stage 2 results in a 
cohort are of high interest for efficacy (in terms of examining the 
risk benefit ratio and not only in terms of ORR), enrollment may be 
expanded to as many as 40 patients total in that cohort to narrow 
the 95% Confidence Interval (CI) around the ORR point estimate 
and to further characterize the durability of disease control.   


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Table 1: 
Schedule of Assessments: Cohorts 1 through 8 
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 
Cycles 1, 2, and 3 
≥Cycle 4 
End of Treatment 
Within 28 
days 
Day 1 
(± 2 days for 
Cycles 2 & 3) 
Day 15 
(± 2 days) 
Day 1 
(± 2 days) 
Day 15 
(± 2 days) 
End of 
Treatment/ 
Withdrawal14 
Post 
Treatment 
Follow Up 
Study Participation 
Informed Consent1 
Before study 
specific 
assessments 
 
 
 
 
 
 
Tumor Tissue Collection 
for PD-L1 Expression, 
Immune Cell Populations 
and Tumor Gene 
Alterations2 
X2 
  
X (Cycle 2 
only) 
Optional2 
 
 
 
 
Medical History, Disease 
History, Prior Therapy  
X 
 
 
 
 
 
 
ECOG Performance 
Status 
X 
 
 
 
 
 
 
Physical Exam3 
X 
 
 
 
 
X 
 
Abbreviated Physical 
Exam3 
 
X 
X 
X 
X if nivolumab 
Q2W 
 
 
Vital Signs4 
X 
X 
X 
X 
X if nivolumab 
Q2W 
X 
 
Pregnancy Test5 
X 
As clinically indicated 
 


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Table 1: 
Schedule of Assessments: Cohorts 1 through 8 (Continued) 
Assessments 
Screen/ 
Baseline 
Cycles 1, 2 and 3 
≥ Cycle 4 
End of Treatment 
Within 28 
days 
Day 1 
(± 2 days for 
Cycles 2 & 3) 
Day 15 
(± 2 days) 
Day 1  
(± 2 days) 
Day 15 
(± 2 days) 
End of 
Treatment/ 
Withdrawal14 
Post Treatment 
Follow Up 
Hematology6, 7  
X 
X 
X 
X 
 
X 
 
Coagulation6, 7 
X 
As clinically indicated 
 
Urinalysis6, 7 
X 
As clinically indicated 
 
Serum Chemistry6, 7  
X 
X 
X 
X 
 
X 
 
Thyroid Function Test6, 7  
X 
X 
 
X 
 
X 
 
Blood for Sitravatinib 
Pharmacokinetics8 
 
See Table 2 
 
ctDNA blood sample9 
X 
At assessment for confirmation of disease response (PR or CR) 
X 
 
Single 12-Lead ECG10 
X 
As clinically indicated 
X 
 
Triplicate 12-Lead ECG10 
 
See Table 2 
 
Echocardiogram or 
MUGA 
X (Within 35 
days) 
Cycle 3 only 
(± 7 days) 
 
As clinically 
indicated after C3 
 
X 
 
Disease Evaluation11 
X 
Every 8 weeks (± 10 days) for ~12 months  
and then every 16 weeks 
 
Sitravatinib Dispensing 
and/or Reconciliation 
 
X 
 
X 
 
 
 
Nivolumab 
Administration 
 
Throughout as directed in protocol 
 
 
Adverse Events12 and 
Concomitant Medications 
SAEs only 
Throughout 
 
Long Term Follow-up13 
 
 
 
 
 
 
X 


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1  
Study Participation Informed Consent: May be performed more than 28 days prior to the first dose of study treatment and must be completed prior to initiation of any 
study specific assessments. 
2  
Tumor Testing for PD-L1 Expression, Tumor Immune Cell Populations, and Tumor Gene Alterations: 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.  An optional tumor tissue collection after and as close as possible to C2D15 is 
desirable for all patients and is not dependent on the type of tumor tissue submitted at screening.  A urinalysis should be performed prior to any study-related biopsy 
involving the genitourinary tract.  If the results are consistent with a urinary tract infection, tumor lesions in other anatomical areas should be selected, if present. 
3  
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. 
4  
Vital Signs: Weight, temperature, blood pressure, and pulse rate to be assessed prior to dosing as indicated. 
5  
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.  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. 
6  
Selected Day 1 Assessments: Repeat assessment not required if screening assessment performed within 7 days before the first dose. 
7  
Safety Laboratory Assessments: Hematology, coagulation, chemistry, thyroid function and urinalysis evaluations (see Table 11) will be performed by local 
laboratories.  
8  
Pharmacokinetic Samples: Blood samples to be collected following ECGs and assessment of vital signs as scheduled in Table 2.  
9  
Blood samples for ctDNA analysis:  Blood will be collected in two 10 mL Streck brand Cell-Free DNA Blood Collection tubes allowing shipping and stability at 
ambient temperatures. 
10  12-Lead ECGs: 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. 
11  Disease Evaluations: To be performed at screening (28-day window allowed) and every 8 weeks from Cycle 1 Day 1(± 10-day window for all other assessments 
except screening) until week 49 (~12 months) and then every 16 weeks.  All on-study disease evaluations should be based on a calendar beginning from the first day 
of dosing. At screening/baseline, assessments are to include CT with contrast of the chest, CT or MRI of the abdomen and pelvis, as well as brain Magnetic 
Resonance Imaging (MRI) with and without gadolinium or CT with contrast, a whole-body bone scan (or PET or PET/CT if local standard for clinical trials) and 
evaluation of any superficial lesions.  Subsequent disease assessments should include all sites of disease identified at baseline or suspected to have developed; bone 
scans may be performed half as often (every 16 weeks) as other radiology evaluations and should be performed during assessment for confirmation of disease 
response.  More detailed guidance on exceptional circumstances is provided in the protocol.  Patients who discontinued the study for reasons other than objective 
disease progression will continue to have disease assessments at the same frequency until patient has radiologically confirmed progression, initiates a new anticancer 
therapy, or death. 
12  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.   
13  Long Term 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.  Follow-up may be performed by telephone contact or email. 
14  End of Treatment: Perform within 7-14 days of decision to permanently discontinue all study treatment.  Assessments that have been completed in the previous 4 
weeks do not need to be repeated (8 or 16 weeks for tumor assessments in accordance with schedule).  


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Table 2: 
Sitravatinib Schedule of PK, Biomarker Samples and Triplicate ECG Assessments: Cohorts 1 
through 8 
 
Screen/ 
Baseline 
Cycle 1 Day 1 
Cycle 1 Day 15  
(± 2 days) 
Cycle 2, 3, 5  
Day 1 only 
Cycle 2  
Day 15 only 
Collection Time 
and Allowable 
Window 
Within 28 
days 
Pre-dose 
(-0.5-0 hour) 
30 min 
(± 10 
min) 
7 hour5 
(5-9 hour) 
Pre-dose 
(-0.5-0 
hour) 
7 hour5 
(5-9 hour) 
Pre-dose 
(-0.5-0 hour) 
Pre-dose 
(-0.5-0 hour) 
PK Sample1,2 
 
X 
X 
X 
X 
X 
X 
 
TCR Sequencing3 
 
X 
 
 
X 
 
 
 
Flow Cytometry3 
X 
X 
 
 
X 
 
 
X 
Protein and Cytokine 
Biomarkers3 
 
X 
 
 
X 
 
 
X 
Triplicate ECG4 
 
X 
(-1 hour) 
X 
(-0.5 hour) 
 
X 
X 
X 
X 
 
1  Scheduled vital signs and triplicate ECGs precede PK sample collection in all cases.  Sitravatinib dosing and sampling should precede nivolumab infusion.  
Post-dose PK sample collections are not required for visits where sitravatinib dose is held but should be subsequently collected at the next visit following at 
least 7 days of sitravatinib intake.  Alternatively, both pre-dose and post-dose PK collections are not required for visits preceded by more than 4 days of 
sitravatinib hold but should be subsequently collected at the next visit following at least 7 days of sitravatinib intake. 
2  In addition to the scheduled samples, an unscheduled PK blood sample should be drawn before a daily sitravatinib dose (trough sample) in the event of any 
of the following events: 1) as soon as possible after an SAE, 2) at a clinic visit at least one week following a dose modification of the investigational agent, 
and 3) as soon as possible after renal function declines by one Stage as defined in Appendix 2, if the patient continues study treatment. 
3  The Day 1 blood samples for TCR sequencing, flow cytometry, protein and cytokine biomarker studies may be drawn up to 2 hours before dosing.  The 
screen/baseline sample should not be collected on the same day as the pre-dose Cycle 1 Day 1 sample. 
4  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 (e.g., 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: 
o 
Example for Cycle 1 Day 1 pre-dose ECGs/PK: ~-1.0 hr (Triplicate ECGs); ~-30 mins (Triplicate ECGs); ~-15 mins (Vitals/PK) 
o 
Example for all other pre-dose ECG/PK assessments: ~-30 mins (Triplicate ECGs); ~-15 mins (Vitals/PK) 
5  Timepoints changed in Version 3.0 of protocol to 7 hours (5-9 hours).  In preceding versions, these timepoints were 4 hours (2-6 hours). 
 
 


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Table 3: 
Schedule of Assessments: Cohorts 9 and 10 
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 
Cycles 1, 2, and 3 
≥Cycle 4 
End of Treatment 
Within 28 
days 
Day 1 
(± 2 days for 
Cycles 2 & 3) 
Day 8 
(± 2 days) 
Day 15 
(± 2 days) 
Only Lead-in 
Dose Escalation 
of Cohort 9 
Day 1 
(± 2 days) 
Day 8 
(± 2 days) 
End of 
Treatment/ 
Withdrawal14 
Post 
Treatment 
Follow Up 
Study Participation 
Informed Consent1 
Before 
study 
specific 
assessments 
 
 
 
 
 
 
 
Tumor Tissue Collection 
for PD-L1 Expression, 
Immune Cell Populations 
and Tumor Gene 
Alterations2 
X2 
X (Cycle 3 
only) 
Optional2 
 
 
 
 
 
 
Medical History, Disease 
History, Prior Therapy  
X 
 
 
 
 
 
 
 
ECOG Performance Status 
X 
 
 
 
 
 
 
 
Physical Exam3 
X 
 
 
 
 
 
X 
 
Eye Exam15 
X (Within 
≤ 3 months) 
As clinically indicated 
X 
 
Abbreviated Physical 
Exam3 
 
X 
X 
X 
X 
X 
 
 
Vital Signs4 
X 
X 
X 
X 
X 
X 
X 
 


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Table 3: 
Schedule of Assessments: Cohorts 9 and 10 (Continued) 
Assessments 
Screen/ 
Baseline 
Cycles 1, 2, and 3 
≥Cycle 4 
End of Treatment 
Within 28 
days 
Day 1 
(± 2 days for 
Cycles 2 & 3) 
Day 8 
(± 2 days) 
Day 15 
(± 2 days) 
Only Lead-in 
Dose Escalation 
of Cohort 9 
Day 1 
(± 2 days) 
Day 8 
(± 2 days) 
End of 
Treatment/ 
Withdrawal14 
Post 
Treatment 
Follow Up 
Pregnancy Test5 
X 
As clinically indicated 
 
Hemoglobin A1c7 
X 
 
 
 
 
 
 
 
Hematology6, 7 
X 
X 
X 
X 
X 
X 
X 
 
Coagulation6, 7 
X 
As clinically indicated 
 
Urinalysis6, 7 
X 
As clinically indicated 
 
Serum Chemistry6, 7 
X 
X 
X 
X 
X 
X 
X 
 
Thyroid Function Test6, 7 
X 
X 
 
 
X 
 
X 
 
Blood for Sitravatinib PK8 
 
See Table 4 
 
ctDNA blood sample9 
X 
At assessment for confirmation of disease response (PR or CR) 
X 
 
Single 12-Lead ECG10 
X 
As clinically indicated 
X 
 
Triplicate 12-Lead ECG10 
 
See Table 4 
 
Echocardiogram or MUGA 
X (Within 
35 days) 
 
Cycle 3 
only 
(± 7 days) 
 
As clinically 
indicated 
after C3 
 
X 
 
Disease Evaluation11 
X 
Every 9 weeks (± 10 days) for ~12 months and then every 18 weeks 
 
Sitravatinib Dispensing 
and/or Reconciliation 
 
X 
 
 
X 
 
 
 
 


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Table 3: 
Schedule of Assessments: Cohorts 9 and 10 (Continued) 
Assessments 
Screen/ 
Baseline 
Cycles 1, 2, and 3 
≥Cycle 4 
End of Treatment 
Within 28 
days 
Day 1 
(± 2 days for 
Cycles 2 & 3) 
Day 8 
(± 2 days) 
Day 15 
(± 2 days) 
Only Lead-in 
Dose Escalation 
of Cohort 9 
Day 1 
(± 2 days) 
Day 8 
(± 2 days) 
End of 
Treatment/ 
Withdrawal14 
Post 
Treatment 
Follow Up 
Enfortumab and 
Pembrolizumab 
Administration 
 
Throughout as directed in protocol 
(Note: pembrolizumab should be administered after sitravatinib, and enfortumab 
should be administered at least 30 minutes after pembrolizumab)  
 
 
Adverse Events12 and 
Concomitant Medications 
SAEs only 
Throughout 
 
Long Term Follow-up13 
 
 
 
 
 
 
 
X 
1  
Study Participation Informed Consent: May be performed more than 28 days prior to the first dose of study treatment and must be completed prior to initiation of any 
study specific assessments. 
2  
Tumor Testing for PD-L1 Expression, Tumor Immune Cell Populations, and Tumor Gene Alterations: 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.  An optional tumor tissue collection after and as close as possible to C3D1 is 
desirable for all patients and is not dependent on the type of tumor tissue submitted at screening.  A urinalysis should be performed prior to any study-related biopsy 
involving the genitourinary tract.  If the results are consistent with a urinary tract infection, tumor lesions in other anatomical areas should be selected, if present.  
Nectin-4 testing by immunohistochemistry may be evaluated. 
3  
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. 
4  
Vital Signs: Weight, temperature, blood pressure, and pulse rate to be assessed prior to dosing as indicated. 
5  
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.  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. 
6  
Selected Day 1 Assessments: Repeat assessment not required if screening assessment performed within 7 days before the first dose. 
7  
Safety Laboratory Assessments: Hematology, coagulation, chemistry, thyroid function and urinalysis evaluations (see Table 11) will be performed by local 
laboratories.  If HbA1c is elevated (≥ 6.5 %), refer patient to appropriate provider during Cycle 1 for glucose management. 
8  
Pharmacokinetic Samples: Blood samples to be collected following ECGs and assessment of vital signs as scheduled in Table 4.  


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9  
Blood samples for ctDNA analysis:  Blood will be collected in two 10 mL Streck brand Cell-Free DNA Blood Collection tubes allowing shipping and stability at 
ambient temperatures. 
10  12-Lead ECGs: Triplicate ECGs will accompany PK sampling as described in Table 4.  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. 
11  Disease Evaluations: To be performed at screening (28-day window allowed) and every 9 weeks from Cycle 1 Day 1 (± 10-day window for all other assessments 
except screening) until week 49 (~12 months) and then every 18 weeks.  All on-study disease evaluations should be based on a calendar beginning from the first day 
of dosing. At screening/baseline, assessments are to include CT with contrast of the chest, CT or MRI of the abdomen and pelvis, as well as brain Magnetic 
Resonance Imaging (MRI) with and without gadolinium or CT with contrast, a whole-body bone scan (or PET or PET/CT if local standard for clinical trials) and 
evaluation of any superficial lesions.  Subsequent disease assessments should include all sites of disease identified at baseline or suspected to have developed; bone 
scans may be performed half as often (every 18 weeks) as other radiology evaluations and should be performed during assessment for confirmation of disease 
response.  More detailed guidance on exceptional circumstances is provided in the protocol.  Patients who discontinued the study for reasons other than objective 
disease progression will continue to have disease assessments at the same frequency until patient has radiologically confirmed progression, initiates a new anticancer 
therapy, or death. 
12  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.   
13  Long Term 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.  Follow-up may be performed by telephone contact or email. 
14  End of Treatment: Perform within 7-14 days of decision to permanently discontinue all study treatment.  Assessments that have been completed in the previous 4 
weeks do not need to be repeated (8 or 16 weeks for tumor assessments in accordance with schedule). 
15  Eye exam: Patients with recent ocular complaints (within ≤ 3 months of screening) must have a complete eye examination at Screening Visit performed by a 
qualified ophthalmologist or optometrist, including but not limited to: uncorrected, corrected and best corrected visual acuity, slit lamp, tonometry 
examination, and dilated fundus examination.  Prior ophthalmologic exam done within 3 months of screening is acceptable provided there are no new 
symptoms since that exam.  End of Treatment Visit slit lamp examinations are required for all patients who experience corneal adverse events during the 
study and must be performed ≥ 28 days from last dose of enfortumab.  Additional eye examinations are to be conducted as clinically indicated. 
 
 


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Table 4: 
Sitravatinib Schedule of PK, Biomarker Samples and Triplicate ECG Assessments: Cohorts 9 
through 11 
 
Screen/ 
Baseline 
Cycle 1 Day 1 
Cycle 2 Day 1  
(± 2 days) 
Cycle 2, 3, 6  
Day 8 only 
Cycle 3  
Day 1 only 
Collection Time 
and Allowable 
Window 
Within 28 
days 
Pre-dose 
(-0.5-0 hour) 
30 min 
(± 10 
min) 
7 hour5 
(5-9 hour) 
Pre-dose 
(-0.5-0 
hour) 
7 hour5 
(5-9 hour) 
Pre-dose 
(-0.5-0 hour) 
Pre-dose 
(-0.5-0 hour) 
PK Sample1,2 
 
X 
X 
X 
X 
X 
X 
 
TCR Sequencing3 
 
X 
 
 
X 
 
 
 
Flow Cytometry3 
X 
X 
 
 
X 
 
 
X 
Protein and Cytokine 
Biomarkers3 
 
X 
 
 
X 
 
 
X 
Triplicate ECG4 
 
X 
(-1 hour) 
X 
(-0.5 hour) 
 
X 
X 
X 
X 
 
1  Scheduled vital signs and triplicate ECGs precede PK sample collection in all cases.  Sitravatinib dosing and sampling should precede nivolumab infusion.  
Post-dose PK sample collections are not required for visits where sitravatinib dose is held but should be subsequently collected at the next visit following at 
least 7 days of sitravatinib intake.  Alternatively, both pre-dose and post-dose PK collections are not required for visits preceded by more than 4 days or 
sitravatinib hold but should be subsequently collected at the next visit following at least 7 days of sitravatinib intake. 
2  In addition to the scheduled samples, an unscheduled PK blood sample should be drawn before a daily sitravatinib dose (trough sample) in the event of any 
of the following events: 1) as soon as possible after an SAE, 2) at a clinic visit at least one week following a dose modification of the investigational agent, 
and 3) as soon as possible after renal function declines by one Stage as defined in Appendix 2, if the patient continues study treatment. 
3  The Day 1 blood samples for TCR sequencing, flow cytometry, protein and cytokine biomarker studies may be drawn up to 2 hours before dosing.  The 
screen/baseline sample should not be collected on the same day as the pre-dose Cycle 1 Day 1 sample. 
4  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 (e.g., 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: 
o 
Example for Cycle 1 Day 1 pre-dose ECGs/PK: ~-1.0 hr (Triplicate ECGs); ~-30 mins (Triplicate ECGs); ~-15 mins (Vitals/PK) 
o 
Example for all other pre-dose ECG/PK assessments: ~-30 mins (Triplicate ECGs); ~-15 mins (Vitals/PK) 
5  Timepoints changed in Version 3.0 of protocol to 7 hours (5-9 hours).  In preceding versions, these timepoints were 4 hours (2-6 hours). 
 


 
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TABLE OF CONTENTS 
CLINICAL RESEARCH PROTOCOL ..........................................................................1 
DOCUMENT HISTORY ..................................................................................................2 
STUDY SUMMARY ........................................................................................................16 
TABLE OF CONTENTS ................................................................................................36 
TABLE OF TABLES .......................................................................................................41 
TABLE OF FIGURES .....................................................................................................42 
LIST OF ABBREVIATIONS .........................................................................................43 
1 
INTRODUCTION AND RATIONALE .................................................................47 
1.1 
Disease and Therapeutic Strategy ......................................................................47 
1.1.1 
Urothelial Carcinoma ....................................................................................47 
1.1.2 
Checkpoint Pathway ......................................................................................47 
1.1.3 
Checkpoint Inhibitor Therapy in Urothelial Carcinoma ...........................47 
1.1.4 
Antibody-Drug Conjugates (ADCs) .............................................................48 
1.1.5 
ADC Targeted Therapy in Urothelial Carcinoma ......................................48 
1.2 
Overall Rationale for the Proposed Combination Regimens ...........................49 
1.2.1 
Sitravatinib in Combination with a Checkpoint Inhibitor ........................49 
1.2.2 
Sitravatinib in Combination with a Checkpoint Inhibitor and an 
Antibody-Drug Conjugate (ADC) ................................................................50 
1.3 
Sitravatinib ...........................................................................................................51 
1.3.1 
Sitravatinib Drug Substance .........................................................................51 
1.3.2 
Nonclinical Data .............................................................................................52 
1.3.3 
Sitravatinib Clinical Experience ...................................................................53 
1.3.3.1 
Sitravatinib Pharmacokinetics ...............................................................53 
1.3.3.2 
Sitravatinib Clinical Safety .....................................................................54 
1.3.3.3 
Sitravatinib Clinical Efficacy ..................................................................57 
1.3.3.4 
Sitravatinib Capsule Formulation Study ...............................................57 
1.4 
Nivolumab .............................................................................................................58 
1.4.1 
Nivolumab Drug Substance ..........................................................................58 
1.4.2 
Nivolumab Nonclinical Data .........................................................................59 
1.4.3 
Nivolumab Clinical Data ...............................................................................59 
1.4.3.1 
Nivolumab Pharmacokinetics .................................................................59 
1.4.3.2 
Nivolumab Anti-Drug Antibodies ..........................................................59 
1.4.3.3 
Nivolumab Adverse Reactions Common in Clinical Trials .................59 
1.4.3.4 
Nivolumab Immune-Mediated Adverse Events ....................................60 
1.4.3.5 
Nivolumab Safety Reported in Urothelial Carcinoma Clinical 
Trials .........................................................................................................60 
1.4.3.6 
Nivolumab Efficacy Reported in Urothelial Carcinoma Clinical 
Trials .........................................................................................................61 
1.5 
Pembrolizumab ....................................................................................................61 
1.5.1 
Pembrolizumab Drug Substance ..................................................................62 
1.5.2 
Pembrolizumab Nonclinical Data .................................................................62 
1.5.3 
Pembrolizumab Clinical Data .......................................................................62 


 
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1.5.3.1 
Pembrolizumab Pharmacokinetics.........................................................62 
1.5.3.2 
Pembrolizumab Anti-Drug Antibodies ..................................................62 
1.5.3.3 
Pembrolizumab Adverse Reactions Common in Clinical Trials .........63 
1.5.3.4 
Pembrolizumab Immune-Mediated Adverse Events ............................63 
1.5.3.5 
Pembrolizumab Safety Reported in Urothelial Carcinoma 
Clinical Trials ...........................................................................................63 
1.5.3.6 
Pembrolizumab Efficacy Reported in Urothelial Carcinoma 
Clinical Trials ...........................................................................................64 
1.6 
Enfortumab ..........................................................................................................65 
1.6.1 
Enfortumab Drug Substance ........................................................................65 
1.6.2 
Enfortumab Nonclinical Data .......................................................................65 
1.6.3 
Enfortumab Clinical Data .............................................................................66 
1.6.3.1 
Enfortumab Pharmacokinetics ...............................................................66 
1.6.3.2 
Enfortumab Anti-Drug Antibodies ........................................................67 
1.6.3.3 
Enfortumab Adverse Reactions Common in Clinical Trials ...............67 
1.6.3.4 
Enfortumab Safety Reported in Urothelial Carcinoma Clinical 
Trials .........................................................................................................67 
1.6.3.5 
Enfortumab Efficacy Reported in Urothelial Carcinoma 
Clinical Trials ...........................................................................................69 
1.7 
Expectations for Safety of Sitravatinib Combination Regimens .....................69 
1.7.1 
Potential for Drug-Drug Interactions with Sitravatinib 
Combination Regimens .................................................................................69 
1.7.1.1 
Potential for Drug-Drug Interactions with the Combination of 
Sitravatinib and Nivolumab ....................................................................69 
1.7.1.2 
Potential for Drug-Drug Interactions with the Combination of 
Sitravatinib, Pembrolizumab and Enfortumab ....................................69 
1.7.2 
Potential for Increased Toxicity with Sitravatinib Combination 
Regimens .........................................................................................................70 
1.7.2.1 
Potential for Increased Toxicity with Combination of 
Sitravatinib and a PD-(L)1 Checkpoint Inhibitor ................................70 
1.7.2.2 
Potential for Increased Toxicity with the Combination of 
Sitravatinib, Pembrolizumab and Enfortumab ....................................72 
1.8 
Study Rationale ....................................................................................................74 
2 
STUDY OBJECTIVES ............................................................................................77 
2.1 
Objectives..............................................................................................................77 
2.1.1 
Primary Objective ..........................................................................................77 
2.1.2 
Secondary Objectives.....................................................................................77 
2.1.3 
Exploratory Objectives ..................................................................................78 
2.2 
Endpoints ..............................................................................................................78 
2.2.1 
Primary Endpoints.........................................................................................78 
2.2.2 
Secondary Endpoints .....................................................................................78 
2.2.3 
Exploratory Endpoints ..................................................................................78 
3 
STUDY DESIGN ......................................................................................................79 
4 
SUBJECT SELECTION AND ENROLLMENT ..................................................83 
4.1 
Inclusion Criteria .................................................................................................84 


 
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4.2 
Exclusion Criteria ................................................................................................86 
4.3 
Life Style Guidelines ............................................................................................90 
4.4 
Enrollment into Study .........................................................................................90 
5 
STUDY TREATMENTS ..........................................................................................91 
5.1 
Sitravatinib ...........................................................................................................91 
5.1.1 
Formulation, Packaging and Storage ...........................................................91 
5.1.2 
Preparation, Dispensing, Administration and Accountability ..................92 
5.1.3 
Sitravatinib Dose Modification and Discontinuation .................................93 
5.2 
Nivolumab Study Drug ........................................................................................94 
5.2.1 
Formulation and Packaging ..........................................................................95 
5.2.2 
Preparation and Dispensing ..........................................................................95 
5.2.3 
Administration ...............................................................................................95 
5.2.4 
Nivolumab Dose Modification ......................................................................95 
5.3 
Pembrolizumab Study Drug ...............................................................................95 
5.3.1 
Formulation and Packaging ..........................................................................96 
5.3.2 
Preparation and Dispensing ..........................................................................96 
5.3.3 
Administration ...............................................................................................96 
5.3.4 
Pembrolizumab Dose Modification ..............................................................96 
5.4 
Enfortumab Study Drug......................................................................................96 
5.4.1 
Formulation and Packaging ..........................................................................96 
5.4.2 
Preparation and Dispensing ..........................................................................96 
5.4.3 
Administration ...............................................................................................97 
5.4.4 
Enfortumab Dose Modification ....................................................................97 
5.5 
Management of Adverse Events .........................................................................98 
5.5.1 
Sitravatinib-Related Adverse Events ...........................................................98 
5.5.1.1 
General Management of Non-Hematological Toxicities ......................98 
5.5.1.2 
General Management of Hematological Toxicities ...............................99 
5.5.1.3 
Management of Selected Adverse Event ................................................99 
5.5.2 
Nivolumab Adverse Event Management Guidelines ................................101 
5.5.3 
Pembrolizumab Adverse Event Management Guidelines........................101 
5.5.4 
Enfortumab Adverse Event Management Guidelines ..............................102 
5.5.5 
Management of Immune-Related Adverse Events ...................................102 
5.5.6 
Management of Hy’s Law Cases ................................................................103 
5.6 
Medication Error ...............................................................................................103 
5.7 
Concomitant Therapies .....................................................................................104 
5.7.1 
Concomitant Medication(s) .........................................................................104 
5.7.2 
Concomitant Medication(s) Restrictions in Cycle 1 of Lead-In 
Dose Escalation Evaluation (Cohort 9) for Patients Undergoing a 
DLT Assessment ...........................................................................................106 
5.7.3 
Concomitant Surgery or Radiation Therapy ............................................106 
5.7.4 
Other Anticancer or Experimental Therapy .............................................107 
6 
STUDY ASSESSMENTS .......................................................................................107 
6.1 
Screening .............................................................................................................107 
6.2 
Study Period .......................................................................................................107 
6.3 
End of Treatment Assessment ..........................................................................107 


 
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6.4 
Long-Term Follow-up and End of Study Assessment ....................................107 
6.5 
Patient Discontinuation/Withdrawal ...............................................................108 
7 
PROCEDURES .......................................................................................................109 
7.1 
Efficacy................................................................................................................109 
7.2 
Safety Assessments .............................................................................................111 
7.2.1 
Medical History ............................................................................................111 
7.2.2 
Physical Examination and Vital Signs .......................................................111 
7.2.3 
Eye Examination (Only for Cohorts 9 and 10) ..........................................111 
7.2.4 
Laboratory Safety Assessments ..................................................................111 
7.2.5 
Electrocardiogram (ECG) ...........................................................................112 
7.2.6 
Echocardiogram (ECHO) ...........................................................................113 
7.3 
Laboratory Studies ............................................................................................113 
7.3.1 
Pharmacokinetic Evaluation .......................................................................113 
7.3.2 
Pharmacodynamic Evaluation in Blood ....................................................113 
7.3.3 
Circulating Tumor DNA .............................................................................113 
7.3.4 
Pharmacodynamic Evaluation in Tumor Tissue ......................................114 
7.4 
Post-treatment Follow-up ..................................................................................114 
8 
ADVERSE EVENT REPORTING .......................................................................115 
8.1 
Sponsor Medical Monitor Personnel ................................................................115 
8.2 
Adverse Events ...................................................................................................115 
8.2.1 
Laboratory Abnormalities ..........................................................................116 
8.2.2 
Severity Assessment .....................................................................................116 
8.2.3 
Causality .......................................................................................................117 
8.3 
Serious Adverse Events .....................................................................................117 
8.3.1 
Definition of a Serious Adverse Events ......................................................117 
8.3.2 
Exposure During Pregnancy .......................................................................118 
8.4 
Reporting of SAEs and AEs ..............................................................................119 
8.4.1 
Reporting Period ..........................................................................................119 
8.4.2 
Reporting Requirements .............................................................................120 
9 
STATISTICS ...........................................................................................................120 
9.1 
Hypothesis and Sample Size ..............................................................................120 
9.2 
Data Handling ....................................................................................................122 
9.3 
Analysis Populations ..........................................................................................122 
9.3.1 
Full Analysis Population .............................................................................122 
9.3.2 
Clinical Activity Evaluable Population ......................................................122 
9.3.3 
Safety Population .........................................................................................123 
9.3.4 
Molecular Marker Evaluable Population ..................................................123 
9.3.5 
Pharmacokinetic Evaluable Population .....................................................123 
9.3.6 
Pharmacodynamic Evaluable Population..................................................123 
9.3.7 
DLT Evaluable Population (only applicable to lead-in dose 
escalation portion of Cohort 9) ...................................................................123 
9.4 
Efficacy Endpoint Definitions and Analyses ...................................................124 
9.4.1 
Objective Response Rate .............................................................................124 
9.4.2 
Clinical Benefit Rate ....................................................................................124 
9.4.3 
Duration of Response ...................................................................................124 


 
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9.4.4 
Progression-Free Survival ...........................................................................124 
9.4.5 
Overall Survival ...........................................................................................125 
9.4.6 
Subgroup Analyses.......................................................................................125 
9.5 
Safety Data Presentations and Summaries ......................................................125 
9.5.1 
Adverse Events .............................................................................................125 
9.5.2 
Prior and Concomitant Medications ..........................................................125 
9.5.3 
Clinical and Laboratory Assessments ........................................................126 
9.5.4 
Patient Demographics, Baseline Characteristics and Disposition ...........126 
9.5.5 
Analysis of Study Treatment Dosing ..........................................................126 
9.6 
Other Study Endpoints ......................................................................................127 
9.6.1 
Pharmacokinetic Analysis ...........................................................................127 
9.6.2 
Pharmacodynamic and Exploratory Analyses ..........................................127 
9.7 
Interim Analysis .................................................................................................127 
9.8 
Data Monitoring Committee .............................................................................127 
10 ETHICS AND RESPONSIBILITIES ...................................................................127 
10.1 
Ethical Conduct of the Study ............................................................................127 
10.2 
Obligations of Investigators ..............................................................................128 
10.3 
Institutional Review Board/Ethics Committee/Research Ethics Board 
(IRB/EC/REB) ....................................................................................................128 
10.4 
Informed Consent Form ....................................................................................129 
10.5 
Confidentiality ....................................................................................................129 
10.6 
Reporting of Serious Breaches of the Protocol or ICH GCP .........................130 
11 RECORDS MANAGEMENT................................................................................130 
11.1 
Source Documentation.......................................................................................130 
11.2 
Study Files and Records Retention ..................................................................130 
12 QUALITY CONTROL AND QUALITY ASSURANCE ....................................131 
12.1 
Monitoring Procedures ......................................................................................131 
12.2 
Auditing and Inspection Procedures ................................................................131 
13 CHANGES IN STUDY CONDUCT .....................................................................131 
13.1 
Protocol Amendments .......................................................................................131 
13.2 
Protocol Deviations ............................................................................................132 
14 END OF TRIAL ......................................................................................................132 
14.1 
End of Trial in a European Union Member State ..........................................132 
14.2 
End of Trial in all other Participating Countries ...........................................133 
14.3 
Premature Termination.....................................................................................133 
15 STUDY REPORT AND PUBLICATION POLICY ............................................133 
16 REFERENCES .......................................................................................................134 
APPENDIX 1. ECOG PERFORMANCE STATUS ...................................................140 
APPENDIX 2. CALCULATION OF GLOMERULAR FILTRATION RATE 
AND RENAL IMPAIRMENT SCALE ................................................................141 
APPENDIX 3. MEDICATIONS OR SUBSTANCES TO BE AVOIDED OR 
USED WITH CAUTION DURING TREATMENT WITH 
SITRAVATINIB .....................................................................................................143 
APPENDIX 4. ABBREVIATED PRESENTATION OF RECIST VERSION 
1.1 GUIDELINES ...................................................................................................151 


 
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APPENDIX 5. CONTINGENT STUDY COHORTS IN PATIENTS 
PREVIOUSLY RECEIVING TREATMENT WITH SELECTED 
IMMUNOTHERAPIES .........................................................................................156 
APPENDIX 6. CONTINGENT STUDY COHORTS IN CHECKPOINT 
INHIBITOR THERAPY NAÏVE POPULATIONS ............................................157 
APPENDIX 7. EVALUATION OF THE PHARMACOKINETICS OF 
SITRAVATINIB IN PATIENTS WITH RENAL IMPAIRMENT ...................159 
APPENDIX 8. CONTINGENT STUDY COHORTS IN PATIENTS 
PREVIOUSLY RECEIVING TREATMENT WITH AN ANTIBODY-
DRUG CONJUGATE ............................................................................................161 
APPENDIX 9. CONTINGENT STUDY COHORTS EVALUATING 
SITRAVATINIB COMBINATION WITH A CHECKPOINT 
INHIBITOR AND AN ANTIBODY-DRUG CONJUGATE ..............................163 
APPENDIX 10. EXAMPLES OF PROHIBITED P-GP INHIBITORS AND 
STRONG CYP3A4 INHIBITORS DURING TREATMENT WITH 
ENFORTUMAB .....................................................................................................169 
APPENDIX 11. DOSE DE-ESCALATION DECISION TABLE USING THE 
mTPI METHOD .....................................................................................................170 
APPENDIX 12. COVID-19 PANDEMIC CHANGES TO STUDY 
CONDUCT ..............................................................................................................171 
 
TABLE OF TABLES 
Table 1: Schedule of Assessments: Cohorts 1 through 8 ...........................................27 
Table 2: Sitravatinib Schedule of PK, Biomarker Samples and Triplicate 
ECG Assessments: Cohorts 1 through 8 ......................................................30 
Table 3: Schedule of Assessments: Cohorts 9 and 10 ................................................31 
Table 4: Sitravatinib Schedule of PK, Biomarker Samples and Triplicate 
ECG Assessments: Cohorts 9 through 11 ....................................................35 
Table 5: Sitravatinib Sequential Dose Reductions for Individual Patients on 
Free Base Capsule Formulation ...................................................................94 
Table 6: Sitravatinib Sequential Dose Reductions for Individual Patients on 
Malate Capsule Formulation ........................................................................94 
Table 7: Enfortumab Sequential Dose Reductions for Individual Patients ............97 
Table 8: Sitravatinib Dose Modifications – Non-Hematological Drug-
Related Toxicities1 ..........................................................................................98 
Table 9: Sitravatinib Dose Modification for Increased Blood Pressure ................100 
Table 10: Sitravatinib Dose Modification for Increased Hepatic 
Transaminases ..............................................................................................103 
Table 11: Laboratory Safety Parameters ...................................................................112 
Table 12: Estimates of 95% CI Using Clopper-Pearson in After Enrollment 
of 40 Patients ................................................................................................122 


 
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Table 13: Substitute Day 1 and 15 Sitravatinib PK Sample Schedule During 
Renal Impairment Sub-study3 ....................................................................160 
Table 14: Sitravatinib Starting Dose Levels for Lead-In Dose Escalation 
Cohort 9 (Malate Formulation) ..................................................................164 
Table 15: Pembrolizumab and Enfortumab Dose Levels..........................................165 
 
TABLE OF FIGURES 
Figure 1: 
Study Schema ...........................................................................................24 
 


 
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LIST OF ABBREVIATIONS 
ADC 
Antibody-Drug Conjugate 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
APC 
Antigen Presenting Cells 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Curve 
BCRP 
Breast Cancer Resistance Protein 
Cave,ss  
Average Steady State Plasma Drug Concentration During Multiple-Dose Administration 
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 
ctDNA 
Circulating Tumor Deoxyribonucleic Acid 
DDI 
Drug-Drug Interaction 
DLT 
Dose-Limiting Toxicity 
DOR 
Duration of Response 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EIU 
Exposure In-Utero 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate  
HDPE 
High-Density Polyethylene 
hERG 
human Ether-a-go-go Related Gene 
HGF 
Hepatocyte Growth Factor 


 
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LIST OF ABBREVIATIONS (CONTINUED) 
hr 
Hour 
IC50 
Half Maximal Inhibitory Concentration 
ICD 
Immunogenic Cell Death 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IFN-γ 
Interferon Gamma 
IgG4 
Immunoglobulin G4 
IND 
Investigational New Drug 
INR 
International Normalized Ration 
irAE 
Immune-related Adverse Event 
IRB 
Institutional Review Board 
IUD 
Intrauterine Device 
kg 
Kilogram 
MAb 
Monoclonal Antibody 
MDSC 
Myeloid-Derived Suppressor Cell 
MDSCs 
Myeloid-Derived Suppressor Cells   
MedDRA 
Medical Dictionary for Regulatory Activities 
MET 
Mesenchymal-Epithelial Transition 
mg 
Milligram 
mITT 
Modified Intent-to-Treat 
mL 
Milliliter 
MMAE 
Microtubule-inhibitor Monomethyl Auristatin E 
MRI 
Magnetic Resonance Imaging 
mRNA 
Messenger Ribonucleic Acid 
MSCs 
Mesenchymal Stem Cells 
MTD 
Maximum Tolerated Dose 
MUGA 
Multigated Acquisition Scan  
NCI 
National Cancer Institute 
NE 
Not Evaluable 
NK 
Natural Killer 
NPCB 
No Prior Clinical Benefit 
NSCLC 
Non-Small Cell Lung Cancer 
ORR 
Objective Response Rate 


 
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LIST OF ABBREVIATIONS (CONTINUED) 
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 
PFS 
Progression-Free Survival 
P-gp 
P-glycoprotein 
PK 
Pharmacokinetics 
PKAP 
Pharmacokinetic Analysis Plan 
PPE 
Palmar-plantar Erythrodysesthesia 
PR 
Partial Response 
PTT 
Partial Thromboplastin Time 
Q2W 
Every 2 Weeks 
Q3W 
Every 3 Weeks 
Q4W 
Every 4 Weeks 
QD 
Once Daily 
QTc 
Corrected QT Interval 
RP2D 
Recommended Phase 2 Combinatorial Dose 
REB 
Research Ethics Board 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RTKs 
Receptor Tyrosine Kinases 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
SOC 
System Organ Class 
TAM 
Tyro3, Axl and MERTK 
TCR 
T-Cell Receptor 
TKIs 
Tyrosine Kinase Inhibitors 
TME 
Tumor Microenvironment 
Tregs 
T Regulatory Cells 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cell 
WHO 
World Health Organization 


 
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LIST OF ABBREVIATIONS (CONTINUED) 
WOCBP 
Women of Childbearing Potential 
μg 
Microgram 
μM 
Micromolar 
 


 
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1 INTRODUCTION AND RATIONALE 
1.1 
Disease and Therapeutic Strategy 
1.1.1 
Urothelial Carcinoma 
Urothelial carcinoma comprises approximately 90% of bladder cancer cases, which are a 
major cause of morbidity and mortality, resulting in an estimated 165,000 deaths annually 
worldwide (Miyazaki-2017; Antoni-2017).  Approximately 25% of patients are 
diagnosed with locally advanced or metastatic urothelial carcinoma, and while platinum-
based chemotherapy is the cornerstone of first-line therapy, most patients experience 
treatment resistance or intolerance (Bambury-2013; Burger-2013; von der Maase-2005).  
In addition, due to renal impairment, about 25-50% of patients with metastatic urothelial 
carcinoma are not able to receive platinum-based chemotherapy (Dash-2006).   
Until recently, there were no established treatment options for patients with platinum-
refractory urothelial carcinoma (Bellmunt-2009; Choueiri-2012; Vaughn-2002).  Indeed, 
second-line chemotherapy was associated with modest efficacy and, survival times of 
approximately 7 months underscored the need for alternate treatment approaches.  Since 
2016, treatment options for platinum-refractory or platinum-ineligible advanced 
urothelial carcinoma have been expanded to include agents targeting programmed death 
protein-1 (PD-1) and its ligand (PD-L1), and there are now 5 FDA-approved 
immunotherapies in this setting (Rosenberg-2016; Sharma-2016; Massard-2016; 
Bellmunt-2017a; Apolo-2017; Balar-2017a; Balar-2017b).  While overall survival 
benefits of immunotherapy have been demonstrated in a large-scale randomized 
controlled trial (Bellmunt-2017a), response rates are relatively low. 
1.1.2 
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 IFNγ.  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.   
1.1.3 
Checkpoint Inhibitor Therapy in Urothelial Carcinoma 
Checkpoint inhibitors studied in patients with urothelial carcinoma include nivolumab, 
atezolizumab, avelumab, durvalumab, and pembrolizumab (Sharma-2016; Sharma-2017; 
Rosenberg-2016; Patel-2018; Massard-2016; Bellmunt-2017a; Apolo-2017; Balar-2017a; 
Balar-2017b).  Objective Response Rates for single agent checkpoint inhibitors hover 
around 20% (Bellmunt-2017b; Aggen-2017; Davarpanah-2017).  The effect of tumor 


 
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PD-L1 expression on clinical response in urothelial carcinoma has been variable and 
depended on the assay and the checkpoint inhibitor.   
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.  It has been approved by the FDA for the 
treatment of patients with advanced or metastatic urothelial carcinoma who have disease 
progression during or following platinum-containing chemotherapy. 
Pembrolizumab, a fully humanized 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.  Pembrolizumab has been 
approved by the FDA for the treatment of patients with advanced or metastatic urothelial 
carcinoma who have disease progression during or following platinum-based 
chemotherapy, and of patients with locally advanced or metastatic urothelial carcinoma 
who are not eligible for cisplatin-containing chemotherapy and whose tumors express 
PD-L1 [Combined Positive Score ≥10] as determined by an FDA-approved test, or in 
patients who are not eligible for any platinum-based chemotherapy regardless of PD-L1 
status. 
Combining an immunotherapeutic PD-(L)1 checkpoint inhibitor with an agent that has 
both immune modulatory and antitumor properties and targets the molecular and cellular 
mechanisms of resistance to checkpoint inhibitor therapy could enhance the antitumor 
efficacy observed with either agent alone. 
1.1.4 
Antibody-Drug Conjugates (ADCs) 
Antibody-drug conjugates (ADCs), comprising of a highly specific monoclonal antibody 
(mAb) for a tumor antigen (Ag) and a highly active cytotoxic agent connected via a 
linker molecule, are designed as a targeted therapy by selective delivery of cytotoxic 
drugs to cancer cells while sparing healthy cells resulting in a broad therapeutic window 
(Khongorzul-2020; Vlachostergios-2018).  Upon antibody-antigen binding on the surface 
of cancer cells, the conjugate is internalized by endocytosis and its cytotoxic payload is 
released after lysosomal degradation. 
1.1.5 
ADC Targeted Therapy in Urothelial Carcinoma 
ADCs studied in patients with advanced urothelial carcinoma include enfortumab and 
sacituzumab govitecan.  Objective Response Rates for single agent ADCs in platinum-
based chemotherapy and/or checkpoint inhibitor therapy pretreated vary between 29 to 
44% (Rosenberg-2019; Tagawa-2019).  Based on evidence of tolerable toxicity and 
clinical activity, ADCs are being explored in the frontline metastatic setting in 
combination regimens with checkpoint inhibitor therapy and/or platinum-based 
chemotherapy. 


 
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Enfortumab is an investigational ADC that is comprised of a fully human anti-Nectin-4 
IgG1 kappa mAb conjugated to the microtubule-inhibitor monomethyl auristatin E 
(MMAE) via a protease-cleavable linker.  Nectin-4, also known as poliovirus receptor-
related protein 4 (PVRL4), is an adhesion protein located on the surface of cells, with 
weak to moderate expression in normal skin.  Copy number gain of the PVRL4 gene is a 
frequent event in carcinogenesis and promotes epithelial-to-mesenchymal transition, 
invasion and metastasis, resulting in high expression of Nectin-4 in several solid tumors, 
particularly urothelial carcinomas.  Enfortumab binds to cells that express Nectin-4 with 
high affinity, triggering the internalization and release of MMAE in target cells.  MMAE 
disrupts the microtubule network within the cell, subsequently inducing cell cycle arrest 
and apoptotic cell death (Rosenberg-2019; Vlachostergios-2018).  It has been approved 
under accelerated approval by the FDA based on tumor response rate for the treatment of 
adult patients with locally advanced or metastatic urothelial cancer who have previously 
received a PD-(L)1 checkpoint inhibitor, and a platinum-based chemotherapy in the 
neoadjuvant/adjuvant, locally advanced or metastatic setting.  Continued approval for this 
indication may be contingent upon verification and description of clinical benefit in 
confirmatory trials. 
Preclinical studies show that ADCs linked to MMAE induce immunogenic cell death and 
may enhance anti-tumor activity such that the combination of enfortumab and an 
immunotherapeutic PD-(L)1 checkpoint inhibitor may have greater anti-tumor activity 
than either agent alone (Rosenberg-2020).  Based on initial results from the EV-103 trial, 
enfortumab in combination with pembrolizumab has been granted Breakthrough Therapy 
designation for the treatment of patients with unresectable locally-advanced or metastatic 
urothelial cancer who are unable to receive cisplatin-based chemotherapy in the first-line 
setting, and is being explored in treatment-naïve, platinum-eligible patients in a Phase 3 
study (EV-302 trial). 
With its distinct immune modulatory mechanism of action which primarily targets the 
molecular and cellular mechanisms of resistance to checkpoint inhibitor therapy in key 
immune suppressive cell types, sitravatinib in combination with enfortumab and 
pembrolizumab could further augment the antitumor efficacy observed with enfortumab 
and pembrolizumab combination regimen. 
1.2 
Overall Rationale for the Proposed Combination Regimens 
1.2.1 
Sitravatinib in Combination with a Checkpoint Inhibitor 
Mechanisms of resistance to checkpoint inhibitor therapy have been described based on 
fundamental knowledge of the immune system as well as emerging clinical data.  
Expression of PD-L1 in immune and / or tumor cells appears to correlate with response in 
some but not all urothelial carcinoma clinical studies (Rosenberg-2016; Bellmunt-2017a; 
Sharma-2017; Apolo-2017; Patel-2018; Massard-2016; Hahn-2017).  In the tumor 
microenvironment, PD-L1 can be upregulated in tumor cells via oncogenic signaling or 
in response to immune stimulatory factors such as interferon gamma (IFN-γ).  Therefore, 


 
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the absence of PD-L1 expression may reflect a tumor cell population and 
microenvironment with a suppressed immune response.   
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 (Tregs), Myeloid-Derived Suppressor 
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 tumor 
microenvironment and increase the effectiveness of PD-(L)1 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 augment or restore anti-tumor immunity when combined with nivolumab, a 
checkpoint inhibitor therapy. 
1.2.2 
Sitravatinib in Combination with a Checkpoint Inhibitor and an 
Antibody-Drug Conjugate (ADC) 
The antitumor activity of ADCs that, similar to enfortumab, are linked to MMAE such as 
brentuximab vedotin, ladiratuzumab vedotin and tisotumab vedotin resulting primarily 
from the intracellular payload release, leading to mitotic arrest and apoptotic cell death, 
has been extensively studied.  Emerging data indicates a potential immune modulatory 
activity with these ADCs by inducing immunogenic cell death (ICD) that enhances innate 
and adaptive antitumor immunity in vitro and in vivo (Cao-2016; Cao-2017; Cao-2018; 
Alley-2019).  Preclinical studies reveal induction of key hallmarks of ICD including 
activation of ER stress response pathways, ATP secretion, and release of HMGB1, which 
are important for immune cell activation and recruitment into the tumor 
microenvironment.  Other Fc-mediated effector mechanisms like antibody-dependent 
cellular phagocytosis and cytotoxicity are also involved.  Addition of ADC-killed 
tumor-like cells to autologous PBMCs results in the expansion of cytotoxic T-cells.  In 
vivo administration of these ADCs leads to directed proinflammatory immune responses 
against the tumor and this activity is further potentiated by PD-1 checkpoint inhibitor 
therapy as demonstrated by accelerated tumor regressions and greater antitumor activity 
than either agent alone, demonstrating complementary modes of action for these agents 
and providing a rationale for exploring therapeutic strategies that combine ADCs with 
other immune stimulatory regimens.  Multiple clinical trials are ongoing to evaluate the 
efficacy of similar combinations.  In particular, early efficacy results from enfortumab in 
combination with the PD-1 checkpoint inhibitor pembrolizumab in frontline cisplatin-
ineligible urothelial carcinoma in the ongoing EV-103 study has shown encouraging 
activity with a safety profile that appears manageable and tolerable.  Sitravatinib targets 
the molecular and cellular mechanisms of resistance to checkpoint inhibitor therapy that 
are primarily operative in innate and adaptive immune cell types and is distinct from the 
mechanism of action of the tumor cell-targeting enfortumab and checkpoint inhibitor 
therapy.  Therefore, sitravatinib in combination with enfortumab and pembrolizumab is 


 
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hypothesized to complement these therapies in mounting a productive anti-tumor immune 
response and could further augment the antitumor efficacy observed with enfortumab and 
pembrolizumab combination regimen (refer to Section 1.2.1). 
1.3 
Sitravatinib 
Sitravatinib (MGCD516) is an orally available, potent small molecule inhibitor of a 
closely related spectrum of receptor tyrosine kinases (RTKs) including MET, Axl, 
MERTK, VEGFR family, PDGFR family, KIT, FLT3, Trk family, RET, DDR2, and 
selected Eph family members.  Receptor tyrosine kinases (RTKs) 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 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 
tumor microenvironment 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, formula, and molecular weight of sitravatinib (MGCD516) free 
base and malate salt are as follows: 
Sitravatinib (MGCD516) Free Base 
N
S
O
N
H
N
F
H
N
NH
O
O
O
F
 
 
 


 
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Sitravatinib (MGCD516) 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 
Nonclinical Data 
Complete information concerning sitravatinib nonclinical data is available in the 
Investigator’s Brochure.  
Sitravatinib demonstrated potent, concentration-dependent inhibition of the kinase 
activity of MET, Axl, MERTK, VEGFR family, PDGFR family, KIT, FLT3, Trk family, 
RET, DDR2, and selected Eph family members in biochemical assays and inhibited 
phosphorylation and kinase dependent function in cell-based assays.  Sitravatinib also 
inhibited oncogenic functions associated with target RTKs including MET-dependent cell 
viability and migration and endothelial tube formation and angiogenesis.  Consistent with 
this anti-tumor and anti-angiogenic mechanism of action, sitravatinib demonstrated 
anti-tumor efficacy over a broad spectrum of human tumor xenograft models including 
robust cytoreductive anti-tumor activity in a subset of models exhibiting genetic 
alterations in RTK targets including MET, RET, FLT3 and others.   
In vitro results from the (human Ether-a-go-go Related Gene) hERG assay demonstrate 
an 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.   


 
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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 M, respectively, these values are much higher than the systemic 
steady state exposure levels observed clinically. 
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.  Overall, 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 mRNA levels, or CYP3A4 activity.  However, 
MGCD516 (up to 3 and 10 µM) 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.   
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 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.  In addition, 
approximate 50% direct inhibition was observed for CYP2B6 at the highest concentration 
of MGCD516 evaluated (20 μM); thus, the IC50 value was reported as greater than 
20 μM. 
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. 
1.3.3 
Sitravatinib Clinical Experience 
1.3.3.1 
Sitravatinib Pharmacokinetics 
Complete information concerning sitravatinib pharmacokinetics is available in the 
Investigator’s Brochure.   


 
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After single dose administration of sitravatinib free base capsules, sitravatinib reaches 
peak concentration in a median time of 3 to 8 hours.  Exposure parameters (maximum 
concentration [Cmax] and area under the curve [AUC]) are dose proportional with doses 
up to 200 mg.  Mean elimination half-life varies between 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 1.25 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 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 PD-(L)1 checkpoint 
inhibitors 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 
checkpoint inhibitor nivolumab (MRTX-500, 516-002, 516-003 and 516-005), and 
combination studies with the PD-1 checkpoint inhibitor tislelizumab (BGB-900-103 and 
BGB-900-104).  Sitravatinib has also been administered as single agent in healthy subject 


 
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studies (516-006 and 516-007).  Details regarding the clinical studies most relevant for 
this study, 516-003, 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 study 
evaluated dose levels between 10 mg and 200 mg administered QD.  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 disease progression either on or after prior treatment with a 
checkpoint inhibitor therapy (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 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 evaluation of sitravatinib in 
combination with nivolumab administered by intravenous infusion, 240 mg Q2W.  
Sitravatinib is administered orally, once daily in cycles of 28 days.  The starting dose for 
sitravatinib was 120 mg QD administered orally, in 28-day cycles.  No protocol defined 
DLTs were reported in the first 6 evaluable patients treated at the sitravatinib starting 
dose of 120mg QD 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 QD was selected as the recommended 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), 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. 
DLTs with single-agent administration of sitravatinib in Study 516-001 included Grade 3 
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 
Q2W) and sitravatinib (120 mg QD). 
Sitravatinib-related adverse events (AEs) reported in ≥ 20% of 186 patients in sitravatinib 
monotherapy studies were diarrhea (50%), fatigue (42%), hypertension (39%), nausea 


 
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(29%), decreased appetite (27%), vomiting (24%), and palmar-plantar erythrodysesthesia 
(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%). 
In particular, treatment-related AEs reported in ≥20% of 40 patients treated with 
sitravatinib in combination with nivolumab in Study 516-003 as of 26 June 2019 
(enrolled mostly in Cohorts 1 through 4) were fatigue (58%), diarrhea (55%), decreased 
appetite (38%), dysphonia (38%), nausea (30%), lipase increased (28%), alanine 
aminotransferase increased (25%), PPE (25%), hypertension (20%), dysgeusia (20%), 
vomiting (20%), and proteinuria (20%).  Treatment-related Grade 3 AEs reported in ≥5% 
of patients were hypertension (20%), diarrhea (10%), fatigue (10%), lipase increased 
(10%), and PPE (5%).  No treatment-related Grade 4 or Grade 5 AEs were reported. 
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, PPE, 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 adverse events 
in Section 5.5.1. 


 
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1.3.3.3 
Sitravatinib Clinical Efficacy 
As of protocol Version 4.0, early clinical activity with the combination of sitravatinib and 
nivolumab in Study 516-003 is promising with multiple cohorts (Cohorts 1, 2, 3 and 5) 
having met the efficacy criteria per the PPD design to advance to Stage 2, and Cohort 1 
having further advanced to the Expansion stage.  Other cohorts are pending such 
decisions as enrollment progresses.  As of 26 July 2019, updated data from an interim 
analysis of clinical activity from Cohort 1 at the time of expansion from Stage 2 to the 
Expansion stage of the PPD design, showed a preliminary objective response rate (ORR) 
of 27% among 22 clinical activity evaluable patients (Msaouel-2019).  Cohort 1 has since 
completed enrollment and final efficacy updates including secondary efficacy endpoints 
are awaited.  Similarly, early efficacy updates are awaited for the remaining active 
cohorts of Study 516-003. 
Final efficacy results are awaited from both the Phase 1b segment of Study 516-001, and 
Study MRTX-500. 
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. 
Preliminary results from patients enrolled into the prior clinical benefit (PCB) stratum of 
MRTX-500 were updated as of 04 September 2019, and included 79 patients enrolled 
into the PCB stratum of MRTX-500.  Patients in the PCB stratum have experienced 
clinical benefit (confirmed CR or PR or stable disease for at least 12 weeks) on their prior 
CIT.  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 (DOR) 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 


 
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capsule formulation, and that a free base to malate ratio of approximately 1.25 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). 
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 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. 
1.4 
Nivolumab 
Nivolumab (OPDIVO®) is a human monoclonal antibody 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 is a human immunoglobulin G4 
(IgG4) monoclonal antibody 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.  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 US Prescribing Information. 
1.4.1 
Nivolumab Drug Substance 
Generic Name: 
Nivolumab 
Other Name:  
OPDIVO® 


 
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Molecular Weight:  
146 kDa 
1.4.2 
Nivolumab Nonclinical Data 
The nonclinical experience is described in the OPDIVO US Prescribing Information.   
1.4.3 
Nivolumab Clinical Data 
The following reports information included in the OPDIVO US Prescribing Information 
dated June 2020.  Refer to the current Prescribing Information 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 Q2W or Q3W 
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 (CL) 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 (t1/2) 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 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 >1 
to 1.5 times ULN and any AST) or moderate hepatic impairment (TB >1.5 to 3 times 
ULN and any AST).  Nivolumab has not been studied in patients with severe hepatic 
impairment (TB >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. 
1.4.3.3 
Nivolumab Adverse Reactions Common in Clinical Trials 
Refer to the current OPDIVO US Prescribing Information for information concerning 
adverse reactions occurring in clinical trials. 


 
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As of June 2020, 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, and vomiting.  
1.4.3.4 
Nivolumab Immune-Mediated Adverse Events 
Refer to the current OPDIVO US Prescribing Information for information concerning 
immune-mediated adverse events occurring during treatment with nivolumab.   
As of June 2020, the OPDIVO US Prescribing Information includes warnings and 
precautions for a range of immune-mediated adverse events documented in patients 
across cancer indications, including, pneumonitis, colitis, hepatitis, endocrinopathies 
(such as adrenal insufficiency, hypophysitis, hypothyroidism and hyperthyroidism, 
Type 1 diabetes mellitus), nephritis and renal dysfunction, skin adverse reactions, 
encephalitis, other rarer immune-mediated adverse events, and infusion reactions.   
1.4.3.5 
Nivolumab Safety Reported in Urothelial Carcinoma Clinical Trials 
Refer to the current OPDIVO US Prescribing Information for safety information 
concerning OPDIVO in clinical trials enrolling patients with urothelial carcinoma. 
In both studies reported below, patients received 3 mg/kg of nivolumab administered 
intravenously over 60 minutes Q2W until unacceptable toxicity or either radiographic or 
clinical progression.   
The CheckMate 032 study (Sharma-2016) was a Phase 1/2 trial that included 78 patients 
with advanced or metastatic urothelial carcinoma who experienced progression during or 
following one prior platinum-based chemotherapy regimen.  Grade 3 or 4 
treatment-related AEs occurred in 22% of the patients and included elevated lipase (5%), 
elevated amylase (4%), fatigue, maculopapular rash, dyspnea, decreased lymphocyte 
count, and decreased neutrophil count (3% each).  Treatment-related AEs of special 
interest potentially associated with the use of nivolumab were skin (42%), gastrointestinal 
(10%), renal (9%), hepatic (5%), and pulmonary adverse events (3%).  Forty-six percent 
of the patients experienced SAEs considered related to nivolumab treatment, including 
colitis, diarrhea, mouth ulceration, nausea, oral pain, thrombocytopenia, fatigue, 
hyponatremia, acute kidney injury, and pneumonitis. Two patients discontinued treatment 
due to treatment-related AEs of pneumonitis and thrombocytopenia, both grade 4 events.  
The CheckMate 275 study (Sharma-2017) was a single-arm Phase 2 trial in 270 patients 
with metastatic or surgically unresectable locally advanced disease who had experienced 
disease progression during or following platinum-containing chemotherapy or had 
disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum 
containing chemotherapy.  Grade 3 or 4 AEs occurred in 18% of patients including 
fatigue and diarrhea (2% each).  Treatment-related AEs of special interest (potentially 
immunomediated) were skin (17%) and endocrine (14%).  SAEs occurred in 54% of 


 
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patients, including at least 2% of patients experiencing urinary tract infection, sepsis, 
diarrhea, small intestine obstruction, and general physical health deterioration.  
Nivolumab was discontinued for AEs in 5% of patients.  Of the 14 deaths not related to 
disease progression, three were attributed to treatment, including pneumonitis, acute 
respiratory failure, and cardiovascular failure (1 each).  
1.4.3.6 
Nivolumab Efficacy Reported in Urothelial Carcinoma Clinical Trials 
Refer to the current OPDIVO US Prescribing Information for efficacy information 
concerning OPDIVO in clinical trials enrolling patients with urothelial carcinoma. 
In the CheckMate 032 study (Sharma-2016), the median duration of therapy for the 78 
treated patients was 17 weeks (range 1-46 weeks) and the minimum follow-up was 
9 months (median 15.2 months).  The ORR as confirmed by the Investigator was 24.4%.  
In the CheckMate 275 study (Sharma-2017), the median duration of therapy for the 270 
treated patients was 3.3 months (range: 0 to 13.4+ months) and the minimum follow-up 
was 6 months (median 7 months).  The overall ORR as confirmed by central review was 
19.6%.  Response to nivolumab appears to be independent of tumor cell PD-L1 
expression as objective response rates of 28.4%, 23.8% and 16.1% were reported for 
tumor cell PD-L1 expression of >5%, ≥ 1%, or <1%, respectively.  Median overall 
survival was 8·74 months.  Median overall survival for patients with PD-L1 expression 
≥ 1% was 11.30 months compared to 5.95 months for patients with <1%.  Despite these 
promising results, not all patients benefit from the treatment and patients will eventually 
exhibit disease progression. 
1.5 
Pembrolizumab 
Pembrolizumab (KEYTRUDA®) is a humanized monoclonal antibody that blocks the 
interaction between PD-1 and its ligands, PD-L1 and PD-L2.  Pembrolizumab 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.  Pembrolizumab is a monoclonal antibody 
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.  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 
KEYTRUDA US Prescribing Information. 


 
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1.5.1 
Pembrolizumab Drug Substance 
• Generic Name: 
Pembrolizumab 
• Other Name:  
KEYTRUDA® 
• Molecular Weight:  
149 kDa 
1.5.2 
Pembrolizumab Nonclinical Data 
The nonclinical experience is described in the KEYTRUDA US Prescribing Information.   
1.5.3 
Pembrolizumab Clinical Data 
The following reports information included in the KEYTRUDA US Prescribing 
Information dated April 2020.  Refer to the current Prescribing Information for updates 
during the conduct of this clinical trial.   
1.5.3.1 
Pembrolizumab Pharmacokinetics 
The PK of pembrolizumab was characterized using a population PK analysis with 
concentration data collected from 2993 patients with various cancers who received 
pembrolizumab doses of 1 to 10 mg/kg Q2W, 2 to 10 mg/kg Q3W, or 200 mg Q3W.  The 
geometric mean (% coefficient of variation [CV%]) clearance (CL) is 195 mL/d (40%), 
geometric mean volume of distribution at steady state (Vss) is 6.0 L (20%), and geometric 
mean terminal elimination half-life (t1/2) is 22 days (32%).  Steady-state concentrations of 
pembrolizumab were reached by 16 weeks of repeated dosing with a Q3W regimen, and 
systemic accumulation was approximately 2.1-fold.  The steady-state exposure to 
pembrolizumab increased dose proportionally over the dose range of 2 to 10 mg/kg 
administered Q3W. 
The population PK analysis suggested that the following factors had no clinically 
important effect on the clearance of pembrolizumab: age (15 to 94 years), sex, race (89% 
White), renal impairment (eGFR ≥15 mL/min/1.73 m2), mild hepatic impairment (total 
bilirubin [TB] less than or equal to the upper limit of normal [ULN] and AST greater than 
ULN or TB <1 to 1.5 times ULN or AST>ULN), or tumor burden.  The impact of 
moderate or severe hepatic impairment on the PK of pembrolizumab is unknown. 
1.5.3.2 
Pembrolizumab Anti-Drug Antibodies 
Of 1289 patients who were treated with KEYTRUDA as a single agent, at a dose of 
2 mg/kg Q3W, 200 mg Q3W, or 10 mg/kg Q2W or Q3W and evaluable for the presence 
of anti-pembrolizumab antibodies, 2% tested positive for treatment-emergent anti-
pembrolizumab antibodies by an electrochemiluminescent (ECL) assay of whom 0.5% 
had neutralizing antibodies against pembrolizumab.  There was no evidence of an altered 


 
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pharmacokinetic profile or increased incidence of infusion reactions with anti-
pembrolizumab binding antibody development. 
1.5.3.3 
Pembrolizumab Adverse Reactions Common in Clinical Trials 
Refer to the current KEYTRUDA US Prescribing Information for information concerning 
adverse reactions occurring in clinical trials. 
As of April 2020, the most common adverse reactions (≥20%) in patients administered 
KEYTRUDA as a single agent were fatigue, musculoskeletal pain, decreased appetite, 
pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and 
abdominal pain. 
As of April 2020, the most common adverse reactions (≥20%) in patients administered 
KEYTRUDA in combination with chemotherapy were fatigue/asthenia, nausea, 
constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, pyrexia, 
alopecia, peripheral neuropathy, mucosal inflammation, and stomatitis. 
As of April 2020, the most common adverse reactions (≥20%) in patients administered 
KEYTRUDA in combination with lenvatinib were fatigue, hypertension, musculoskeletal 
pain, diarrhea, decreased appetite, hypothyroidism, nausea, stomatitis, vomiting, 
decreased weight, abdominal pain, headache, constipation, urinary tract infection, 
dysphonia, hemorrhagic events, hypomagnesemia, PPE, dyspnea, cough, and rash. 
1.5.3.4 
Pembrolizumab Immune-Mediated Adverse Events 
Refer to the current KEYTRUDA US Prescribing Information, for information 
concerning immune-mediated adverse events occurring during treatment with nivolumab.   
As of April 2020, the KEYTRUDA US Prescribing Information includes warnings and 
precautions for a range of immune-mediated adverse events documented in patients 
across cancer indications, including, pneumonitis, colitis, hepatitis, endocrinopathies 
(such as adrenal insufficiency, hypophysitis, hypothyroidism and hyperthyroidism, 
Type 1 diabetes mellitus), nephritis and renal dysfunction, skin adverse reactions 
(including Stevens Johnson syndrome [SJS] and toxic epidermal necrolysis [TEN]), other 
rarer immune-mediated adverse events, and infusion reactions. 
1.5.3.5 
Pembrolizumab Safety Reported in Urothelial Carcinoma Clinical 
Trials 
Refer to the current KEYTRUDA US Prescribing Information for safety information 
concerning KEYTRUDA in clinical trials enrolling patients with urothelial carcinoma. 
In both studies reported below, patients received 200 mg of pembrolizumab administered 
intravenously over 30 minutes Q3W until unacceptable toxicity or progressive disease, or 
up to 24 months of therapy without disease progression. 


 
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The KEYNOTE-045 study (Bellmunt-2017; Fradet-2019) was a randomized Phase 3 trial 
of pembrolizumab (n=270) versus Investigator’s choice of chemotherapy with paclitaxel 
(n=84), docetaxel (n=84) or vinflunine (n=87) in patients with advanced or metastatic 
urothelial carcinoma that experienced progression during or following one prior 
platinum-based chemotherapy regimen.  The most common AEs (reported in ≥20% of 
patients) were fatigue (38%), musculoskeletal pain (32%), pruritus (23%), decreased 
appetite, and nausea (21% each), and rash (20%).  AEs of Grade 3, 4 or 5 severity that 
were observed in two or more patients who were treated with pembrolizumab were 
pneumonitis (2%), and colitis, diarrhea, fatigue, anemia and nephritis (1% each); there 
was only one Grade 5 event (<1%), which was pneumonitis.  Treatment-related AEs of 
special interest potentially associated with the use of pembrolizumab were 
hypothyroidism (6%), hyperthyroidism, and pneumonitis (4% each), colitis (2%), 
infusion reaction, nephritis, severe skin reaction, and thyroiditis (1% each), and adrenal 
insufficiency (<1%).  Twelve percent of the patients experienced SAEs considered 
related to pembrolizumab.  None of the treatment-related SAEs in the pembrolizumab 
arm occurred with a frequency of >2%; the most frequently occurring (in >1% of 
patients) were colitis, and pneumonitis (2% each), and interstitial lung disease (1%).  
Pembrolizumab was discontinued due to AEs in 8% of patients. The most common AE 
resulting in permanent discontinuation of pembrolizumab was pneumonitis (2%). 
The KEYNOTE-052 study (Balar-2017; O’Donnell-2017; O’Donnell-2019) was a 
single-arm Phase 2 trial in 374 cisplatin-ineligible patients with advanced urothelial 
cancer who had not been previously treated with systemic chemotherapy.  The most 
common AEs (reported in ≥20% of patients) were fatigue (38%), musculoskeletal pain 
(24%), decreased appetite (22%), constipation, and rash (21% each), and diarrhea (20%).  
The most common Grade 3 or 4 treatment-related adverse events were alkaline 
phosphatase increase, fatigue, and colitis (2% each), and hepatitis, and muscle weakness 
(1% each).  There was only one Grade 5 event (<1%), which was myositis.  Other 
immune-mediated adverse occurring in ≥2 or more patients were hypothyroidism (11%), 
pneumonitis (5%), colitis, hyperthyroidism, and severe skin reaction (3%), hepatitis, and 
adrenal insufficiency (2% each), thyroiditis, type 1 diabetes mellitus (1% each), 
hypophysitis, myocarditis, nephritis, and pancreatitis (<1% each).  Serious adverse 
reactions occurred in 42% of patients. The most frequent serious adverse reactions (≥2%) 
were urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis.  
Pembrolizumab was discontinued due to adverse reactions in 11% of patients. 
1.5.3.6 
Pembrolizumab Efficacy Reported in Urothelial Carcinoma Clinical 
Trials 
Refer to the current KEYTRUDA US Prescribing Information for efficacy information 
concerning KEYTRUDA in clinical trials enrolling patients with urothelial carcinoma. 
In the KEYNOTE-045 study (Bellmunt-2017; Fradet-2019), the median duration of 
therapy in the pembrolizumab group was 3.5 months (range, <0.1 to 20.0) and the median 
follow-up was 27.7 months.  The overall ORR as confirmed by central review in the 


 
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pembrolizumab group was 21% (20% for patients with CPS ≥10).  The median DOR was 
not reached (range, 1.6+ to 30.0+ months).  Median overall survival was 10.1 months.  
Pembrolizumab continued to demonstrate an OS benefit over chemotherapy in all 
subgroups examined, including those with visceral disease and liver metastases, and 
across the different levels of PD-L1 expression and risk groups. 
In the KEYNOTE-052 study (Balar-2017; O’Donnell-2017; O’Donnell-2019), the overall 
ORR as confirmed by central review was 29%, compared to 47% for patients with 
CPS ≥10.  With a median follow-up of 15.3 months, the median DOR was 30.1 months 
(range, 18.8 months to not reached) in the overall population; and was not reached for 
patients with CPS ≥10.  Median overall survival was 11.3 months (range, 9.7 to 13.1 
months), compared to 18.5 months (range, 12.2 to 28.5 months) for patients with 
CPS ≥10. 
1.6 
Enfortumab 
Enfortumab vedotin-ejfv (enfortumab, PADCEV™) is a Nectin-4 directed antibody-drug 
conjugate (ADC) comprised of a fully human anti-Nectin-4 IgG1 kappa monoclonal 
antibody (AGS-22C3) conjugated to the small molecule microtubule disrupting agent, 
monomethyl auristatin E (MMAE) via a protease-cleavable maleimidocaproyl valine-
citrulline linker (SGD-1006). 
Enfortumab vedotin-ejfv is an ADC.  The antibody is a human IgG1 directed against 
Nectin-4, an adhesion protein located on the surface of cells.  The small molecule, 
MMAE, is a microtubule-disrupting agent, attached to the antibody via a 
protease-cleavable linker.  Nonclinical data suggest that the anticancer activity of 
enfortumab vedotin-ejfv is due to the binding of the ADC to Nectin-4-expressing cells, 
followed by internalization of the ADC-Nectin-4 complex, and the release of MMAE via 
proteolytic cleavage.  Release of MMAE disrupts the microtubule network within the 
cell, subsequently inducing cell cycle arrest and apoptotic cell death. 
Background information in addition to that presented below is available in the PADCEV 
US Prescribing Information. 
1.6.1 
Enfortumab Drug Substance 
• Generic Name: 
Enfortumab Vedotin-ejfv 
• Other Name:  
PADCEV™ 
• Molecular Weight:  
152 kDa 
1.6.2 
Enfortumab Nonclinical Data 
The nonclinical experience is described in the PADCEV US Prescribing Information.   


 
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1.6.3 
Enfortumab Clinical Data 
The following reports information included in the PADCEV US Prescribing Information 
dated December 2019.  Refer to the current Prescribing Information for updates during 
the conduct of this clinical trial.   
1.6.3.1 
Enfortumab Pharmacokinetics 
Population pharmacokinetic analysis included data from 369 patients based on three 
Phase 1 studies and one Phase 2 study.  Enfortumab pharmacokinetics were characterized 
after single and multiple doses in patients with locally advanced or metastatic urothelial 
carcinoma (UC) and other solid tumors.  Enfortumab exhibited linear dose-proportional 
PK at doses ranging from 0.5 to 1.25 mg/kg when administered as an intravenous 
infusion over ~30 minutes on days 1, 8, and 15 of a 28-day cycle in patients with locally 
advanced or metastatic UC.  Peak enfortumab concentrations were attained at the end of 
infusion.  In contrast, plasma concentrations of free MMAE increased until ~2 days after 
enfortumab dosing.  The mean clearance (CL) of enfortumab and free MMAE in patients 
was 0.10 L/h and 2.7 L/h, respectively, in patients.  Elimination of MMAE appeared to be 
limited by its rate of release from enfortumab.  The estimated mean volume of 
distribution of ADC at steady state (Vss) was 11 liters following administration of 
enfortumab.  ADC and MMAE exhibited multi-exponential declines with an elimination 
half-life of 3.4 days and 2.4 days, respectively.  Steady-state concentrations of ADC and 
MMAE were reached after 1 treatment cycle with a 1.25 mg/kg Q3W regimen, and 
minimal accumulation of the ADC and MMAE was observed following repeat 
administration of enfortumab in patients. 
Based on population pharmacokinetic analysis, no clinically significant differences in the 
pharmacokinetics of enfortumab were observed based on age (24 to 87 years), sex, or 
race/ethnicity (Caucasian, Asian, Black, or others). 
Based on population pharmacokinetics analysis, there was a 48% AUC increase in 
unconjugated MMAE exposure observed in patients with mild hepatic impairment 
(bilirubin of 1 to 1.5 the upper limit of normal [ULN] and AST less than ULN, or 
bilirubin less than or equal to ULN and AST greater than ULN, n=31) compared to 
normal hepatic function.  The effect of moderate or severe hepatic impairment (AST or 
ALT greater than 2.5 times ULN or total bilirubin greater than 1.5 times ULN) or liver 
transplantation on the pharmacokinetics of ADC or unconjugated MMAE is unknown. 
The pharmacokinetics of enfortumab and MMAE were evaluated after the administration 
of 1.25 mg/kg of enfortumab to patients with mild (creatinine clearance; CrCL greater 
than 60 to 90 mL/min; n=135), moderate (CrCL 30 to 60 mL/min; n=147) and severe 
(CrCL less than 30 mL/min; n=8) renal impairment.  No significant differences in 
exposure (AUC) of ADC and MMAE were observed in patients with mild, moderate or 
severe renal impairment compared to patients with normal renal function.  The effect of 


 
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end stage renal disease with or without dialysis on the pharmacokinetics of ADC or 
unconjugated MMAE is unknown. 
1.6.3.2 
Enfortumab Anti-Drug Antibodies 
Of 365 patients who were treated with PADCEV as a single agent Q3W (1.0 and 
1.25 mg/kg Q3W) and evaluable for the presence of for immunogenicity to PADCEV, 
1% were confirmed to be transiently positive for anti-therapeutic antibody (ATA), and 
0.3% were confirmed to be persistently positive for ATA at any post-baseline time point.  
No impact of ATA on efficacy, safety and pharmacokinetics was observed. 
1.6.3.3 
Enfortumab Adverse Reactions Common in Clinical Trials 
Refer to the current PADCEV US Prescribing Information for information concerning 
adverse reactions occurring in clinical trials. 
As of December 2019, the most common AEs (≥20%) in patients administered PADCEV 
as a single agent included fatigue, peripheral neuropathy, decreased appetite, rash, 
alopecia, nausea, dysgeusia, diarrhea, dry eye, pruritus and dry skin.  Hyperglycemia 
occurred in patients treated with PADCEV, including death, and diabetic ketoacidosis 
(DKA) in those with and without pre-existing diabetes mellitus.  The incidence of 
Grade 3-4 hyperglycemia increased consistently in patients with higher body mass index 
and in patients with higher baseline A1C.  In EV-201, 8% of patients developed 
Grade 3-4 hyperglycemia. 
The most common treatment-related AEs (≥20%) from initial safety updates in Study 
EV-103 (Rosenberg-2020) in patients administered PADCEV in combination with 
pembrolizumab were rash, fatigue, alopecia, peripheral sensory neuropathy, diarrhea, 
decreased appetite, dysgeusia, nausea, pruritus, anemia, and weight decreased. Additional 
AEs of clinical interest included immune-mediated AEs requiring systemic steroids 
(29%; including 18% ≥Grade 3) and hyperglycemia (11%; including 7% ≥Grade 3). 
1.6.3.4 
Enfortumab Safety Reported in Urothelial Carcinoma Clinical Trials 
Refer to the current PADCEV US Prescribing Information for safety information 
concerning PADCEV in clinical trials enrolling patients with urothelial carcinoma. 
In the enfortumab monotherapy study below, patients received 1.25 mg/kg (up to a 
maximum dose of 125 mg) of enfortumab given as an intravenous infusion over 
30 minutes on Days 1, 8 and 15 of a 28-day cycle until disease progression or 
unacceptable toxicity.  In the combination study below of enfortumab with 
pembrolizumab, patients received 1.25 mg/kg of enfortumab given as an intravenous 
infusion over 30 minutes on Days 1 and 8 of a 21-day cycle and 200 mg of 
pembrolizumab administered intravenously over 30 minutes on Day 1 of Q3W until 
disease progression or unacceptable toxicity. 


 
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The EV-201 study (Petrylak-2019; Rosenberg-2019) was a single-arm Phase 2 trial of 
enfortumab monotherapy in 125 patients with locally advanced or metastatic urothelial 
carcinoma who were previously treated with platinum chemotherapy and a PD-(L)1 
checkpoint inhibitor.  The most common AEs (reported in ≥20% of patients) were fatigue 
and peripheral neuropathy (56%), decreased appetite and rash (52% each), alopecia 
(50%), nausea (45%), dysgeusia and diarrhea (42% each), dry eye (40%), and dry skin 
and pruritus (26% each).  The most common Grade 3, 4, or 5 AEs (reported in ≥5% of 
patients) were rash (13%), and fatigue and diarrhea (6% each).  Grade 5 AEs occurred in 
3% of patients, including acute respiratory failure, aspiration pneumonia, cardiac 
disorder, and sepsis (each 1%).  An AE of clinical interest was treatment-related 
hyperglycemia which occurred in 11% of patients, of which 8% were Grade 3 or 4.  
SAEs occurred in 46% of patients.  The most frequent SAEs (≥3%) were urinary tract 
infection (6%), cellulitis (5%), febrile neutropenia and diarrhea (4%), and sepsis, acute 
kidney injury, dyspnea and rash (3% each).  Enfortumab was discontinued due to AEs in 
16% of patients.  The most common AE resulting in permanent discontinuation of 
enfortumab was peripheral neuropathy (6%). 
The EV-103 study (Rosenberg-2020, Hoimes-2019) was a single-arm Phase 1/2 trial of 
enfortumab combination therapies including enfortumab plus pembrolizumab in 45 
cisplatin-ineligible, treatment-naïve patients with locally-advanced or metastatic 
urothelial carcinoma.  The study initiated with a 5-patient dose escalation that led into an 
additional 40-patient expansion.  The dose escalation confirmed the combination regimen 
doses consisting of  pembrolizumab at 200 mg Q3W and enfortumab at 1.25 mg/kg on 
days 1 and 8 of 3-week cycles.  It is worth noting that the pembrolizumab dose and 
frequency in the combination matches single agent pembrolizumab dosing, whereas the 
enfortumab dosing was similar but the frequency was matched to a 3-week cycle (from 
the usual 4-week cycle with single agent use).  The most common treatment-related AEs 
(reported in ≥20% of patients) were rash (62%), alopecia, fatigue and peripheral 
neuropathy (49% each), diarrhea (44%), decreased appetite (38%), dysgeusia (33%), 
nausea and pruritus (29% each), and anemia and weight decreased (20% each).  The most 
common Grade 3, 4, or 5 treatment-related AEs (reported in ≥5% of patients) were 
fatigue and rash maculo-papular (9% each), and anemia and diarrhea (7% each).  There 
was only one treatment-related Grade 5 AE (2%), which was multiple organ dysfunction 
syndrome.  Additional AEs of clinical interest included immune-mediated AEs requiring 
systemic steroids (29%; including 18% ≥Grade 3) and hyperglycemia (11%; including 
7% ≥Grade 3).  Treatment-related SAEs occurred in 16% of patients.  The only 
treatment-related SAE occurring in ≥1 patient was colitis (4%).  Enfortumab and 
pembrolizumab were discontinued due to treatment-related AEs in 13% of patients.  The 
most common AE resulting in permanent discontinuation of enfortumab and 
pembrolizumab was peripheral neuropathy (7%). 


 
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1.6.3.5 
Enfortumab Efficacy Reported in Urothelial Carcinoma Clinical 
Trials 
Refer to the current PADCEV US Prescribing Information for safety information 
concerning PADCEV in clinical trials enrolling patients with urothelial carcinoma. 
In the EV-201 study (Petrylak-2019; Rosenberg-2019), the median duration of therapy 
was 4.6 months (maximum duration of 15.6 months) and the median follow-up was 
10.2 months.  The overall ORR as confirmed by central review was 44% (including a 
12% complete response rate).  The median DOR was 7.6 months (range, 0.95 to 11.30+ 
months).  Median overall survival was 11.7 months. 
In the EV-103 study (Rosenberg-2020; Hoimes-2019), the median follow-up was 
10.4 months.  The overall ORR as confirmed by central review was 73% (including a 
16% complete response rate) with activity regardless of PD-L1 expression level.  With a 
median follow-up was 10.4 months, the median DOR was not reached (range, 1.2 to 
12.9+ months).  Median overall survival was also not reached, with a 12-month overall 
survival rate of 82%. 
1.7 
Expectations for Safety of Sitravatinib Combination Regimens 
1.7.1 
Potential for Drug-Drug Interactions with Sitravatinib Combination 
Regimens 
1.7.1.1 
Potential for Drug-Drug Interactions with the Combination of 
Sitravatinib and Nivolumab 
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. 
1.7.1.2 
Potential for Drug-Drug Interactions with the Combination of 
Sitravatinib, Pembrolizumab and Enfortumab 
Sitravatinib administered in combination pembrolizumab and enfortumab is unlikely to 
result in drug-drug interactions (DDI) based on absorption, metabolism, elimination or 
protein binding.  Both pembrolizumab and enfortumab are mAbs and are intravenously 
administered, whereas sitravatinib is a small molecule therapeutic administered orally; no 
absorption interactions are expected.  The only potential for DDI stems from MMAE 


 
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being an in vitro substrate of both CYP3A4 and P glycoprotein (P-gp) (see below), and 
sitravatinib being an in vitro inhibitor of both CYP3A4 and P-gp.  To mitigate the 
potential for increased MMAE exposure with the combination of sitravatinib, 
pembrolizumab and enfortumab and any subsequent clinical impact, the lead-in dose 
escalation evaluation (Cohort 9) of the combination will initiate with a sitravatinib 
starting dose representing three dose levels (~65%) below the dose administered as a 
single-agent and in combination with nivolumab in Phase 2 and Phase 3 trials.  In 
addition, a dose de-escalation step for enfortumab may be undertaken as appropriate.  
Refer to Appendix 9 for study design details of cohorts investigating the combination of 
sitravatinib, pembrolizumab and enfortumab. 
No studies on the metabolism of pembrolizumab have been reported in vitro or in 
humans.  Like most therapeutic proteins, pembrolizumab 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. 
On the other hand, whereas no clinical studies evaluating the drug-drug interaction 
potential of enfortumab have been conducted, in vitro studies indicate that MMAE is a 
substrate of CYP3A4.  Concomitant use with a strong CYP3A4 inhibitor may increase 
free MMAE exposure, which may increase the incidence or severity of enfortumab 
toxicities (PADCEV US Prescribing Information).  Since in vitro studies suggest 
sitravatinib could be an inhibitor of CYP3A4, there is the potential that co-administration 
with sitravatinib could result in increased MMAE exposure.   
Finally, no clinical studies evaluating the drug-drug interaction potential of enfortumab 
have been conducted, in vitro studies indicate that MMAE is a substrate of P-gp, but not 
an inhibitor of P-gp (PADCEV US Prescribing Information).  Since in vitro studies 
suggest sitravatinib could be an inhibitor of P-gp, there is the potential that 
co-administration with sitravatinib could result in increased MMAE exposure. 
1.7.2 
Potential for Increased Toxicity with Sitravatinib Combination 
Regimens 
1.7.2.1 
Potential for Increased Toxicity with Combination of Sitravatinib and 
a PD-(L)1 Checkpoint Inhibitor 
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 PD-1 checkpoint inhibitors (including nivolumab and pembrolizumab) 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, immune-related AEs (irAEs) using PD-1 checkpoint inhibitors monotherapy 
include pneumonitis, colitis, hepatitis, endocrinopathies (such as adrenal insufficiency, 


 
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hypophysitis, hypothyroidism and hyperthyroidism, Type 1 diabetes mellitus), 
nephritis/renal dysfunction, skin adverse reactions, and encephalitis.  While sitravatinib 
may have immunostimulatory effects, autoimmune adverse effects have not been 
reported in clinical trials of this investigational study agent, including to date in 
combination with nivolumab, nor are they recognized as class effects for this agent.  
However, the potential for sitravatinib to exacerbate or promote these adverse events 
when administered in combination with nivolumab should be borne in mind.  AE 
incidence data presented below are as reported in the OPDIVO US Prescribing 
Information dated June 2020, the KEYTRUDA US Prescribing Information dated April 
2020 and the Sitravatinib Investigator’s Brochure dated November 2019.  Updates to 
these data during the conduct of this clinical trial will be found in the current OPDIVO 
US Prescribing Information, the current KEYTRUDA US Prescribing Information and 
current Sitravatinib Investigator’s Brochure. 
A clinically relevant overlap in toxicity may arise between the immune-mediated colitis 
attributed to PD-1 checkpoint inhibitors (such as nivolumab and pembrolizumab) and the 
non-specific, most often mild to moderate diarrhea observed with sitravatinib.  
Immune-mediated colitis has been reported in 2.9% (58/1994) and 1.7% (48/2799) of 
patients treated with nivolumab and pembrolizumab, respectively; with respective median 
times to onset of 5.3 months (range: 2 days to 20.9 months) and 3.5 months (range: 
10 days to 16.2 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 and 
pembrolizumab, occurring in approximately 17% and 18-20%, respectively, of urothelial 
carcinoma patients treated with nivolumab at 3 mg/kg Q2W in the CheckMate 275 
clinical trial (Sharma-2017) and pembrolizumab at 200 mg Q3W in both the 
KEYNOTE-045 (Bellmunt-2017) and KEYNOTE-052 (Balar-2017) clinical trials.  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 or pembrolizumab as a single agent, 
immune-mediated hepatitis occurred in 1.8% (35/1994) and 0.7% (19/2799) of patients, 
respectively; with respective median times to onset of 3.3 months (range: 6 days to 9 
months) and 1.3 months (range: 8 days to 21.4 months). 
Hypothyroidism, including thyroiditis, was reported in 15% and 9%, respectively, of 
urothelial carcinoma patients treated with nivolumab and pembrolizumab monotherapy.  
Hypothyroidism has been reported in approximately 17% of patients treated with 
sitravatinib. 


 
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A clinically relevant overlap in toxicity may arise between the immune-related rash 
attributed to PD-1 checkpoint inhibitors (such as nivolumab and pembrolizumab) and the 
non-specific, most often mild (Grade 1) rash observed with sitravatinib.  Rash, described 
as dermatitis, dermatitis acneiform, dermatitis bullous, generalized, macular, 
maculopapular or pruritic, has been reported in 16% and 20-21%, respectively, of 
urothelial carcinoma patients treated with nivolumab and pembrolizumab monotherapy.  
Rash has been reported in 11% of patients treated with sitravatinib.   
1.7.2.2 
Potential for Increased Toxicity with the Combination of Sitravatinib, 
Pembrolizumab and Enfortumab 
Frequent AEs, such as fatigue, weight decreased, musculoskeletal pain, decreased 
appetite, cough, nausea, and constipation, which are non-specific and typical of cancer 
treatment regimens have been observed with sitravatinib monotherapy, and with the 
combination of pembrolizumab and enfortumab.  Potential exists for these AEs to be 
observed with increased severity or frequency with the combination of sitravatinib, 
pembrolizumab and enfortumab.  Management of these effects in patients receiving 
cancer therapy is well precedented.  
Importantly, immune-related AEs (irAEs) using PD-1 checkpoint inhibitors monotherapy 
include pneumonitis, colitis, hepatitis, endocrinopathies (such as adrenal insufficiency, 
hypophysitis, hypothyroidism and hyperthyroidism, Type 1 diabetes mellitus), 
nephritis/renal dysfunction, skin adverse reactions, and encephalitis.  Immune-mediated 
AEs requiring systemic steroids occurred in 29% (13/45) of urothelial carcinoma patients 
receiving the combination of pembrolizumab and enfortumab in Study EV-103 
(Rosenberg-2020; Hoimes-2019).  While sitravatinib may have immunostimulatory 
effects, autoimmune adverse effects have not been reported in sitravatinib monotherapy 
studies, nor are they recognized as class effects for this agent.  And whereas the incidence 
of irAEs in combination with checkpoint inhibitors has not been fully characterized, early 
safety reviews do not indicate a significant increase in the incidence of irAEs with the 
combination compared to checkpoint inhibitor monotherapy.  However, the potential for 
sitravatinib to exacerbate or promote these adverse events when administered in 
combination with pembrolizumab and enfortumab should be borne in mind.  AE 
incidence data presented below are as reported in the KEYTRUDA US Prescribing 
Information dated April 2020, the PADCEV US Prescribing Information dated December 
2019 and the Sitravatinib Investigator’s Brochure dated November 2019.  Updates to 
these data during the conduct of this clinical trial will be found in the current 
KEYTRUDA US Prescribing Information, the current PADCEV US Prescribing 
Information and current Sitravatinib Investigator’s Brochure. 
A clinically relevant overlap in toxicity may arise between the immune-mediated colitis 
attributed to PD-1 checkpoint inhibitors (such as pembrolizumab) and the non-specific, 
most often mild to moderate diarrhea observed with sitravatinib.  Immune-mediated 
colitis has been reported in 1.7% (48/2799) of patients treated with pembrolizumab, with 
a median time to onset of 3.5 months (range: 10 days to 16.2 months).  Diarrhea has been 


 
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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 pembrolizumab, occurring in approximately 18-20% of urothelial 
carcinoma patients treated with pembrolizumab (Bellmunt-2017; Balar-2017).  However, 
diarrhea is common with the combination of pembrolizumab and enfortumab occurring in 
44% (20/45) of urothelial carcinoma patients receiving the combination of 
pembrolizumab and enfortumab in Study EV-103 (Rosenberg-2020).  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 pembrolizumab as a single agent, immune-mediated 
hepatitis occurred in 0.7% (19/2799) of patients, with a median time to onset of 
1.3 months (range: 8 days to 21.4 months).  Enfortumab monotherapy is not associated 
with increases in AST or ALT.  Increases in transaminases will be closely monitored. 
Hypothyroidism, including thyroiditis, was reported in 7% of urothelial carcinoma 
patients treated with pembrolizumab monotherapy.  Hypothyroidism has been reported in 
approximately 17% of patients treated with sitravatinib.  Enfortumab monotherapy is not 
associated with thyroid dysfunction.  Thyroid dysfunctions will be closely monitored. 
A clinically relevant overlap in toxicity may arise between the immune-related rash 
attributed to PD-1 checkpoint inhibitors (such as nivolumab and pembrolizumab) and the 
non-specific, most often mild (Grade 1) rash observed with sitravatinib.  Rash, described 
as dermatitis, dermatitis acneiform, dermatitis bullous, generalized, macular, 
maculopapular or pruritic, has been reported in 20-21% and 31%, respectively, of 
urothelial carcinoma patients treated with pembrolizumab monotherapy and combination 
of pembrolizumab and enfortumab.  Rash has been reported in 11% of patients treated 
with sitravatinib. 
Increased lipase has been observed in patients treated with sitravatinib and other 
inhibitors of the VEGF pathway.  Although the mechanism has not been fully elucidated, 
inhibition of VEGF may lead to acinar cell apoptosis resulting in the release of 
autodigestive enzymes (Sevin-2012).  Most sitravatinib treatment-emergent events of 
increased amylase and lipase were asymptomatic while some were associated with signs 
and/or symptoms of pancreatitis.  Treatment-related increased lipase has been observed in 
10% of patients treated with sitravatinib monotherapy.  Increased lipase is rare with 
pembrolizumab monotherapy, however it occurs in 18% (8/45) of urothelial carcinoma 
patients receiving the combination of pembrolizumab and enfortumab in Study EV-103 
(Rosenberg-2020). 


 
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Finally, whereas sitravatinib administered in combination pembrolizumab and 
enfortumab is unlikely to result in drug-drug interactions (DDI), the only potential for 
DDIs stems from MMAE being an in vitro substrate of both CYP3A4 and P-glycoprotein 
(P-gp) (see below), and sitravatinib being an in vitro inhibitor of both CYP3A4 and P-gp 
(see Section 1.7.1.2).  To mitigate the potential for increased MMAE exposure with the 
combination of sitravatinib, pembrolizumab and enfortumab and any subsequent clinical 
impact, the lead-in dose escalation evaluation (Cohort 9) of the combination will initiate 
with a sitravatinib starting dose representing three dose levels (~65%) below the dose 
administered as a single-agent and in combination with nivolumab in Phase 2 and Phase 3 
trials.  In addition, a dose de-escalation step for enfortumab may be undertaken as 
appropriate.  Refer to Appendix 9 for study design details of cohorts investigating the 
combination of sitravatinib, pembrolizumab and enfortumab. 
1.8 
Study Rationale 
Immune checkpoint inhibitors targeting the PD-(L)1 pathway have demonstrated clinical 
activity in patients with urothelial carcinoma.  While checkpoint inhibitor 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 checkpoint inhibitor therapy is a rational approach to 
improving outcomes in patients. 
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 (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).  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 (Paolino-2014).  Given the 
immunosuppressive function of TAM RTKs in the TME, inhibition of Axl and MERTK 


 
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may complement PD-(L)1 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, hepatocyte growth factor (HGF), is secreted by tumor stroma and 
mesenchymal stem cells (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 (i.e., 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 receptor tyrosine kinases (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 nodes and stages of 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 checkpoint inhibitor therapy [anti-PD-(L)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 checkpoint 
inhibitor therapy [anti-PD-(L)1] in patients with cancer that has progressed on checkpoint 
inhibitor therapy. 


 
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Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody 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 clinical activity of nivolumab in combination with 
sitravatinib.  Nivolumab will be administered in accordance with approved labeling, by 
intravenous infusion, 240 mg every 2 weeks (Q2W) or 480 mg every 4 weeks (Q4W).  
Under previous versions of this protocol, sitravatinib was administered in accordance 
with findings of the prior nivolumab combination study (MRTX-500), orally, with the 
starting dose of 120 mg once daily (QD) of the free base capsule formulation (in 28-day 
cycles).  Nonclinical studies indicate that sitravatinib administered to patients at 120 mg 
QD should achieve the plasma exposure required for inhibition of VEGF and TAM 
receptors, necessary to achieve antitumor efficacy in the combination setting.  Newly 
enrolled patients under Cohorts 1 through 6 will continue to receive the free base 
formulation with the starting dose of 120 mg QD.  For Cohorts 7 and 8, transition to use 
of an alternative formulation, sitravatinib malate capsule formulation, is being 
implemented with this protocol Version 4.0.  Newly enrolled patients in Cohorts 7 and 8 
under this protocol Version 4.0 will receive a starting dose of 100 mg QD of the malate 
capsule formulation (an equivalent dose to 120 mg QD of the free base capsule 
formulation), based on the results of Study 516-006 described in Section 1.3.3.4.  Patients 
who began treatment with the free base capsule formulation will remain on the free base 
capsule formulation throughout the duration of the study. 
Pembrolizumab is a humanized IgG4 monoclonal antibody 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.  Enfortumab is a Nectin-4 directed antibody-drug conjugate (ADC) comprised 
of a fully human anti-Nectin-4 IgG1 kappa monoclonal antibody (AGS-22C3) conjugated 
to the small molecule microtubule disrupting agent, monomethyl auristatin E (MMAE).  
Binding of the ADC to Nectin-4-expressing cells such as urothelial carcinoma cells, leads 
to internalization of the ADC-Nectin-4 complex and intratumoral release of MMAE 
disrupting the microtubule network within the cell, and subsequently inducing cell cycle 
arrest and apoptotic cell death.  Emerging preclinical data indicates a potential immune 
modulatory activity with ADCs that are linked to MMAE by inducing immunogenic cell 
death, antibody-dependent cellular phagocytosis and cytotoxicity (Cao-2016; Cao-2017; 
Cao-2018; Alley-2019).  In vivo administration of these ADCs leads to directed 
proinflammatory immune responses against the tumor and this activity is further 
potentiated by PD-1 checkpoint inhibitor therapy as demonstrated by accelerated tumor 
regressions and greater antitumor activity than either agent alone, demonstrating 
complementary modes of action for these agents and providing a rationale for exploring 
therapeutic strategies that combine ADCs with other immune stimulatory regimens.  
Early efficacy results from enfortumab in combination with pembrolizumab in frontline 
cisplatin-ineligible urothelial carcinoma in the ongoing EV-103 Phase 2 trial has shown 
encouraging activity with a safety profile that appears manageable and tolerable.  


 
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Addition of sitravatinib to this combination might further augment clinical activity by 
selectively inhibiting key molecular and cellular pathways strongly implicated in 
checkpoint inhibitor resistance. 
This study may evaluate the safety of sitravatinib administered in combination with 
pembrolizumab and enfortumab starting with a lead-in dose escalation evaluation of up to 
three dose levels of sitravatinib in combination with up to two dose levels of 
pembrolizumab and enfortumab combination regimen.  The starting dose for sitravatinib 
using the malate formulation will represent three dose levels below the dose administered 
as a single agent and in combination (with nivolumab) Phase 2 and Phase 3 trials.  The 
starting doses for pembrolizumab and enfortumab will represent the recommended doses 
from the EV-103 Phase 2 trial of pembrolizumab and enfortumab used in combination 
(Rosenberg-2020; Hoimes-2019).  It is of note that the EV-302 Phase 3 trial also uses 
these recommended doses of pembrolizumab and enfortumab in the triple combination 
investigation arm combining pembrolizumab and enfortumab with the 
platinum-chemotherapy agents cisplatin or carboplatin.  In addition, dose de-escalation 
step for enfortumab may be undertaken as appropriate.  If a tolerable dose is identified for 
sitravatinib in combination with pembrolizumab and enfortumab, the clinical activity of 
this combination may be evaluated in 2 populations of patients with urothelial carcinoma. 
 
2 STUDY OBJECTIVES 
2.1 
Objectives 
2.1.1 
Primary Objective 
To evaluate the clinical activity of sitravatinib in combination with PD-(L)1 checkpoint 
inhibitor regimens in patients with advanced or metastatic urothelial carcinoma. 
2.1.2 
Secondary Objectives 
• To evaluate the safety and tolerability of the combination regimens in the selected 
population. 
• To evaluate secondary efficacy endpoints of the combination regimens in the 
selected population. 
• To evaluate the pharmacokinetics (PK) of sitravatinib administered in 
combination regimens.   
• To evaluate the PK of sitravatinib in patients with renal impairment, to be 
implemented in selected study sites contingent upon early results in the study or 
sitravatinib program. 


 
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• Cohort 9 only: To identify recommended Phase 2 combinatorial doses (RP2Ds) of 
sitravatinib, pembrolizumab and enfortumab combination treatment. 
2.1.3 
Exploratory Objectives 
• To assess the effect of the combination regimens on circulating PD-L1, immune 
cell populations and cytokines. 
• To assess the effect of the combination regimens on tumor cell PD-L1 expression, 
tumor infiltrating immune cell populations and gene expression signatures. 
• To assess the correlation of tumor PD-L1 protein expression and tumor gene 
alterations in circulation and in tumor tissue with treatment outcome. 
2.2 
Endpoints 
2.2.1 
Primary Endpoints 
ORR as defined by RECIST 1.1. 
2.2.2 
Secondary Endpoints 
• Safety characterized by type, incidence, severity, timing, seriousness and 
relationship to study treatment of adverse events and laboratory abnormalities. 
• Secondary efficacy endpoints: 
− DOR; 
− CBR; 
− PFS; 
− 1-Year Survival Rate; and 
− OS. 
• Blood plasma concentrations of sitravatinib. 
• Lead-in dose escalation portion of Cohort 9 only: Dose-limiting toxicities (DLTs). 
2.2.3 
Exploratory Endpoints 
• Circulating PD-L1 concentration. 
• Circulating immune cell populations. 


 
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• Circulating cytokine concentrations. 
• ctDNA. 
• T-Cell Receptor Sequencing. 
• Tumor PD-L1 expression. 
• Immune cell populations in the tumor. 
• Gene expression signatures in the tumor. 
• Tumor gene alterations. 
 
3 STUDY DESIGN 
Study 516-003 is an open-label, Phase 2 evaluation of the investigational agent 
sitravatinib in combination with PD-(L)1 checkpoint inhibitor regimens in patients with 
locally advanced or metastatic urothelial carcinoma.  The study will evaluate the 
combination of sitravatinib in combination with the PD-1 checkpoint inhibitor 
nivolumab, and may subsequently evaluate sitravatinib in combination with the PD-1 
checkpoint inhibitor pembrolizumab and the antibody-drug conjugate (ADC) enfortumab.  
An initial lead-in dose escalation evaluation may be initiated followed by further 
evaluation of clinical activity in 2 populations if a tolerable dose regimen for this 
combination is identified. 
The primary objective is to evaluate the clinical activity of the combination regimens 
using ORR in accordance with RECIST 1.1.  Secondary objectives include evaluation of 
safety, secondary efficacy endpoints, PK of sitravatinib, and (for lead-in dose escalation 
portion of Cohort 9) DLTs.  The Schedule of Assessments to be performed in the study 
are presented in Table 1 and Table 3.  The schedule for collection of pharmacokinetic and 
pharmacodynamic samples and ECG assessment time points are presented in Table 2 and 
Table 4. 
Initial Study Cohorts 
The initial study population will include patients with documented disease progression on 
or after a PD-(L)1 checkpoint inhibitor therapy as the most recent treatment, stratified 
into 2 cohorts based on whether patients were previously treated with or were ineligible 
for a platinum-based chemotherapy, as depicted in Figure 1.   
• Cohort 1: Patients who were previously treated with a platinum-based 
chemotherapy.  


 
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• Cohort 2: Patients ineligible for platinum-based chemotherapy.  
Enrollment will occur in 3 stages.  Stage 1 enrollment will include a minimum of 9 
evaluable patients in each cohort.  Patients included in the evaluable population will have 
received treatment with both sitravatinib and nivolumab and will have at least one 
on-study disease assessment prior to discontinuation.  The exact stopping rules will be 
calculated based on the Predictive Probability Design (Lee-2008), once the exact number 
of patients evaluable at Stage 1 is known.  With exactly 9 evaluable patients at Stage 1, if 
at least 1 patient has an Objective Response, 8 additional evaluable patients will be 
enrolled in the treatment cohort, for a total sample size of 17 evaluable patients.  If at 
least 3 Objective Responses are observed in a treatment cohort, further investigation may 
be warranted.  If Stage 2 results in a cohort are of high interest for efficacy in terms of 
ORR and secondary efficacy endpoints, enrollment may be expanded to as many as 40 
patients total in that cohort to narrow the 95% Confidence Interval (CI) around the ORR 
point estimate and to further characterize the durability of disease control.   
Contingent Study Cohorts 
In the event that results in the initial cohorts are of high interest for efficacy, contingency 
plans are described in Appendix 5, Appendix 6, Appendix 8 and Appendix 9 to add one 
or more study cohorts.  Decisions for implementation of additional cohorts in the study 
will be made in collaboration with the Investigators and documented for Regulators and 
Institutional Review Boards by an Administrative Letter to Investigators.  
Appendix 5 describes addition of contingent Cohort 3 and Cohort 4 (other prior selected 
immunotherapy cohorts, including anti-CTLA-4, anti-OX40 or anti-CD137).  The 
statistical design for these cohorts will be the same as applied to Cohorts 1 and 2.  These 
contingent cohorts described below were implemented by Administrative Letter and still 
enrolling, as depicted in Figure 1. 
• Cohort 3: Patients with documented disease progression on or after a previous 
anti-PD-(L)1 as most recent treatment, who previously received (in combination or 
separately) other selected immunotherapies, and who were previously treated with a 
platinum-based chemotherapy.  
• Cohort 4: Patients with documented disease progression on or after a previous 
anti-PD-(L)1 as most recent treatment, who previously received (in combination or 
separately) other selected immunotherapies, and considered ineligible for platinum-
based chemotherapy.  
Appendix 6 describes addition of contingent Cohort 5 and Cohort 6 [anti-PD-(L)1 naïve 
cohorts].  The statistical design for these cohorts is described in the appendix.  These 
contingent cohorts described below were implemented by Administrative Letter and still 
enrolling, as depicted in Figure 1. 


 
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• Cohort 5: Patients who have not previously received an anti-PD-(L)1, and who 
were previously treated with a platinum-based chemotherapy.  
• Cohort 6: Patients who have not previously received an anti-PD-(L)1, and 
considered ineligible for platinum-based chemotherapy. 
Appendix 8 describes addition of contingent Cohort 7 and Cohort 8 [post-ADC 
(antibody-drug conjugate) cohorts].  The statistical design for these new cohorts is 
described in the appendix.  These contingent cohorts described below were implemented 
by Administrative Letter and still enrolling, as depicted in Figure 1. 
• Cohort 7: Patients with documented disease progression on or after a previous 
anti-PD-(L)1 and ADC (in combination or separately, and in any order), and who 
were previously treated with a platinum-based chemotherapy.  
• Cohort 8: Patients with documented disease progression on or after a previous 
anti-PD-(L)1 and ADC (in combination or separately, and in any order), and 
considered ineligible for platinum-based chemotherapy. 
Appendix 9 describes addition of Cohort 9 and Cohort 10 to evaluate sitravatinib in 
combination with pembrolizumab and enfortumab.  The appendix describes the initial 
lead-in dose escalation followed by further evaluation of clinical activity in 2 populations 
if a tolerable dose regimen is identified.  Cohort 9 is introduced and implemented with 
protocol Version 4.0, whereas Cohort 10 is introduced in protocol Version 4.0 and may 
be implemented by Administrative Letter, as described below and depicted in Figure 1. 
• Cohort 9 (including lead-in dose escalation and dose expansion portions): Patients 
who have previously received a PD-(L)1 checkpoint inhibitor and a platinum-based 
chemotherapy. 
• Cohort 10: Patients with previously untreated unresectable, locally advanced or 
metastatic urothelial cancer. 
Study Treatments 
Throughout the study, nivolumab, pembrolizumab and enfortumab (where applicable) 
will be administered in accordance with approved labeling.  Nivolumab is to be 
administered by intravenous infusion, 240 mg Q2W or 480 mg Q4W.  Guidance for 
adverse event management and associated nivolumab treatment modifications are 
provided in product labeling.  Pembrolizumab is to be administered by intravenous 
infusion, 200 mg Q3W.  Guidance for adverse event management and associated 
pembrolizumab treatment modifications are provided in product labeling.  Enfortumab is 
to be administered by intravenous infusion, with a starting dose of 1.25mg/kg on days 1 
and 8 of Q3W (a lower dose may be used if necessary; see Appendix 9).  In addition, a 
dose de-escalation step for enfortumab may be undertaken as appropriate.  Guidance for 


 
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adverse event management and associated enfortumab treatment modifications are 
provided in product labeling.  Note: nivolumab (for Cohorts 1 through 8) or 
pembrolizumab (for Cohort 9 and 10) should be administered after sitravatinib (and 
specifically after the 30 minute PK sampling on applicable study visits), whereas 
enfortumab (for Cohort 9 and 10) should be administered at least 30 minutes after 
pembrolizumab. 
Sitravatinib capsules will be administered orally.  A starting dose of 120 mg QD of the 
free base capsule formulation (in 28-day cycles) was used for the sitravatinib and 
nivolumab combination cohorts under previous versions of this protocol.  Newly enrolled 
patients under Cohorts 1 through 6 will continue to receive the free base formulation with 
the starting dose of 120 mg QD.  For Cohorts 7 and 8, transition to use of an alternative 
formulation, sitravatinib malate capsule formulation, is being implemented with this 
protocol Version 4.0.  Newly enrolled patients in Cohorts 7 and 8 under this protocol 
Version 4.0 will receive a starting dose of 100 mg QD of the malate capsule formulation 
(an equivalent dose to 120 mg QD of the free base capsule formulation), based on the 
results of Study 516-006 described in Section 1.3.3.4.  Patients who began treatment with 
the free base capsule formulation will remain on the free base capsule formulation 
throughout the duration of the study.  A lead-in dose escalation will determine the 
starting dose of sitravatinib using the malate capsule formulation (21-day cycles) for 
sitravatinib combination with pembrolizumab and enfortumab Cohorts 9 and 10.  
Guidelines for sitravatinib administration and dose reduction in the event of toxicity are 
provided in Section 5.1. 
Contingent PK Evaluation in Patients with Renal Impairment 
In the event results in initial patient cohorts enrolled in this study or results emerging 
from other ongoing clinical trials of sitravatinib are of high interest for efficacy, the 
evaluation of the pharmacokinetics of sitravatinib in patients with mild or moderate renal 
impairment may be implemented.  Appendix 7 describes the plan for this assessment. 
Correlative Endpoints 
Investigation of correlative endpoints will involve collection of blood and tumor tissue 
samples as indicated in Table 1 and Table 2, Table 3, and Table 4.  Further detail on 
sample collection and analyses are presented in Section 7.3 and the Study Laboratory 
Manual.  Protocol guidance of special interest is listed below.   
• Freshly biopsied tumor tissue collections at pre-treatment and on-treatment 
timepoints 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.  Archival 
samples may be submitted as pre-treatment samples if more recent tumor 
specimens or fresh biopsies cannot be obtained.  An on-treatment tumor biopsy as 
close to Cycle 2 Day 15 as possible is desirable for all treated patients and is not 


 
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dependent on the type of pre-treatment tumor tissue submitted (i.e., archival or 
freshly collected biopsy).   
• 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 Case Report Form (CRF) include the type of 
assay employed and percent tumor and/or immune cell staining.   
• Tumor gene expression in freshly biopsied tumor samples will be determined 
using next generation sequencing performed by a central laboratory.  For patients 
in whom tumor tissue has previously been tested using next generation 
sequencing, presence of specific tumor gene mutations and estimation of total 
mutation burden will be collected in the CRF. 
Disease response and progression as documented by the Investigator in the CRF will be 
the basis for patient management and study expansion decision-making.  Unconfirmed 
objective responses recorded in the CRF may be used as the initial basis for expansion of 
study enrollment; however, follow-up evaluations on patients with unconfirmed 
responses must continue to support the decision to continue to the full number of patients 
to be included in the next stage.   
Patients will continue to receive study treatment at the discretion of the Investigator until 
disease progression, unacceptable adverse events, 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-defined disease progression must be 
provided with and sign an informed consent form notifying the patient that they have 
other treatment options available and any potential clinical benefit that the patient may be 
foregoing by continuing study treatment. 
Patients discontinuing treatment will be followed for receipt of subsequent anti-cancer 
therapies and survival. 
 
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 included in the study.  No 
exceptions to the patient eligibility requirements will be granted by the Sponsor. 


 
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4.1 
Inclusion Criteria 
Patients must meet all of the following inclusion criteria as applicable for phase of the 
study to be eligible for enrollment into the study. 
1. 
Histologically confirmed urothelial (transitional cell) carcinoma with metastatic 
disease or with unresectable, locally advanced disease.  
2. 
Most recent treatment must have included a PD-(L)1 checkpoint inhibitor 
(e.g., nivolumab, pembrolizumab, durvalumab, atezolizumab or avelumab) with 
radiographic progression of disease on or after treatment.  Note: This criterion 
only applies to Cohorts 1 and 2 and is to be substituted with criteria below for 
other cohorts: 
a. Cohorts 3 and 4 (Appendix 5): Most recent treatment must have included a 
PD-(L)1 checkpoint inhibitor (e.g., nivolumab, pembrolizumab, durvalumab, 
atezolizumab or avelumab) with radiographic progression of disease on or 
after treatment.  Patients must have previously received treatment with 
selected immunotherapies, including but not limited to anti-CTLA-4, anti-
OX40 or anti-CD137 therapy. 
b. Cohorts 5 and 6 (Appendix 6): Patients must not have received prior therapy 
with a PD-(L)1 checkpoint inhibitor (CIT-naïve). 
c. Cohorts 7 and 8 (Appendix 8): Patients must have experienced radiographic 
progression of disease on or after treatment with a PD-(L)1 checkpoint 
inhibitor (CIT; e.g., nivolumab, pembrolizumab, durvalumab, atezolizumab or 
avelumab) and an antibody-drug conjugate (ADC; e.g. enfortumab vedotin, 
sacituzumab govitecan), in any order or in combination together.  Patients 
who discontinued CIT or ADC treatment due to toxicity are eligible provided 
that the patients have evidence of disease progression following 
discontinuation.  The CIT or ADC treatment need not be the most recent 
therapy.  Patients for whom the most recent therapy has been a non-CIT or 
ADC-based regimen are eligible if the patients have radiographic progression 
of disease on or after the most recent therapy. 
d. Cohort 9 (Appendix 9): Patients must have experienced radiographic 
progression of disease on or after treatment with a PD-(L)1 checkpoint 
inhibitor (CIT; e.g., nivolumab, pembrolizumab, durvalumab, atezolizumab or 
avelumab).  Patients who discontinued CIT due to toxicity are eligible 
provided that the patients have evidence of disease progression following 
discontinuation.  The CIT need not be the most recent therapy.  Patients for 
whom the most recent therapy has been a non-CIT-based regimen are eligible 
if the patients have radiographic progression of disease on or after the most 
recent therapy. 


 
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e. Cohort 10 (Appendix 9): Patients must not have received prior systemic 
therapy for locally-advanced or metastatic urothelial carcinoma.  
Peri-operative chemotherapy with progression or relapse > 1 year from the 
last date of treatment is permitted. 
3. 
Prior treatment with a platinum-based chemotherapy regimen: 
a. Cohort 1, Cohort 3 (Appendix 5), Cohort 5 (Appendix 6), and Cohort 7 
(Appendix 8), and Cohort 9 (Appendix 9): Patients must have received prior 
chemotherapy which included a platinum agent.  Therapy may have been 
administered in the peri-operative or metastatic setting.  In the case of peri-
operative treatment, disease progression or relapse must have occurred within 
1 year of the last date of treatment. 
b. Cohort 2, Cohort 4 (Appendix 5), Cohort 6 (Appendix 6), and Cohort 8 
(Appendix 8): Patients must have been ineligible for platinum-based 
chemotherapy. 
4. 
Resolution of toxicities from prior therapy to baseline or Grade 1 (excluding any 
grade alopecia and ≤ Grade 2 dysgeusia or peripheral neuropathy).  Note: This 
criterion is modified for Cohorts 9 and 10 (Appendix 9) as follows: Absence of 
preexisting ≥ Grade 2 sensory or motor neuropathy, and resolution of toxicities 
from prior therapy to baseline or Grade 1 (excluding any grade alopecia and 
≤ Grade 2 dysgeusia). 
5. 
Measurable disease as per RECIST version 1.1.   
6. 
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.Note: 
This criterion is modified for Cohort 10 (Appendix 9) as follows: ECOG 
performance status 0, 1 or 2. 
7. 
Adequate bone marrow and organ function demonstrated by:  
a. Absolute neutrophil count  1,000/mm3 ( 1.0 × 109/L). 
b. Hemoglobin ≥ 9.0 g/dL.  Note for the lead-in dose escalation portion of 
Cohort 9 (Appendix 9): no RBC transfusions are allowed within 14 days of 
the first dose of enfortumab. 
c. Platelet count ≥ 50 × 109/L (≥ 50,000 per mm3).  Note: This criterion is 
modified for Cohorts 9 and 10 (Appendix 9) as follows: Platelet count ≥ 100 
× 109/L (≥ 100,000 per mm3).  For the lead-in dose escalation portion of 
Cohort 9, no platelet transfusions are allowed within 14 days of the first dose 
of enfortumab. 


 
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d. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 
≤ 2.5 × Upper Limit of Normal (ULN), or ≤ 5.0 × ULN for patients with 
documented liver metastases.  Note: This criterion is modified for Cohorts 9 
and 10 (Appendix 9) as follows: ALT and AST ≤ 2.5 × ULN, or ≤ 3.0 × ULN 
for patients with documented liver metastases. 
e. Serum bilirubin ≤ 1.5 × ULN, or ≤ 3.0 × ULN for patients with Gilbert 
Syndrome or documented liver metastases.  
f. Serum creatinine: 
i. patient weight > 55 kgs (~120 lbs), ≤ 3.0 × ULN or calculated* 
Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI, 
Levey-2009) glomerular filtration rate (GFR) ≥ 30 mL/min. 
ii. patient weight ≤ 55 kgs (~120 lbs), ≤ 3.0 × ULN and calculated* 
CKD-EPI glomerular filtration rate ≥ 30 mL/min. 
Link to CKD-EPI calculator and information for use provided in 
Appendix 2. 
g. Cohorts 9 and 10 (Appendix 9): Serum albumin ≥ 2.5 g/dL. 
h. Cohorts 9 and 10 (Appendix 9): INR < 1.3 or ≤ institutional ULN (or ≤ 3.0 if 
on therapeutic anticoagulation). 
8. 
≥ 18 years of age. 
9. 
Women of childbearing potential (WOCBP) or men whose partner is a WOCBP 
agrees to use contraception while participating in this study, and for a period of 
6 months following termination of study treatment. 
10. 
Completed informed consent process, including signing IRB/EC-approved 
informed consent form. 
11. 
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. 
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 enrollment without the use of corticosteroids or, are on a stable 
or decreasing dose of ≤10 mg daily prednisone (or equivalent).  


 
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2. 
Patients with carcinomatous meningitis.  
3. 
Prior therapies: 
a. Cohorts 1 and 2, and Cohorts 5 and 6 (Appendix 6): Immunotherapies not 
previously specified, including anti-CTLA-4, anti-OX40 and anti–CD137. 
b. Combination therapy with a PD-(L)1 checkpoint inhibitor and cancer therapy 
having the same mechanism of action as sitravatinib (e.g., tyrosine kinase with 
similar target profile). 
4. 
Unacceptable toxicity on prior PD-(L)1 checkpoint inhibitor treatment: 
a. ≥ Grade 3 immune-related AE with a PD-(L)1 checkpoint inhibitor. 
b. Grade 2 immune-related AE associated with a PD-(L)1 checkpoint inhibitor 
unless the AE resolved or was well controlled by withholding the checkpoint 
inhibitor and/or treatment with steroids, with the exception of prior colitis, 
encephalitis, myocarditis, uveitis and pneumonitis, which are exclusionary. 
c. Criterion deleted in Version 3.0 of protocol: Grade 1 immune-related AE 
associated with a PD-(L)1 checkpoint inhibitor unless the AE resolved or 
could be well controlled. 
d. CNS or ocular AE of any grade related to a PD-(L)1 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. 
5. 
Active or prior documented autoimmune disease: 
a. Inflammatory bowel disease (e.g., 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 and medically-important autoimmune disease 
within the past 2 years.  Note: Patients with Type I diabetes, vitiligo, Graves’ 
disease, residual hypothyroidism due to an autoimmune condition only 
requiring hormone replacement, or psoriasis or Sjögren’s syndrome not 
requiring systemic treatment (within the past 2 years) are not excluded. 
6. 
Active or prior immunocompromising conditions: 
a. Current or prior use of immunosuppressive medication within 28 days before 
the first dose of study treatment, with the exceptions of intranasal and inhaled 


 
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corticosteroids or systemic corticosteroids at physiological doses, which are 
not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid.   
b. Known acute or chronic human immunodeficiency virus (HIV). 
c. History of primary immunodeficiency. 
d. History of allogeneic transplant. 
7. 
History of severe hypersensitivity reaction to any monoclonal antibody 
8. 
Use of live vaccines against infectious disease (e.g. varicella) within 28 days of 
initiation of study therapy; killed vaccinations (e.g. influenza) are allowed at any 
appropriate time before and during the study. 
9. 
Known acute or chronic hepatitis B or hepatitis C. Patients treated for hepatitis C 
with no detectable viral load are permitted. 
10. 
History of hypersensitivity to study treatment excipient.   
11. 
History of stroke or transient ischemic attack within the previous 6 months. 
12. 
Any of the following cardiac abnormalities: 
a. Unstable angina pectoris. 
b. Congestive heart failure ≥ NYHA Class 3. 
c. QTc >480 milliseconds.   
d. LVEF < 40% 
13. 
Concomitant medication known to cause prolonged QT which cannot be 
discontinued or changed to a different medication prior to enrollment (Refer to 
Appendix 3). 
14. 
Uncontrolled arterial hypertension (> 150 mm Hg systolic or > 100 mm Hg 
diastolic) on multiple observations despite standard of care treatment 
15. 
Undergone major surgery within 4 weeks of first dose date. 
16. 
History of significant hemorrhage within 4 weeks of first dose date. 
17. 
Undergone radiation or systemic therapy within approximately 2 weeks of first 
dose date. 


 
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18. 
Known or suspected presence of another malignancy that could be mistaken for 
the malignancy under study during disease assessments. 
19. 
Pregnancy.  WOCBP must have a negative serum or urine pregnancy test 
documented within the screening period prior to start of study drug. 
20. 
Breast-feeding or planning to breast-feed during the study or within 6 months 
after study treatment. 
21. 
Any serious illness, uncontrolled inter-current illness, psychiatric illness, active or 
uncontrolled infection, or other medical history, including laboratory results, 
which, in the Investigator’s opinion, would be likely to interfere with the patient’s 
participation in the study, or with the interpretation of the results. 
22. 
Cohorts 9 and 10 (Appendix 9): Any P-gp inducers/inhibitors or strong CYP3A4 
inhibitors (see Appendix 10 for examples) within 2 weeks of first dose date of 
enfortumab. 
23. 
Cohorts 9 and 10 (Appendix 9): Thromboembolic events and/or bleeding 
disorders ≤ 14 days (e.g., DVT or PE) prior to the first dose of study drug. 
24. 
Cohorts 9 and 10 (Appendix 9): Decompensated liver disease as evidenced by 
clinically significant ascites refractory to diuretic therapy, hepatic 
encephalopathy, or coagulopathy. 
25. 
Cohorts 9 and 10 (Appendix 9): History of uncontrolled diabetes mellitus or 
diabetic neuropathy within 3 months of the first dose of study drug. Uncontrolled 
diabetes is defined as hemoglobin A1C (HbA1c) ≥ 8% or HbA1c > 7 to < 8% 
with associated diabetes symptoms (polyuria or polydipsia) that are not otherwise 
explained. 
26. 
Cohorts 9 and 10 (Appendix 9): Has ocular conditions such as: 
a. Active infection or corneal ulcer (e.g., keratitis). 
b. Monocularity. 
c. History of corneal transplantation. 
d. Contact lens dependent (if using contact lens, must be able to switch to glasses 
during the entire study duration). 
e. Uncontrolled glaucoma (topical medications allowed). 
f. Uncontrolled or evolving retinopathy, wet macular degeneration, uveitis, 
papilledema, or optic disc disorder. 


 
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4.3 
Life Style Guidelines 
Patients who are biologically capable of having children and sexually active must agree 
to use an acceptable method of contraception 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 forms of contraception include: 
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 condom or female condom used WITH a spermicide. 
4. 
Male sterilization with confirmed absence of sperm in the post-vasectomy 
ejaculate. 
5. 
Bilateral tubal ligation or bilateral salpingectomy. 
The Investigator will instruct the patient to call immediately if the selected birth control 
method is discontinued or if pregnancy is known or suspected.   
Note: Women are considered post-menopausal and/or not of child bearing potential if 
they have had 12 months of natural (spontaneous) amenorrhea with an appropriate 
clinical profile (e.g., age appropriate, history of vasomotor symptoms) or have had 
surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least 
6 months ago.  In case of any ambiguity, the reproductive status of the woman should be 
confirmed by hormone level assessment. 
4.4 
Enrollment into Study 
Following completion of the study-specific informed consent process and review of all 
screening procedures, patient eligibility will be confirmed by appropriately qualified staff 
at the investigational site.  Patients will be enrolled by entry into a patient registration log 
provided by the Sponsor and maintained by the study site, and completion of the patient 
registration procedure detailed in the Study Manual.  Each patient will be assigned a 
sequential number by the study site.  The patient number must be used on all 
documentation and correspondence with the Sponsor, Contract Research Organization 
(CRO) and laboratory vendors. 
 


 
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5 STUDY TREATMENTS 
5.1 
Sitravatinib  
5.1.1 
Formulation, Packaging and Storage 
This study began patient treatment with the sitravatinib free base capsule formulation 
used in previous clinical trials.  Cohorts 1 through 6 will continue to receive the free base 
formulation.  For Cohorts 7 through 10, transition to use of an alternative formulation, 
sitravatinib malate capsule formulation, is being implemented with protocol Version 4.0.  
Newly enrolled patients in Cohorts 7 through 10 will receive the malate capsule 
formulation.  Patients on study treatment with the free base capsule formulation at the 
time the malate capsule formulation is introduced will remain on the free base capsule 
formulation until treatment discontinuation.  The formulations are described below. 
• 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 strengths of all sitravatinib capsule formulations are expressed based on sitravatinib 
free base weight. Dose strengths of sitravatinib and additional packaging differences 
between formulations 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 United States. 
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.   


 
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5.1.2 
Preparation, Dispensing, Administration 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. 
Study site personnel will dispense bottles containing sitravatinib capsules on Day 1 of 
each treatment cycle.  Sufficient supply will be provided for each cycle and extra 
capsules may be provided to cover additional days in case of delayed clinic visits or lost 
capsules.  Study capsules will be dispensed in HDPE bottles provided by the Sponsor.   
Sitravatinib capsules will be administered orally, once daily (QD), in a continuous 
regimen expressed in 28-day cycles for the sitravatinib and nivolumab combination 
cohorts and in 21-day cycles for the sitravatinib, pembrolizumab and enfortumab 
combination cohorts. 
• For all patients in Cohorts 1 through 6, the starting dose using the free base 
formulation is 120 mg QD. 
• For newly enrolled patients in Cohorts 7 and 8, the starting dose using the malate 
capsule formulation is 100 mg QD.  The starting dose using the free base capsule 
formulation (for patients who began treatment on free base capsule formulation at 
the time the malate capsule formulation is introduced) is 120 mg QD. 
• For the sitravatinib, pembrolizumab and enfortumab combination cohorts, the 
sitravatinib starting dose for the lead-in dose escalation portion of Cohort 9 using 
the malate capsule formulation will be 35 mg QD which represents three dose 
levels below the dose administered as a single agent and in combination (with 
nivolumab) Phase 2 and Phase 3 trials.  If a dose is identified for sitravatinib in 
combination with pembrolizumab and enfortumab, this recommended starting 
dose will be used for subsequent contingent sitravatinib, pembrolizumab and 
enfortumab combination cohorts (dose expansion portion of Cohort 9 and 
Cohort 10). 
Depending on safety observations, the sitravatinib dose during treatment may be reduced 
in accordance with Table 5 for patients administered the free base capsule formulation 
and in accordance with Table 6 for patients administered the malate capsule formulation. 
The following guidelines should be followed for sitravatinib administration: 
• Dosing in the morning is preferred. 
• Capsules should be taken on an empty stomach (at least 2-hour fast before each 
dose and no food for a minimum of 1 hour after each dose).  The fasting 
requirement may be eliminated based on the outcome of an ongoing food-effect 
study under a separate study protocol.  Any change in fasting will be implemented 


 
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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 (~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.   
On days when nivolumab, pembrolizumab or enfortumab are administered, the daily dose 
of sitravatinib should precede the nivolumab, pembrolizumab or enfortumab infusion for 
logistical reasons.  This order of dosing is of particular interest on days when blood 
sampling is scheduled for sitravatinib PK. 
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 
(e.g., 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 Dose Modification and Discontinuation 
This protocol provides guidance for dose modification of sitravatinib (i.e., interruption, 
dose reduction or discontinuation) for AEs attributed to sitravatinib.  For adverse events 
attributed to nivolumab, pembrolizumab or enfortumab see the current OPDIVO US 
Prescribing Information, KEYTRUDA US Prescribing Information and PADCEV US 
Prescribing Information, Section 5.2.4 for dose nivolumab modifications, Section 5.3.4 
for dose for pembrolizumab modifications, and Section 5.4.4 for dose for enfortumab 
modifications. 
Available dose levels for each of the sitravatinib formulations are outlined in Table 5 and 
Table 6.  Dose modifications guidelines for the malate capsule formulation (Table 6) 


 
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follow comparable dose reduction proportions used for the free base capsule formulation.  
Guidelines for sitravatinib dose modifications to be implemented to manage adverse 
events are described in Section 5.3.1 and 5.3.3.  Once the dose has been reduced, re-
escalation is generally not recommended but may be considered on a case-by-case basis 
with approval from the Medical Monitor.  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 QD. 
Table 5: 
Sitravatinib Sequential Dose Reductions for Individual Patients 
on Free Base Capsule Formulation 
120 mg once daily 
80 mg once daily 
60 mg once daily 
40 mg once daily 
 
The starting dose for sitravatinib using the malate capsule formulation is 100 mg QD. 
Table 6: 
Sitravatinib Sequential Dose Reductions for Individual Patients 
on Malate Capsule Formulation 
100 mg once daily 
70 mg once daily 
50 mg once daily 
35 mg once daily 
20 mg once daily* 
* This dose level is only available for Cohorts 9 and 10.  
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 of 
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 obtained from commercial sources and managed in accordance with 
the OPDIVO US Prescribing Information.  The following reports information and 
guidance included in the OPDIVO US Prescribing Information dated June 2020.  Refer 
the current OPDIVO US Prescribing Information provided by the manufacturer for 
updates during the conduct of this clinical trial. 


 
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5.2.1 
Formulation and Packaging 
Refer to the current OPDIVO US Prescribing Information. 
5.2.2 
Preparation and Dispensing 
Refer to the current OPDIVO US Prescribing Information. 
5.2.3 
Administration 
Nivolumab (OPDIVO) will be administered in this study as an intravenous infusion over 
approximately 30 minutes (+/- 5 minutes) at 240 mg every 2 weeks (Q2W) or 480 mg 
every 4 weeks (Q4W), at the discretion of the Investigator and in accordance with the 
current OPDIVO US Prescribing Information.  Note: nivolumab should be administered 
after sitravatinib (and specifically after the 30 minute PK sampling on applicable study 
visits). 
5.2.4 
Nivolumab Dose Modification 
Required dose modifications (i.e., interruption or discontinuation) for nivolumab should 
be performed per the current OPDIVO US Prescribing Information, in addition to 
potential dose modifications for sitravatinib in accordance to Section 5.1.3.  
If one agent is interrupted or discontinued, administration of the other agent may continue 
at the discretion of the Investigator.   
Change from OPDIVO US Prescribing Information for This Study 
One change from the Prescribing Information will be implemented in this study.  This 
protocol allows enrollment of patients having a limited degree of renal impairment.  For 
this reason, the guidance for management of patients who experience nephritis and renal 
dysfunction that is not thought to be immune-mediated will be adjusted.  The Prescribing 
Information indicates that dosing should be withheld in the event of serum creatinine 
more than 1.5 and up to 6 times the upper limit of normal and discontinued permanently 
if more than 6 times the upper limit of normal. 
In this study, the baseline (screening) value will substitute for the upper limit of normal.  
Nivolumab dosing should be withheld if the serum creatinine increases to more than 1.5 
and up to 6 times the baseline (screening) value and discontinued permanently if more 
than 6 times the baseline (screening) value. 
5.3 
Pembrolizumab Study Drug  
Pembrolizumab will be obtained from commercial sources and managed in accordance 
with the KEYTRUDA US Prescribing Information.  The following reports information 
and guidance included in the KEYTRUDA US Prescribing Information dated April 2020.  


 
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Refer to the current KEYTRUDA US Prescribing Information provided by the 
manufacturer for updates during the conduct of this clinical trial. 
5.3.1 
Formulation and Packaging 
Refer to the current KEYTRUDA US Prescribing Information. 
5.3.2 
Preparation and Dispensing 
Refer to the current KEYTRUDA US Prescribing Information. 
5.3.3 
Administration 
Pembrolizumab (KEYTRUDA) will be administered in this study as an intravenous 
infusion over approximately 30 minutes (+/- 5 minutes) at 200 mg every 3 weeks (Q3W), 
in accordance with the current KEYTRUDA US Prescribing Information.  Note: 
pembrolizumab should be administered after sitravatinib (and specifically after the 
30 minute PK sampling on applicable study visits), and at least 30 minutes before 
enfortumab. 
5.3.4 
Pembrolizumab Dose Modification 
Required dose modifications (i.e., interruption or discontinuation) for pembrolizumab 
should be performed per the current KEYTRUDA US Prescribing Information, in 
addition to potential dose modifications for sitravatinib in accordance to Section 5.1.3 
and dose modifications for enfortumab per the current PADCEV US Prescribing 
Information in Section 5.4.4. 
If one agent is interrupted or discontinued, administration of the other agent may continue 
at the discretion of the Investigator. 
5.4 
Enfortumab Study Drug 
Enfortumab will be obtained from commercial sources and managed in accordance with 
the PADCEV US Prescribing Information.  The following reports information and 
guidance included in the PADCEV US Prescribing Information dated December 2019.  
Refer the current PADCEV US Prescribing Information provided by the manufacturer for 
updates during the conduct of this clinical trial. 
5.4.1 
Formulation and Packaging 
Refer to the current PADCEV US Prescribing Information. 
5.4.2 
Preparation and Dispensing 
Refer the current PADCEV US Prescribing Information. 


 
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5.4.3 
Administration 
Dosing is based on patient weight.  Enfortumab will be administered at mg/kg doses 
based on the patient’s actual body weight at Cycle 1 Day 1.  For on-study dosing, the 
dose must be adjusted if the patient’s weight changes by ≥ 10% from their Cycle 1 Day 1 
weight, or if enfortumab dose modification criteria (see Section 5.4.4) are met.  Other 
dose adjustments for changes in body weight <10% are permitted per institutional 
standard.  For patients who weigh > 100 kg, the dose will be calculated based on 100 kg 
weight.  Institutional dose rounding rules may be applied to this protocol, but otherwise, 
doses of the investigational product will be rounded to the nearest milligram. 
Enfortumab (PADCEV) will be administered in this study as an intravenous infusion over 
approximately 30 minutes (+/- 5 minutes) at the selected dose level (see Appendix 9) on 
Days 1, and 8 of a 21-day cycle, at the discretion of the Investigator and in accordance 
with the current PADCEV US Prescribing Information.  Note: enfortumab should be 
administered at least 30 minutes after pembrolizumab. 
Patients will receive enfortumab administration only if their laboratory results of blood 
drawn within 24 hours prior to dosing meets the following study drug administration 
laboratory criteria: 
• Blood glucose ≤ 250 mg/dL. 
5.4.4 
Enfortumab Dose Modification 
Required dose modifications (i.e., interruption, dose reduction or discontinuation) for 
enfortumab should be performed per the current PADCEV US Prescribing Information, 
in addition to potential dose modifications for sitravatinib in accordance to Section 5.1.3 
and dose modifications for pembrolizumab per the current KEYTRUDA US Prescribing 
Information in Section 5.3.4.  Available dose levels for enfortumab are outlined in 
Table 7. 
Table 7: 
Enfortumab Sequential Dose Reductions for Individual 
Patients 
1.25 mg/kg up to 125 mg 
1.0 mg/kg up to 100 mg 
0.75 mg/kg up to 75 mg 
0.5 mg/kg up to 50 mg 
 
If one agent is interrupted or discontinued, administration of the other agent may continue 
at the discretion of the Investigator.   


 
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5.5 
Management of Adverse Events 
5.5.1 
Sitravatinib-Related Adverse Events 
5.5.1.1 
General Management of Non-Hematological Toxicities 
In the event of symptomatic sitravatinib-related AEs, dose reduction to a level that can be 
administered continuously is preferred over continuing dosing until interruption becomes 
necessary.  Symptomatic Grade 2 sitravatinib-related non-hematological AEs 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 Table 5 (free base capsule formulation) and Table 6 
(malate capsule formulation), rather than treatment interruption. 
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 of toxicity to ≤ Grade 1 or to baseline value.  If the toxicity is 
adequately managed by routine supportive care (such as electrolyte supplementation), or 
is a Grade 3 amylase or lipase elevation, treatment may be resumed at the same dose; if 
not, treatment may be resumed at a reduced dose as outlined in Table 8.  Recurrence of 
the toxicity may be managed similarly.  If sitravatinib is interrupted for ≥ 28 days, 
permanent discontinuation of sitravatinib should be considered. 
Table 8: 
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 discretion2 
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 level one or more levels 
below that inducing the toxicity. 
Exceptions presented in footnotes2,3 
1  Management of adverse events of interest for sitravatinib are presented in Section 5.5.1.3. 
2  The current OPDIVO US Prescribing Information, KEYTRUDA US Prescribing Information and 
PADCEV US Prescribing Information must be consulted to determine appropriate dose modifications 
for nivolumab, pembrolizumab and enfortumab. 
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 or 4 amylase or lipase elevation that is not associated with symptoms or clinical 
manifestations of pancreatitis. 


 
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5.5.1.2 
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.  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 
• Grade 4 thrombocytopenia of any duration or Grade 3 thrombocytopenia with 
bleeding. 
5.5.1.3 
Management of Selected Adverse Event 
The following are guidelines for management of potential adverse events more specific to 
treatment with sitravatinib or agents in the same class of cancer treatment. 
5.5.1.3.1 
Hypertension 
Hypertension, including Grade 3 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 9).  On the other hand, in cases of Grade 3 hypertension 
with clinically significant increases in blood pressure (Table 9), 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 9). 


 
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Table 9: 
Sitravatinib Dose Modification for Increased Blood Pressure 
Toxicity 
Interruption 
Reduction 
Grade 1 or 2 hypertension 
Investigator discretion, as per Table 8. 
Grade 3 hypertension without clinically significant 
increases in BP as defined below 
Investigator discretion. Consider 
anti-hypertensives per Section 5.5.1.3.1. 
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 
 
5.5.1.3.2 
Palmar-Plantar Erythrodysesthesia 
Palmar plantar erythrodysesthesia (PPE) has been reported as a dose-limiting toxicity in 
the Phase 1 study of sitravatinib.  Measures that can be taken to manage PPE include 
avoidance of exposure of hands and feet to hot water when washing dishes or bathing, or 
to other sources of heat, avoidance of activities that cause unnecessary force or friction 
(rubbing) on the hands or feet, avoiding contact with harsh chemicals such as cleaning 
products, use of tools or household items that result in pressure on the hands, such as 
garden tools, knives, and screwdrivers, and wearing of loose fitting, well-ventilated shoes 
and clothes.  Treatment may include use of topical moisturizing agents, topical 
anesthetics, or topical anti-inflammatory medications such as corticosteroid creams.  In 
more severe cases, dose interruption and reduction may be warranted. 
5.5.1.3.3 
Diarrhea 
Diarrhea should be evaluated to determine whether it may be immune-mediated colitis 
due to nivolumab or pembrolizumab (Section 5.5.5.1.1), 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 develops.  Any patients developing 
dehydration or clinically significant electrolyte abnormalities should interrupt treatment, 
but treatment may be restarted once diarrhea is controlled. 
5.5.1.3.4 
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.   


 
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5.5.1.3.5 
Thrombotic Events 
Though thrombotic events (e.g., 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. 
5.5.1.3.6 
Thyroid Dysfunction Other than Immune-Mediated 
Hypothyroidism and increases in TSH have been reported in patients taking sitravatinib.  
Patients diagnosed with hypothyroidism should be treated with thyroid replacement and 
may continue treatment with sitravatinib at the Investigator’s discretion. 
5.5.1.3.7 
Decreased Left Ventricular Ejection Fraction 
Decreased left ventricular ejection fraction (LVEF) has been reported with sitravatinib.  
In addition, decreases of LVEF to <50% on-study were observed in patients undergoing 
scheduled multigated acquisition (MUGA) scans or echocardiograms.  The dose of 
sitravatinib should be interrupted and/or reduced in patients with an ejection fraction 
<50% and >20% below baseline.  Discontinuation should be considered for patients 
requiring acute hospitalization for treatment of congestive heart failure (CHF).  
5.5.1.3.8 
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. 
5.5.2 
Nivolumab Adverse Event Management Guidelines 
Refer to the OPDIVO US Prescribing Information for guidance concerning management 
of adverse events, including immune-mediated adverse events, during treatment with 
nivolumab.   
5.5.3 
Pembrolizumab Adverse Event Management Guidelines 
Refer to the KEYTRUDA US Prescribing Information for guidance concerning 
management of adverse events, including immune-mediated adverse events, during 
treatment with nivolumab.   


 
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5.5.4 
Enfortumab Adverse Event Management Guidelines 
Refer to the PADCEV US Prescribing Information for guidance concerning management 
of adverse events, including immune-mediated adverse events, during treatment with 
nivolumab. 
5.5.5 
Management of Immune-Related Adverse Events 
Sitravatinib has not been associated with immune-mediated AEs.  However, the potential 
exists for one or more of the treatments to contribute to immune-mediated AEs associated 
with nivolumab or pembrolizumab treatment.  In the event of a Grade 2 immune-related 
AE during study treatment, administration of study treatments (sitravatinib and 
nivolumab, or sitravatinib, pembrolizumab and enfortumab) should be interrupted until 
the event stabilizes to Grade ≤1 (consistent with guidance provided in the OPDIVO US 
Prescribing Information and KEYTRUDA US Prescribing Information).  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 immune-mediated adverse events should be performed in 
accordance with the OPDIVO US Prescribing Information and KEYTRUDA US 
Prescribing Information.  However, recurrent Grade 3, or any Grade 4, immune-mediated 
adverse events should generally be managed with permanent discontinuation of 
nivolumab or pembrolizumab.  Administration of sitravatinib should be interrupted and 
may be resumed at the same or lower dose at the discretion of the Investigator after the 
event stabilizes to Grade ≤ 1. 
5.5.5.1.1 
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-mediated colitis.  The presence of abdominal pain, mucus or blood in the stool 
or peritoneal signs should raise the index of suspicion for immune-mediated 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-mediated colitis, all study medications should be 
withheld and treatment with immuno-suppressive therapy initiated as detailed in the 
OPDIVO US Prescribing Information and KEYTRUDA US Prescribing Information. 
5.5.5.1.2 
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-mediated hepatitis.  Increased 


 
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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-mediated, treatment 
management decisions should be made using Investigator discretion in consideration of 
clinical factors.  Recommended treatment modifications for sitravatinib are provided in 
Table 10.  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-mediated hepatitis, all study medications should be 
withheld and treatment with immuno-suppressive therapy initiated as detailed in the 
OPDIVO US Prescribing Information and KEYTRUDA US Prescribing Information. 
Table 10: 
Sitravatinib Dose Modification for Increased Hepatic 
Transaminases 
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 US Prescribing Information and KEYTRUDA US Prescribing Information (and 
Section 5.5.5, in case the event is deemed to be an immune-mediated adverse event) must be consulted 
to determine appropriate dose modifications for nivolumab or pembrolizumab. 
5.5.6 
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 (i.e., 
alkaline phosphatase < 2 × ULN), that is not attributable to other causes (e.g., liver 
metastases, biliary obstruction, viral hepatitis, concomitant medication, etc.), study 
treatments (sitravatinib and nivolumab, or sitravatinib, pembrolizumab and enfortumab) 
should be permanently discontinued and steroids administered.  Hy’s Law cases should 
be reported as SAEs (Section 8.4). 
5.6 
Medication Error 
Medication errors may involve patient exposure to a wrong study drug, at a wrong dosing 
frequency, or at a wrong dose level (e.g., 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 Serious Adverse Event (SAE) forms.  In 
all cases of medication error, the sponsor should be notified immediately. 


 
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There is currently no specific treatment in the event of an overdose of sitravatinib, 
nivolumab, pembrolizumab or enfortumab.  The Investigator will use clinical judgment to 
treat any overdose. 
5.7 
Concomitant Therapies 
5.7.1 
Concomitant Medication(s) 
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 3.  
In addition, see Section 5.7.3 for restrictions on concomitant use of other anticancer or 
experimental therapy. Prohibited medications are listed for enfortumab in Appendix 10.  
Finally, additional restrictions for patients in Cycle 1 who are undergoing a DLT 
assessment in Cohort 9 are covered in Section 5.7.2. 
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. 
Gastric Acid Medications with Sitravatinib:  Proton pump inhibitors (PPIs) should be 
avoided during on-study treatment with sitravatinib.  Switching from PPIs to H2 
antagonists (H2A) or antacids is preferred. Use of H2A/antacids should be avoided at least 
6 hours before and 1 hour after administration of sitravatinib.  Ideally, sitravatinib and the 
H2A/antacid should be taken at different times of the day, such as in the following 
examples: 
• If the H2A/antacid is taken once daily in the morning: take sitravatinib in the 
morning, after overnight fasting, and take the H2A/antacid at least 1 hour later; 
• If the H2A/antacid is taken once daily in the evening: take the H2A/antacid at least 
6 hours prior to the next morning dose of sitravatinib; 
• If the H2A/antacid is taken twice daily, and sitravatinib is administered in the 
morning: take sitravatinib in the morning, after overnight fasting, and take the 
H2A/antacid at least 1 hour later then, take the evening dose of the H2A/antacid at 
least 6 hours prior to the next morning dose of sitravatinib; 


 
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• If the H2A/antacid is taken twice daily, and sitravatinib is administered in the 
evening: take the H2 antagonist or antacid in the morning, wait at least 6 hours 
(and fast for at least 2 hours) before taking sitravatinib, then take the evening dose 
of H2A/antacid at least 1 hour after sitravatinib. 
Medications with QTc Prolonging Activity:  The risk of QTc prolongation in patients 
receiving sitravatinib has not been characterized.  Use of medications known to prolong 
QTc and pose risk of Torsades de Pointes (examples listed in Appendix 3) is to be 
avoided.  Use of medications with conditional risk of Torsades de Pointes should be used 
with caution during sitravatinib treatment (examples listed in Appendix 3). 
P-gp and BCRP transporters 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 3) should be used with caution during sitravatinib treatment. 
Strong P-gp Inhibitors with Enfortumab:  Concomitant use of enfortumab and 
medications that are strong inducers/inhibitors of P-gp may affect exposure to MMAE 
and are prohibited (examples listed in Appendix 10).  Whereas no clinical studies 
evaluating the drug-drug interaction potential of enfortumab have been conducted, in 
vitro studies indicate that monomethyl auristatin E (MMAE), the payload component of 
enfortumab, is a substrate of P-gp (PADCEV US Prescribing Information). 
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 3) should be used with caution during sitravatinib treatment.  
Strong CYP3A4 Inhibitors with Enfortumab:  Concomitant use of enfortumab with a 
strong CYP3A4 inhibitor may increase free MMAE exposure, which may increase the 
incidence or severity of enfortumab toxicities (PADCEV US Prescribing Information).  
and are prohibited (examples listed in Appendix 10).  Whereas no clinical studies 
evaluating the drug-drug interaction potential of enfortumab have been conducted, in 
vitro studies indicate that MMAE is a substrate of CYP3A4 (PADCEV US Prescribing 
Information). 
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.  See Section 5.7.2 for 
Cohort 9 restrictions. 
Antibiotics:  Antibiotics should be used as needed.  Patients with neutropenic fever or 
infection should be treated promptly.   


 
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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. 
Growth Factors:  Therapeutic colony-stimulating factors should be used in accordance 
with ASCO guidelines.  See Section 5.7.2 for Cohort 9 restrictions.  
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 immune-mediated AEs and the extent required to manage comorbidities and 
symptoms of disease.   
Vaccines:  Live attenuated vaccines within 28 days of nivolumab dosing are to be 
avoided.  Inactivated vaccines, such as the injectable influenza vaccine, are permitted. 
5.7.2 
Concomitant Medication(s) Restrictions in Cycle 1 of Lead-In 
Dose Escalation Evaluation (Cohort 9) for Patients Undergoing a 
DLT Assessment 
Treatment with the following concomitant supportive therapies are prohibited for patients 
in Cycle 1 who are undergoing a DLT assessment: 
• Prophylactic use of colony-stimulating factors including G-CSF, PEGylated 
G-CSF or GM-CSF. 
• Thrombopoietin or thrombopoietin-like therapies. 
• Platelet transfusions. 
Patients who receive prohibited therapy during Cycle 1 will be ineligible for DLT 
evaluation and will be replaced unless they experience a DLT event.  See Appendix 9 for 
more information. 
5.7.3 
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 (e.g., bone lesions at risk for 
spontaneous micro-fractures or painful lesions).  However, these treatments may be used 
in cases where it is medically necessary.   
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. 


 
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If radiotherapy is required, the Sponsor will provide guidance on duration of sitravatinib 
interruption.   
5.7.4 
Other Anticancer or Experimental Therapy 
Use of approved or investigational anticancer treatment will not be permitted during the 
study treatment period, including chemotherapy, biological response modifiers, hormone 
therapies* 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 (e.g., 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 did not enroll on the study will be considered as screen failures.  Limited 
information will be recorded in the CRF for these patients. 
6.2 
Study Period 
For details on procedures during the study period, see Schedule of Assessments as shown 
in Table 1 and Table 3. 
6.3 
End of Treatment Assessment 
All patients will be followed for AEs for at least 28 days after the last dose of Study 
Treatment.  See the Schedule of Assessments (Table 1 and Table 3) for evaluations to be 
performed at the End of Treatment visit. 
6.4 
Long-Term Follow-up and End of Study Assessment 
Survival status and subsequent therapies will be collected during long term follow-up as 
outlined in the Schedule of Assessments (Table 1 and Table 3) 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. 


 
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6.5 
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.   
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 


 
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reason for withdrawal, request that the patient returns for a final visit, and if applicable, 
follow-up with the patient regarding any unresolved adverse events. 
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 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 
Efficacy 
All patients enrolled in the study are to be evaluated for disease activity as outlined in the 
Schedule of Assessments (Table 1).  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), CT with contrast or MRI of the brain and evaluation of any 
superficial lesions.  On-study assessments will include all known and suspected sites of 
disease and will be performed at 8-week intervals, based on a calendar beginning from 
first day of dosing, until approximately 1-year and then every 16 weeks; bone scans may 
be performed half as often as other radiology evaluations (i.e., every 16 weeks).  The 
allowable windows for assessments are 4 weeks prior to first study treatment for 
screening/baseline assessments and 10 days for on-study disease assessments.  All 
known and suspected sites of disease should be evaluated at each assessment. 
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 


 
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unless the method does not adequately depict the individual’s disease, in which case CT 
without contrast is preferred.   
For patients having effusions or ascites, cytological proof of malignancy should be 
obtained prior to selection of the effusion as a non-target lesion.  Effusions that have not 
been evaluated using cytology or were found to be non-malignant should not be 
considered to be cancer lesions.  New fluid collections identified on-study and existing 
non-malignant fluid collections that change in character require cytological proof of 
malignancy in order to be reported as a new lesion. 
Disease response will be assessed in accordance with RECIST 1.1 (Eisenhauer-2009).  
Appendix 4 provides guidance in using the response criteria and includes modifications 
to RECIST 1.1 to address potential temporary treatment effects such as tumor lesion 
cavitation or flare response.  Assessments will be performed until objective disease 
progression is documented by the Investigator, or subsequent anti-cancer therapy is 
begun.   
Patients experiencing tumor response (Partial Response [PR] or Complete Response 
[CR]) should undergo confirmatory assessment at least 4 weeks after initial 
documentation of response.  It is acceptable to perform confirmatory assessments at the 
next appointed evaluation per protocol.  Bone scan is required as an element of the 
confirmation of PR or CR if bone lesions were identified at the baseline assessment. 
The Investigator’s assessment of disease response and progression will be the basis for 
patient management and study expansion decision making.  Potential exists for individual 
tumor lesions to cavitate or become otherwise difficult to evaluate for a period of time as 
the result of beneficial study treatment impact.  For example, tumor necrosis and 
cavitation may result in minor increase in overall individual lesion size or unclear tumor 
margins prior to recovery to a smaller lesion, development of scar tissue, or complete 
resolution.  For this reason, Investigators may delay reaching the conclusion of disease 
progression until subsequent on-study disease assessments are performed. 
Central radiology review for disease response and progression may be implemented in 
this study for Cohorts 7 through 10 and would be introduced with a future amendment or 
an Administrative Letter.  Radiographic documentation (either in digital format or 
original films) for independent review must be preserved and be readily available for all 
newly enrolled patients in these cohorts, and attempts should be made to collect and 
preserve such material for previously enrolled patients, for submission to a central 
vendor. 


 
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7.2 
Safety Assessments 
7.2.1 
Medical History 
Signs and symptoms of the patient’s cancer diagnosis and/or comorbidities present at 
baseline will be recorded in the CRF as AEs beginning on Day 1 of study treatment and 
onward throughout the study.  The actual date of onset should be recorded in all cases.   
7.2.2 
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 were both vital signs and PK sampling are scheduled, the vital signs should 
be assessed prior to blood sampling. 
Clinically significant findings noted during screening will be reflected on the medical 
history CRF, while those noted during study treatment will be collected on the AE CRFs.   
7.2.3 
Eye Examination (Only for Cohorts 9 and 10) 
Patients with recent ocular complaints (within ≤ 3 months of screening) must have a 
complete eye examination at Screening Visit performed by a qualified ophthalmologist or 
optometrist, including but not limited to: uncorrected, corrected and best corrected visual 
acuity, slit lamp, tonometry examination, and dilated fundus examination.  Prior 
ophthalmologic exam done within 3 months of screening is acceptable provided there are 
no new symptoms since that exam.  End of Treatment Visit slit lamp examinations are 
required for all patients who experience corneal adverse events during the study and must 
be performed ≥ 28 days from last dose of enfortumab.  Additional eye examinations are 
to be conducted as clinically indicated. 
7.2.4 
Laboratory Safety Assessments 
Laboratory safety assessments for which data will be collected in this study will include 
hematology, coagulation, thyroid tests, urinalysis and chemistry parameters presented in 
Table 11. 
Laboratory tests will be drawn at the time points described in the Schedule of 
Assessments (Table 1 and Table 3) 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.  Performance of an additional urinalysis prior to study-
related collection of fresh tumor tissue from lesions involving the genitourinary tract is 
discussed in Section 7.3.4.   


 
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Table 11: 
Laboratory Safety Parameters 
Hematology Panel 
Blood Chemistry Panel 
Hemoglobin 
Aspartate aminotransferase (AST) 
Platelet count 
Alanine aminotransferase (ALT) 
White blood cell count (WBC) 
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 
Coagulation 
Sodium 
International normalized ratio (INR) 
Potassium 
Partial thromboplastin time (PTT) 
Chloride 
 
Bicarbonate or [CO2] 
Urinalysis (dip stick) 
Blood urea nitrogen (BUN) 
Blood 
Creatinine 
Protein 
Albumin 
 
Total Calcium 
Thyroid Function Test 
Magnesium 
Thyroid-stimulating hormone (TSH) 
Uric acid 
 
Glucose (only for Cohorts 9 and 10) 
 
Pregnancy Testing: For patients of childbearing potential, a serum or urine pregnancy test 
will be performed by the local laboratory at screening.  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.   
7.2.5 
Electrocardiogram (ECG)  
Single and triplicate ECGs are to be performed as outlined in the Schedule of 
Assessments (Table 1, Table 2, Table 3, and Table 4).  It is preferable that the machine 
used has a capacity to calculate the standard intervals automatically.  In addition, QTc 
will be manually calculated using the Fridericia’s formula.  Assessments reported by 
automated read as prolongation of QTc should be over-read by a cardiologist to ensure 
accuracy of interpretation. 


 
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7.2.6 
Echocardiogram (ECHO) 
Echocardiograms will be performed at screening, and thereafter as in the Schedule of 
Assessments (Table 1 and Table 3).  Additional assessments of LVEF may be performed 
as clinically indicated at the Investigator’s discretion if there are signs or symptoms of 
cardiotoxicity. 
7.3 
Laboratory Studies 
Full details on sample collection, processing, storage and shipment are presented in the 
Study Laboratory Manual. 
7.3.1 
Pharmacokinetic Evaluation 
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 and Table 4.  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.  Full details on sample collection, processing, storage and shipment will be 
provided in the Study Laboratory Manual. 
7.3.2 
Pharmacodynamic Evaluation in Blood 
Pharmacodynamic parameters that may be investigated in this study include but are not 
limited to plasma levels of circulating PD-L1, flow cytometry assessment for NK-cells, 
Tregs, macrophages, MDSCs, TCR sequencing, T- and B-cells including CD4, CD8 and 
Ki67+ cells and selected cytokines including CD8A, GZMB, IFNγ, CXCL9, CXCL10, 
CXCL11, and TBX21, prior to and during treatment.  Full details on sample collection, 
processing, storage and shipment will be provided in the Study Laboratory Manual.  
7.3.3 
Circulating Tumor DNA 
Blood samples for ctDNA analysis will be collected at baseline/screening, at 
confirmation of response of PR or CR, and at the End of Treatment visit, as outlined in 
Table 1 and Table 3.  At each ctDNA time point, blood samples will be collected into two 
10 mL Streck brand Cell-Free DNA Blood Collection tubes allowing shipping and 
stability at ambient temperatures.  Full details on sample collection, processing, storage 
and shipment will be provided in the Study Laboratory Manual.   


 
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7.3.4 
Pharmacodynamic Evaluation in Tumor Tissue 
Pharmacodynamic parameters in tumor tissue that may be investigated in this study 
include but are not limited to PD-L1 expression, CD8+ TILs, NK-cells, Tregs, 
macrophages, and MDSCs, prior to and during treatment.  Gene expression signatures 
and mutational assessment may also be measured.  Full details on sample collection, 
processing, storage and shipment will be provided in the Study Laboratory Manual. 
Freshly biopsied tumor tissue collections at pre-treatment and on-treatment timepoints for 
analysis of PD-L1 expression, other immune cell populations 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.  Prior to any study-related 
biopsy involving tumors in the genitourinary tract, a urinalysis should be performed.  If 
the results are consistent with a urinary tract infection, tumor lesions in other anatomical 
sites should be selected, if present.  Archival samples may be submitted as pre-treatment 
samples if more recent tumor specimens or fresh biopsies cannot be obtained.  An on-
treatment tumor biopsy on Cycle 2 Day 15 is desirable for all treated patients and is not 
dependent on the type of pre-treatment tumor tissue submitted (i.e., archival or freshly 
collected biopsy). 
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 Case Report Form (CRF) include the type of assay employed and percent 
tumor and/or immune cell staining. 
Tumor gene expression in freshly biopsied tumor samples will be determined using next 
generation sequencing performed by a central laboratory.  For patients in whom tumor 
tissue has previously been tested using next generation sequencing, presence of specific 
tumor gene mutations and estimation of total mutation burden will be collected in the 
CRF. 
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 (i.e., > 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. 
7.4 
Post-treatment Follow-up 
Survival status and subsequent therapies will be collected during long term follow-up as 
outlined in the Schedule of Assessments (Table 1 and Table 3) until death or lost to 
follow-up.  Beyond 28 days after last treatment, follow-up may be performed by 


 
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telephone contact.  Treatments received following participation in the study will be 
collected in the CRF. 
 
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 adverse event (AE) is any reaction, side effect or other undesirable medical event that 
occurs during participation in a clinical trial, regardless of treatment group or suspected 
causal relationship to study treatment.  Assessment of adverse events 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 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; 


 
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• 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 (i.e., 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 (e.g., cholelithiasis and bile duct obstruction with distended gallbladder) or an 
agent other than study treatment(s). 
Cases meeting Hy’s Law should be reported as SAEs.  Study treatments (sitravatinib, 
nivolumab, or sitravatinib, pembrolizumab and enfortumab) should be permanently 
discontinued for a Hy’s Law case.   
8.2.2 
Severity Assessment 
AEs occurring during this study will be graded in accordance with the National Cancer 
Institute Common Terminology Criteria for Adverse Events (CTCAE, Version 5.0).  
Documentation of AE grading in the source documents and CRF should be consistent 
with provided definitions. 


 
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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 (e.g., 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; 
− Development of drug dependency or drug abuse. 


 
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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; i.e., 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 (e.g., 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, 
e.g., 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 adverse event that is 
associated with drug exposure and is consistent with an immune-mediated mechanism of 
action and where there is no clear alternate 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 irAE. 
8.3.2 
Exposure During Pregnancy 
Exposure during pregnancy (i.e., 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 (e.g., 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 prior to or around the time of 
conception or during the pregnancy of his partner. 
If exposure in-utero 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 (e.g., 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 (i.e., 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 (i.e., 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 


 
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study drug.  These SAEs should be followed until resolved or stabilized to a chronic 
condition.  
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.   
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. 
9.1 
Hypothesis and Sample Size 
This Phase 2 study will use Predictive Probability Designs (Lee-2008) for initial Cohorts 
1 and 2.  The design, hypothesis and sample size considerations for the initial Cohorts 1 
and 2 are described below.  Refer to Appendix 5, Appendix 6, Appendix 8 and Appendix 
9 for study design and statistical considerations applicable to all contingent Cohorts 3 
through 10.  In summary, Cohorts 3 and 4 will also use Predictive Probability Designs 
with the same assumptions as the initial cohorts (Appendix 5), Cohorts 5 and 6 will use 
Predictive Probability Designs with revised assumptions (Appendix 6), Cohorts 7 and 8 


 
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will use confidence interval method with the revised assumptions (Appendix 8), the lead-
in dose escalation portion of Cohort 9 will use the mTPI-2 design (Guo-2017; Appendix 
9), and the dose expansion portion of Cohort 9 and Cohort 10 will use Simon 2-stage 
optimal designs (Simon-1989; Appendix 9). 
In creating the statistical designs for initial Cohorts 1 and 2, the Type 1 error (α) is 
constrained to <0.05 and Power (1-β) is constrained to ≥0.90.   
ORR in accordance with RECIST v1.1 is the primary endpoint.  The ORR using 
nivolumab in the population of advanced/metastatic urothelial carcinoma who 
experienced disease progression on or after treatment with a checkpoint inhibitor is 
assumed to be 5% (p0); thus this rate is considered uninteresting.  The target ORR using 
sitravatinib in combination with nivolumab in this study population is 30% (p1).  Stage 1 
of enrollment will include a minimum of 9 evaluable patients in each cohort.  Patients 
included in the evaluable population will have at least one on-study disease assessment 
prior to discontinuation; patients who discontinue treatment due to adverse events or 
withdrawal of consent prior to the first on-study disease assessment will not be included 
in the evaluable population.  With exactly 9 evaluable patients at Stage 1, if at least 1 
patient has an Objective Response, 8 additional evaluable patients will be enrolled in the 
treatment cohort, for a total sample size of 17 evaluable patients.  If at least 3 Objective 
Responses are observed in a treatment cohort, further investigation may be warranted.  If 
the true ORR is 5% (null hypothesis), the probability of early termination during the 
study is 0.63; the Type 1 error is equal to 0.0466 and the power is equal to 0.9045.   
The exact stopping rules for each cohort will be calculated based on the Predictive 
Probability Design, once the exact number of patients evaluable at Stage 1 is known.  The 
aim is to include a minimum of 9 evaluable patients at Stage 1.  If Stage 2 results in a 
cohort are of high interest for efficacy (in terms of examining the risk benefit ratio and 
not only in terms of ORR), enrollment may be expanded to as many as 40 patients total in 
that cohort to narrow the 95% CI around the ORR point estimate and to further 
characterize the durability of disease control.   
Table 12 presents estimates of the 95% CI around the observed ORR for several potential 
outcomes using the sample size of 40 patients, and the Clopper-Pearson method. 


 
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Table 12: 
Estimates of 95% CI Using Clopper-Pearson in After 
Enrollment of 40 Patients 
Number of  
Observed Responses  
Among 40 Patients 
ORR 
95% CI 
10 
25% 
12.7-41.2% 
12 
30% 
16.6-46.5% 
14 
35% 
20.6-51.7% 
16 
40% 
24.9-56.7% 
20 
50% 
33.8-66.2% 
 
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 
Full Analysis Population 
The full analysis population (FAP) is defined as all patients who receive one dose of all 
study treatments (i.e. at least one dose of both sitravatinib and nivolumab for Cohorts 1 
through 8, or at least one dose each of sitravatinib, pembrolizumab and enfortumab for 
Cohorts 9 and 10). 
The primary efficacy analyses of the primary and secondary efficacy endpoints will be 
performed in the FAP for all cohorts.  In addition, the FAP population will be used 1) in 
making decisions to expand the study to the third stage of enrollment for Cohorts 1 
through 4, and 2) for the interim futility analysis for Cohorts 7 and 8. 
9.3.2 
Clinical Activity Evaluable Population 
The clinical activity evaluable population will include patients who receive at least one 
dose of both sitravatinib and nivolumab and have at least one on-study disease 
assessment prior to discontinuation.  Patients who discontinue treatment due to adverse 


 
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events or withdrawal of consent prior to the first on-study disease assessment will not be 
included in the evaluable population.   
This population will be used to summarize tumor responses as well as to make decisions 
throughout the first two stages of the study on the Predictive Probability Design for 
Cohorts 1 through 6, and on the Simon 2-stage optimal design for Cohorts 9 (dose 
expansion portion) and 10. 
9.3.3 
Safety Population 
The Safety population is defined as all patients who received at least 1 dose of any study 
treatment (sitravatinib, nivolumab, pembrolizumab or enfortumab).  The Safety 
population will be used for all safety analyses. 
9.3.4 
Molecular Marker Evaluable Population 
The molecular marker evaluable population will consist of all patients who receive at 
least one dose of any study treatment (sitravatinib, nivolumab, pembrolizumab or 
enfortumab) and for whom PD-L1 expression or circulating PD-L1 results are available. 
9.3.5 
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 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. 
9.3.6 
Pharmacodynamic Evaluable Population 
The pharmacodynamic evaluable population will consist of all patients who receive at 
least one dose of any study treatment (sitravatinib, nivolumab, pembrolizumab or 
enfortumab) and for whom PD results are available. 
9.3.7 
DLT Evaluable Population (only applicable to lead-in dose 
escalation portion of Cohort 9) 
The DLT evaluable population is defined as patients enrolled in the lead-in dose 
escalation portion of Cohort 9, who experienced a DLT or who cleared the DLT period 
(defined in Appendix 9).  Patients who received prohibited therapy during Cycle 1 (refer 
to Section 5.7.2), or who did not take at least 80% of the planned dose of sitravatinib, and 
1 planned dose of pembrolizumab and 2 planned doses of enfortumab in Cycle 1 will be 
ineligible for DLT evaluation and will be replaced unless they experience a DLT event. 
The DLT evaluable population will be used for dose escalation decisions during the 
lead-in dose escalation evaluation. 


 
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9.4 
Efficacy Endpoint Definitions and Analyses 
9.4.1 
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 Complete Response (CR) or Partial Response (PR).   
Descriptive statistics (frequency and percentage) for ORR, CR, and PR will be presented.  
The exact 95% CI of these response rates will be calculated.  An exact test for single 
proportion (two-sided α = 5%) will be performed to test H0: ORR ≤ 5% against H1: 
ORR > 5%.  Other details will be described in the SAP. 
9.4.2 
Clinical Benefit Rate 
Clinical Benefit Rate (CBR) is defined as the percent of patients documented to have a 
confirmed Complete Response (CR), Partial Response (PR), or Stable Disease (SD) 
documented during at least 1 on-study assessments.   
9.4.3 
Duration of Response 
Duration of Response (DOR) 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 with an 
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.   
9.4.4 
Progression-Free Survival 
Progression-free survival (PFS) is defined as the time from date of first study treatment 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.  For 
patients in whom two or more sequential assessments are missed, followed by the finding 
of tumor progression, the PFS endpoint will be censored on the date of the last tumor 
assessment before the gap.  Patients lacking an evaluation of disease after first study 
treatment will have their PFS time censored on the date of first dose 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 will be used to obtain the estimate of median 
progression-free survival time.   


 
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9.4.5 
Overall Survival 
Time to death is defined as the time from date of first study treatment to death due to any 
cause.  The Kaplan-Meier method will be used to estimate the median OS and 1-year 
Survival Rate; the 95% CI of the 1-year survival rate will also be reported.  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.   
9.4.6 
Subgroup Analyses 
Baseline characteristics to be evaluated in subgroup analyses include most recent tumor 
PD-L1 expression test result indicating high versus low expression and, for cohorts that 
have prior PD-(L)1 checkpoint inhibitor therapy experience (i.e. Cohorts 1 through 4, and 
Cohorts 7 through 9) outcome of prior treatment with checkpoint inhibitor therapy, 
specifically prior clinical benefit versus no prior clinical benefit, defined as:  
• Prior clinical benefit (PCB): RECIST-defined partial or complete response or stable 
disease for at least 12 weeks (-2 week window permitted for radiograph scheduling) 
followed by radiographic progression of disease.  
• No prior clinical benefit (NPCB): does not meet criteria for PCB and has 
radiographic progression of disease ≤ 12 weeks after initiation of treatment 
(+2 week window permitted for radiograph scheduling).   
Efficacy analyses will be presented descriptively per each subgroup listed above, for each 
cohort, as well as for all cohorts combined if deemed appropriate.  
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 will be 
summarized by maximum intensity and relationship to study therapy.  Separate 
summaries will be provided for TEAEs, TESAEs, treatment-related AEs, 
treatment-related SAEs, and other significant AEs (e.g., 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.   


 
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9.5.3 
Clinical and Laboratory Assessments 
Clinical and laboratory assessments include clinical laboratory tests (hematology, 
coagulation, urinalysis, thyroid function tests and chemistry), vital signs, ECHO 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. 
ECG assessments will be evaluated for change of QTc from baseline as an exposure: 
response analysis.  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 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 enrolling in the study: 
• Demographics 
• Baseline disease characteristics 
• Pre-existing conditions/concurrent illness 
• Prior therapies/surgeries 
A summary of patient enrollment and disposition will include reasons for study 
discontinuation. 
9.5.5 
Analysis of Study Treatment Dosing 
Study treatment administration will be described in terms of the total number of cycles 
administered, the median (range) of cycles administered for each agent separately and for 
the combination, dose intensity, and reasons for the deviations from planned therapy. 


 
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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 for each investigational agent.  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 investigational agent concentrations will be reported by dose level, formulation, Day 
and Cycle.  The exposure levels as well as the PK parameters of the investigational drugs 
reported in earlier studies will be compared to the current study PK exposure and 
parameters to evaluate the potential effect of the study population, concomitant 
administration of nivolumab and/or renal function on sitravatinib PK.  Details of this 
analysis will be provided in the PKAP.  Possible relationships between PK parameters, 
PD variables, safety, and clinical activity may be examined. 
9.6.2 
Pharmacodynamic and Exploratory Analyses 
No formal statistical analysis of PD or exploratory endpoints will be performed.  Data 
from each assay will be listed by dose level and Phase 2 cohort.  Possible relationships 
between correlative endpoints, PD variables, PK parameters, safety, and clinical activity 
may be examined if appropriate.   
9.7 
Interim Analysis 
No interim statistical analysis is planned during this study.  As detailed in Section 9.1, per 
the Predictive Probability Design, tumor responses in the clinical activity evaluable 
population will be reviewed and enrollment decisions will be documented. 
9.8 
Data Monitoring Committee 
No Data Monitoring Committee is planned during this study. 
 
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 


 
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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.   
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 (e.g., 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/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 
(IRB/EC/REB) 
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. 


 
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10.4 Informed Consent Form 
The ICF must contain all elements required by the Food and Drug Administration (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.   
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 
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. 


 
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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. 
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 (i.e., 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.  


 
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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. 
 
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 


 
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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 and the justification will be documented in writing by the Sponsor, as an 
Administrative Letter or amended protocol.  Protocol amendments will be provided with 
a separate document describing each change and rationale.  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 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 
(e.g., 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  
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 (i.e., Clinical Trial Application [CTA]) and ethics application 
in the Member State. 


 
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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. 
 
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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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, e.g., 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.  CALCULATION OF GLOMERULAR FILTRATION RATE AND 
RENAL IMPAIRMENT SCALE 
During this study, renal function will be evaluated using the estimated glomerular 
filtration rate (eGFR).  eGFR at study entry will be captured in the CRF to document 
patient eligibility.  For reporting purposes, eGFR will be derived within the study 
database.  The method to be used to calculate eGFR is the Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI, Levey-2009) equation.  The link to the on-line 
calculator, instructions for use and equation are presented below.  In addition, a link to 
download the app or calculator are provided. 
Severity of renal impairment will be categorized using the FDA Guidance for Industry 
dated March 2010.  The scale for renal impairment is presented below.  
Calculation of eGFR Using CKD-EPI Calculator 
Link to CKD-EPI Calculator: 
https://www.kidney.org/professionals/kdoqi/gfr_calculator 
Link to Download CKD-EPI App or Calculator: 
https://www.kidney.org/professionals/tools 
When using the CKD-EPI calculator, ensure that height and weight are entered into the 
calculator.  The result should present as mL/min rather than mL/min/1.73 m2.  Below are 
instructions on patient data entry. 
Enter the following data (it is not necessary to enter data for cystatin C): 
• serum creatinine (standardized mg/dl or μmol/L, traceable to IDMS); 
• age; 
• gender; 
• race; 
• standard assays – yes; 
• remove body surface adjustment – yes; 
• height; 
• weight. 
 
 


 
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The following is the CKD-EPI equation used to calculate eGFR standardized to body 
surface area 1.73 m2, without consideration of height or weight. 
 
𝑒𝐺𝐹𝑅= 141 × min (𝑆𝑐𝑟
κ , 1)
𝛼
× max (𝑆𝑐𝑟
κ , 1)
−1.209
× (0.993)𝐴𝑔𝑒  
× 1.018 [𝑖𝑓 𝑓𝑒𝑚𝑎𝑙𝑒] × 1.159[𝑖𝑓 𝑏𝑙𝑎𝑐𝑘] 
 
Abbreviations / Units 
eGFR (estimated glomerular filtration rate) = mL/min/1.73m2 
SCr (standardized serum creatinine) = mg/dL 
κ = 0.7 (females) or 0.9 (males) 
α = -0.329 (females) or -0.411 (males) 
min = indicates the minimum of SCr/κ or 1 
max = indicates the maximum of SCr/κ or 1 
age = years 
Classification of Renal Impairment Using FDA Guidance for Industry  
The renal impairment classification scale provided in the guidance document considers 
eGFR and Estimated Creatinine Clearance (CLcr).  It allows for the fact that equations to 
calculate eGFR are evolving.  In this study, eGFR will be calculated using the CKD-EPI 
equation with substitution of individual body surface area based on height and weight 
rather than use of the standardized value of 1.73 m2.  The following scale is a reprint 
from the FDA Guidance for Industry and will be used to group patients in the renal 
impairment substudy described in Appendix 7 and in population pharmacokinetic 
analyses. 
Classification of Renal Function Based on Estimated GFR or Estimated Creatinine Clearance 
Stage 
Description 
eGFR 
(mL/min/1.73m2) 
CLcr 
(mL/min) 
1 
Control (Normal) GFR 
≥ 90 
≥ 90 
2 
Mild Decrease in GFR 
60-89 
60-89 
3 
Moderate Decrease in 
GFR 
30-59 
30-59 
4 
Severe Decrease in 
GFR 
15-29 
15-29 
5 
End Stage Renal 
Disease  
<15 not on dialysis or requiring 
dialysis 
<15 not on dialysis or requiring 
dialysis 
 


 
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APPENDIX 3.  MEDICATIONS OR SUBSTANCES TO BE AVOIDED OR 
USED WITH CAUTION DURING TREATMENT WITH 
SITRAVATINIB 
Examples of Drugs with a Known Risk of Torsades de Pointes* 
Generic Name 
Brand Names (Partial List) 
Drug Class 
Therapeutic Use 
Aclarubicin (Only 
on Non US Market) 
Aclacin, Aclacinomycine, 
Aclacinon, Aclaplastin, 
Jaclacin 
Anti-cancer 
Cancer 
Amiodarone 
Cordarone, Pacerone, 
Nexterone 
Antiarrhythmic 
Arrhythmia 
Anagrelide 
Agrylin, Xagrid 
Phosphodiesterase 3 
inhibitor 
Thrombocythemia 
Arsenic trioxide 
Trisenox 
Anti-cancer 
Cancer (leukemia) 
Astemizole 
(Removed from US 
Market) 
Hismanal 
Antihistamine 
Allergic rhinitis 
Azithromycin 
Zithromax, Zmax 
Antibiotic 
Bacterial infection 
Bepridil 
Vascor 
Antianginal 
Angina Pectoris (heart 
pain) 
Cesium Chloride 
Energy Catalyst 
Toxin 
Alternative therapy 
cancer 
Chloroquine 
Aralen 
Antimalarial 
Malaria 
Chlorpromazine 
Thorazine, Largactil, 
Megaphen 
Antipsychotic / 
Antiemetic 
Nausea, schizophrenia, 
many others 
Chlorprothixene 
(Only on Non US 
Market) 
Truxal 
Antipsychotic 
Schizophrenia 
Cilostazol 
Pletal 
Phosphodiesterase 3 
inhibitor 
Intermittent 
claudication 
Ciprofloxacin 
Cipro, Cipro-XR, Neofloxin 
Antibiotic 
Bacterial infection 
Cisapride (Removed 
from US Market) 
Propulsid 
GI stimulant 
Increase GI motility 
Citalopram 
Celexa, Cipramil 
Antidepressant, 
SSRI 
Depression 
Clarithromycin 
Biaxin, Prevpac 
Antibiotic 
Bacterial infection 
Cocaine 
Cocaine 
Local anesthetic 
Anesthesia (topical) 
Disopyramide 
Norpace 
Antiarrhythmic 
Arrhythmia 
Dofetilide 
Tikosyn 
Antiarrhythmic 
Arrhythmia 


 
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Generic Name 
Brand Names (Partial List) 
Drug Class 
Therapeutic Use 
Domperidone (Only 
on Non US Market) 
Motilium, Motillium, 
Motinorm Costi, Nomit 
Antiemetic 
Nausea, vomiting 
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 


 
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Generic Name 
Brand Names (Partial List) 
Drug Class 
Therapeutic Use 
Hydroxychloroquine 
Plaquenil, Quineprox 
Antimalarial, Anti- 
inflammatory 
Malaria, SLE, 
rheumatoid arthritis 
Ibogaine (Only on 
Non US Market) 
Psychedelic 
Narcotic addiction, 
unproven 
Ibutilide 
Corvert 
Antiarrhythmic 
Arrhythmia 
Levofloxacin 
Levaquin, Tavanic 
Antibiotic 
Bacterial infection 
Levomepromazine 
(Methotrimeprazine) 
(Only on Non US 
Market) 
Nosinan, Nozinan, Levoprome 
Antipsychotic 
Schizophrenia 
Levomethadyl 
acetate (Removed 
from US Market) 
Orlaam 
Opioid agonist 
Narcotic dependence 
Levosulpiride (Only 
on Non US Market) 
Lesuride, Levazeo, Enliva 
Antipsychotic 
Schizophrenia 
Mesoridazine 
(Removed from US 
Market) 
Serentil 
Antipsychotic 
Schizophrenia 
Methadone 
Dolophine, Symoron, 
Amidone, Methadose, 
Physeptone, Heptadon 
Opioid agonist 
Narcotic dependence, 
pain 
Moxifloxacin 
Avelox, Avalox, Avelon 
Antibiotic 
Bacterial infection 
Nifekalant (Only on 
Non US Market) 
Shinbit 
Antiarrhythmic 
Arrhythmia 
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) 
* 
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. 


 
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Examples of Drugs with Conditional Risk of Torsades de Pointes* 
Generic Name 
Brand Names (Partial List) 
Drug Class 
Therapeutic Use 
Abiraterone 
Zytiga, Abiratas, Abretone, 
Abirapro 
Anti-androgen 
Cancer (Prostate) 
Amantadine 
Symmetrel, Symadine 
Antiviral 
Viral infection 
(Influenza), 
Parkinson's disease 
Amisulpride 
Barhemsys, Solian, Supitac, 
Soltus, Amitrex, Amazeo 
Antiemetic, 
Antipsychotic 
Nausea and vomiting, 
postoperative 
Amitriptyline 
Elavil (Discontinued 6/13), 
Tryptomer, Tryptizol, Laroxyl, 
Saroten, Sarotex Lentizol, 
Endep 
Antidepressant, 
Tricyclic 
Depression 
Amphotericin B 
Fungilin, Fungizone, Abelcet, 
AmBisome, Fungisome, 
Amphocil, Amphotec 
Antifungal 
Fungal infection 
Amsacrine 
(Acridinyl anisidide) 
(Only on Non US 
Market) 
Amsidine 
Antineoplastic 
Agent 
Cancer (Acute 
Lymphoblastic 
Leukemia) 
Atazanavir 
Reyataz, Evotaz 
Antiviral 
Viral infection 
(HIV/AIDS) 
Bendroflumethiazide 
(Bendrofluazide) 
Aprinox, Corzide 
Diuretic, thiazide 
Hypertension, diuresis 
Chloral hydrate 
Aquachloral, Novo-
Chlorhydrate, Somnos, Noctec, 
Somnote 
Sedative 
Sedation, insomnia 
Cimetidine 
Tagamet 
Antacid 
Gastric hyperacidity, 
GERD 
Clomipramine 
Anafranil 
Antidepressant, 
Tricyclic 
Depression 
Diphenhydramine 
Benadryl, Nytol, Unisom, 
Sominex, Dimedrol, Daedalon, 
Banophen 
Antihistamine 
Allergic rhinitis, 
insomnia 
Doxepin 
Sinequan, Silenor, Aponal, 
Adapine, Doxal, Deptran, 
Sinquan 
Antidepressant, 
Tricyclic 
Depression 
Eperisone (Only on 
Non US Market) 
Myonal, Epry 
Antispasmodic 
Spasticity 
Esomeprazole 
Nexium, Nexum, Inexium 
Proton Pump 
Inhibitor 
Gastric hyperacidity, 
GERD 
Famotidine 
Pepcid, Fluxid, Quamatel 
H2-receptor 
antagonist 
Gastric hyperacidity, 
GERD 


 
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Generic Name 
Brand Names (Partial List) 
Drug Class 
Therapeutic Use 
Fluoxetine 
Prozac, Sarafem, Fontex 
Antidepressant, 
SSRI 
Depression 
Fluvoxamine 
Faverin, Fevarin, Floxyfral, 
Dumyrox, Luvox 
Selective Serotonin 
Reuptake Inhibitor 
Depression, Obsessive 
Compulsive Disorder 
Furosemide 
(frusemide) 
Lasix, Fusid, Frumex, Lasilix 
Diuretic 
Hypertension, diuresis 
Galantamine 
Reminyl, Nivalin, Razadyne-
ER, Lycoremine 
Cholinesterase 
inhibitor 
Dementia (Alzheimer's 
Disease) 
Garenoxacin (Only 
on Non US Market) 
Geninax 
Antibiotic 
Bacterial infection 
Hydrochlorothiazide 
Apo-Hydro, Aquazide H, BP 
Zide, Dichlotride, Hydrodiuril, 
HydroSaluric, Microzide, 
Esidrex, Oretic 
Diuretic 
Hypertension, diuresis 
Hydroxyzine 
Atarax, Vistaril, Aterax, 
Alamon, Durrax, Equipose, 
Masmoran, Orgatrax, Paxistil 
Quiess, Tran-Q, Tranquizine 
Antihistamine 
Allergic reaction, 
anxiety disorders 
Indapamide 
Lozol, Natrilix, Insig 
Diuretic 
Hypertension, diuresis 
Itraconazole 
Sporanox, Onmel 
Antifungal 
Fungal infection 
Ivabradine 
Procoralan, Coralan, Corlentor, 
Coraxan, Ivabid, Bradia 
Antianginal 
Angina Pectoris (heart 
pain) 
Ketoconazole 
Nizoral, Sebizole, Ketomed, 
Keton 
Antifungal 
Fungal infection 
Lansoprazole 
Prevacid, Ogast 
Proton Pump 
Inhibitor 
Gastric hyperacidity, 
GERD 
Loperamide 
Imodium 
Opioid agonist 
Diarrhea 
Metoclopramide 
Reglan, Afipran, Maxolon, 
Cerucal, Clopamon, Clopra, 
Maxeran, Maxolon, 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 


 
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Generic Name 
Brand Names (Partial List) 
Drug Class 
Therapeutic Use 
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/Tazobac
tam 
Tazosyn, Zosyn 
Antibiotic 
Bacterial infection 
Posaconazole 
Noxafil, Posamol 
Antifungal 
Fungal infection 
Propafenone 
Rythmol SR, Rytmonorm 
Sodium channel 
blocker 
Arrhythmia 
Quetiapine 
Seroquel 
Antipsychotic, 
atypical 
Schizophrenia 
Quinine sulfate 
Qualaquin, Hexaquine 
Antimalarial 
Malaria, leg cramps 
Ranolazine 
Ranexa, Ranozex 
Antianginal 
Angina Pectoris (heart 
pain) 
Risperidone 
Risperdal 
Antipsychotic, 
atypical 
Schizophrenia 
Sertraline 
Zoloft, Lustral 
Antidepressant, 
SSRI 
Depression 
Solifenacin 
Vesicare 
Muscle relaxant 
Bladder spasm 
Telaprevir 
Incivo, Incivek 
Antiviral 
Viral infection 
(hepatitis C) 
Torsemide 
(Torasemide) 
Demadex, Diuver, Examide 
Diuretic 
Hypertension, diuresis 
Trazodone 
Desyrel, Oleptro, Beneficat, 
Deprax, Desirel, Molipaxin, 
Thombran, Trazorel, 
Trialodine, Trittico, Mesyrel 
Antidepressant, 
SARI 
Depression, insomnia 
Voriconazole 
VFend 
Antifungal 
Fungal infection 
Ziprasidone 
Geodon, Zeldox 
Antipsychotic, 
atypical 
Schizophrenia 
* 
Woosley RL, Heise CW, Gallo T, Tate J, Woosley D and Romero KA, www.CredibleMeds.org, 
QTdrugs List, [Accession Date: 10 April 2020], AZCERT, Inc. 1822 Innovation Park Dr., Oro Valley, 
AZ 85755; for the most current information, access the website: www.CredibleMeds.org. 


 
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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 
 
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 4.  ABBREVIATED PRESENTATION OF RECIST VERSION 1.1 
GUIDELINES  
A modification to RECIST 1.1 has been made to account for the possibility of temporary 
changes resulting from the potentially beneficial treatment responses of tumor necrosis, 
cavitation or flare response.   
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.   


 
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• 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 treatment.  If the baseline 
assessment is inadequate, subsequent statuses generally should be indeterminate.   
The determination of whether lesions are measurable is performed only at baseline.  
“Measurable” at baseline means eligible for selection as target lesions, and thus for 
quantitative assessment throughout the trial.  Once selected as a target lesion, a lesion 
remains target throughout the trial. 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ, 5 lesions in total, 
representative of all involved organs, should be identified as target lesions at baseline.  
Target lesions should be selected on the basis of size (longest lesions) and suitability for 
accurate repeated measurements.  Record the longest diameter for each lesion, except in 
the case of pathological lymph nodes for which the short axis should be recorded.  The 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions at baseline will be the basis for comparison to look for partial response at 
later assessments.   
• If 2 target lesions coalesce the longest diameter measurement of the coalesced 
mass is used.  If a large target lesion splits, the sum of the parts is used. 
• Measurements for target lesions that become small should continue to be 
recorded.  If a target lesion becomes too small to measure, 0 mm should be 
recorded if the lesion is considered to have disappeared; otherwise a default value 
of 5 mm should be recorded. 
• When nodal lesions decrease to <10 mm (normal), the actual measurement should 
still be recorded. 
Non-Target Lesions 
All non-measurable disease is non-target.  All measurable lesions not identified as target 
lesions are also included as non-target disease.  Measurements are not required but rather 
qualitative evaluations of status will be recorded.  Multiple non-target lesions in one 
organ may be recorded as a single item on the CRF (e.g., ‘multiple liver metastases’). 
Objective Response Status at Each Evaluation 


 
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Disease sites must be assessed using the same technique as baseline, including consistent 
administration of contrast.  If not, subsequent objective statuses may be indeterminate.   
Target Disease 
• Complete Response (CR): Complete disappearance of all target lesions with the 
exception of nodal disease.  All target nodes must decrease to normal size (short 
axis < 10 mm).  All target lesions must be assessed. 
• Partial Response (PR): Greater than or equal to 30% decrease under baseline of 
the sum of diameters of all target measurable lesions.  The short diameter is used 
in the sum for target nodes, while the longest diameter is used in the sum for all 
other target lesions.  All target lesions must be assessed.   
• Stable Disease (SD): Does not qualify for CR, PR or Progression.  All target 
lesions must be assessed.  Stable can follow PR only in the rare case that the sum 
increases by less than 20% from the nadir, but enough that a previously 
documented 30% decrease no longer holds.   
• Progressive Disease (PD): 20% increase in the sum of diameters of target 
measurable lesions above the smallest sum observed (over baseline if no decrease 
in the sum is observed during therapy) with a minimum absolute increase of 
5 mm.   
• Indeterminate: Progression has not been documented, and  
− 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.   


 
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• 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.   
• Indeterminate: Progression has not been determined and 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. 
Lesion Changes That May Be Transient 
Potential exists for individual tumor lesions to develop necrosis, to cavitate, have a flare 
response to treatment or become otherwise difficult to evaluate for a period of time as the 
result of beneficial study treatment impact.  For example, tumor necrosis, cavitation or 
flare may result in increase in overall size of individual lesions or unclear tumor margins 
prior to recovery to smaller lesions, development of scar tissue, or complete resolution.  
The true tumor measurements of lesions should be recorded but the conclusion of 
progressive disease may be suspended until continued assessment clarifies the nature of 
the tumor change.  If repeat assessments indicate progression of disease, then PD should 
be recorded on the date of the first assessment giving the impression of progression.  If 
repeat assessments indicate that the change was a process of transition, then NE (not 
evaluable) should be recorded during the period of transition, and PR or CR may be 
recorded for subsequent evaluations.  The CRF will collect information on the 
observations during the period of transition to support the assessment conclusions.   
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. 


 
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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.  CONTINGENT STUDY COHORTS IN PATIENTS PREVIOUSLY 
RECEIVING TREATMENT WITH SELECTED 
IMMUNOTHERAPIES  
In the event that results in of the initial study cohorts are of high interest for efficacy, one 
or more cohorts in patients with documented disease progression on or after a PD-(L)1 
checkpoint inhibitor therapy as the most recent treatment, and who previously received 
(in combination or separately) treatment with selected immunotherapies, including but 
not limited to anti-CTLA-4, anti-OX40 or anti–CD137 therapy, may be added to the 
study.  Decisions for implementation of additional cohorts in the study will be made in 
collaboration with the Investigators and documented for Regulators and Institutional 
Review Boards by an Administrative Letter to Investigators. 
Based on the evolving treatment landscape of urothelial carcinoma including regimens 
combining selected immunotherapies with checkpoint inhibitors, and in consult with 
Investigators, both Cohort 3 and Cohort 4 described in this appendix were implemented 
by an Administrative Letter dated January 2019. 
The following lists sections of the main protocol and describes any changes to be 
implemented in cohorts of patients that have received selected immunotherapies and 
checkpoint inhibitor therapy. 
Study Objectives – See main protocol. 
Study Endpoints – See main protocol. 
Study Design – Unchanged with the exception of the description of the populations to be 
enrolled into new cohorts.  The population will be stratified into 2 cohorts:  
• Cohort 3: Patients with documented disease progression on or after a previous 
anti-PD-(L)1 as most recent treatment, who previously received (in combination 
or separately) other selected immunotherapies, and who were previously treated 
with a platinum-based chemotherapy. 
• Cohort 4: Patients with documented disease progression on or after a previous 
anti-PD-(L)1 as most recent treatment, who previously received (in combination 
or separately) other selected immunotherapies, and considered ineligible for 
platinum-based chemotherapy.  
Enrollment Criteria – See main protocol (inclusion and exclusion criteria changes 
specific to Cohorts 3 and 4 under Appendix 5 are noted as such in Section 4.1 and 
Section 4.2). 
Study Assessments and Procedures – See main protocol. 
Statistical Design – See main protocol. 


 
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APPENDIX 6.  CONTINGENT STUDY COHORTS IN CHECKPOINT INHIBITOR 
THERAPY NAÏVE POPULATIONS  
In the event that results in the initial study cohorts are of high interest for efficacy, one or 
more cohorts in patients who have not previously received checkpoint inhibitor therapy 
(CIT-naïve) may be added to the study.  Decisions for implementation of additional 
cohorts in the study will be made in collaboration with the Investigators and documented 
for Regulators and Institutional Review Boards by an Administrative Letter to 
Investigators. 
Based on the evolving treatment landscape of urothelial carcinoma and early efficacy and 
safety results from active study cohorts, and in consult with Investigators, both Cohort 5 
and Cohort 6 described in this appendix were implemented by an Administrative Letter 
dated May 2019. 
The following lists sections of the main protocol and describes any changes to be 
implemented in cohorts of CIT-naïve patients. 
Study Objectives – See main protocol.  
Study Endpoints – See main protocol. 
Study Design – Unchanged with the exception of the description of the populations to be 
enrolled into new cohorts.  The population will be stratified into 2 cohorts: 
• Cohort 5: Patients who have not previously received an anti-PD-(L)1, and who 
were previously treated with a platinum-based chemotherapy.  
• Cohort 6: Patients who have not previously received an anti-PD-(L)1, and 
considered ineligible for platinum-based chemotherapy.  
Enrollment Criteria – See main protocol (inclusion and exclusion criteria changes 
specific to Cohorts 5 and 6 under Appendix 6 are noted as such in Section 4.1 and 
Section 4.2). 
Study Assessments and Procedures – See main protocol. 
Statistical Design – Changes to hypothesis and sample size. 
Hypothesis and Sample Size 
The ORR using nivolumab in the population of advanced/metastatic urothelial carcinoma 
who have not previously received treatment with a checkpoint inhibitor therapy is 
assumed to be 20% (p0); thus, this rate is considered uninteresting.  The target ORR using 
sitravatinib in combination with nivolumab in this study population is 40% (p1).  Stage 1 
of enrollment will include approximately 24 evaluable patients in each cohort.  Patients 


 
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included in the evaluable population will have received treatment with both sitravatinib 
and nivolumab and will have at least one on-study disease assessment prior to 
discontinuation; patients who discontinue treatment due to adverse events or withdrawal 
of consent prior to the first on-study disease assessment will not be included in the 
evaluable population.  With exactly 24 evaluable patients at Stage 1, if at least 6 patients 
have Objective Responses, enrollment of 21 additional evaluable patients is needed in the 
treatment cohort, for a total sample size of 45 evaluable patients.  If at least 14 Objective 
Responses are observed in a treatment cohort, further investigation may be warranted.  If 
the true ORR is 20% (null hypothesis), the probability of early termination during the 
study is 0.66; the Type 1 error is equal to 0.0483 and the power is equal to 0.9001.   
The exact stopping rules for both cohorts will be calculated based on the Predictive 
Probability Design, once the exact number of patients evaluable at Stage 1 is known.  The 
aim is to include approximately 24 evaluable patients at Stage 1.  The Sponsor retains the 
option to take more than one look at the data when making decisions based on the PPD 
method to expand cohorts.   


 
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APPENDIX 7.  EVALUATION OF THE PHARMACOKINETICS OF 
SITRAVATINIB IN PATIENTS WITH RENAL IMPAIRMENT 
In the event results in initial patient cohorts enrolled in this study or results emerging 
from other ongoing clinical trials of sitravatinib are of high interest for efficacy, this 
evaluation of the pharmacokinetics of sitravatinib in patients with renal impairment may 
be implemented.  These data are a necessary component in the successful development of 
a new cancer therapy.  The fact that many patients with advanced or metastatic urothelial 
carcinoma have or will develop renal impairment identifies this study as an appropriate 
situation in which to gather these data.  A subset of study sites will participate in this 
evaluation; it is optional for both study sites and individual patients.  The decision to 
implement this aspect of the study will be documented for Regulators and Institutional 
Review Boards by an Administrative Letter to Investigators. 
The evaluation of the PK of sitravatinib in patients with renal impairment was 
implemented by an Administrative Letter dated December 2018. 
With the introduction of cohorts evaluating sitravatinib in combination with 
pembrolizumab and enfortumab with protocol Version 4.0, and in an effort to control for 
confounders, the evaluation of the PK of sitravatinib in patients with renal impairment 
will only to apply to Cohorts 1 through 8 where the study treatment is sitravatinib in 
combination with nivolumab. 
The eligibility criteria for this study allow enrollment of patients having renal impairment 
categorized as mild or moderate, defined as estimated GFR 30-59 mL/min and 
60-89 mL/min, respectively, using the CKD-EPI equation (Appendix 2).  Upon 
implementation of this study appendix, the evaluation of the PK of sitravatinib in at least 
6 patients each having no renal impairment, mild renal impairment or moderate renal 
impairment at enrollment will be undertaken.  Consenting patients with no, mild or 
moderate renal impairment enrolling at selected study sites will substitute blood sample 
collection over a 24-hour period following sitravatinib dosing on Day 1 and Day 15 
(± 2 days) of treatment as described in Table 13, rather than the sparse PK sampling 
schedule described for Day 1 and Day 15 in Table 2.  All other PD biomarker and ECG 
assessments described in Table 2, as well as sparse PK sampling after Cycle 1, will be 
performed in the sub-study population.  On the days of PK sampling, patients should 
delay taking the daily sitravatinib dose until the pre-dose PK sample has been collected in 
the clinic.  PK blood samples will each collect 4 mL of blood. 


 
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Table 13: 
Substitute Day 1 and 15 Sitravatinib PK Sample Schedule 
During Renal Impairment Sub-study3 
 
Cycle 1 Day 1 and Again Cycle 1 Day 15 (± 2 days)  
Collection 
Time and 
Allowable 
Window 
Pre-dose 
(-0.5-0 
hour) 
30 min 
(± 10 min) 
2 hour  
(±15 min) 
4 hour  
(±30 min) 
6 hour  
(±30 min) 
8 hour  
(±30 min) 
24 hour  
(±2 hours) 
PK Sample1, 2 
X 
X 
X 
X 
X 
X 
X 
1  Scheduled vital signs and triplicate ECGs precede PK sample collection in all cases.  Sitravatinib 
dosing and sampling should precede nivolumab infusion. 
2  In addition to the scheduled samples, an unscheduled PK blood sample should be drawn before a daily 
sitravatinib dose (trough sample) in the event of any of the following events: 1) as soon as possible 
after an SAE, 2) at a clinic visit at least one week following a dose modification of the investigational 
agent, and 3) as soon as possible after renal function declines by one Stage as defined in Appendix 2, if 
the patient continues study treatment. 
3  See Table 2 for all other PD biomarker and ECG assessments, as well as sparse PK sampling after 
Cycle 1, that must also be performed. 
PK concentration and parameter data will be descriptively derived and displayed. A 
descriptive comparison to data collected in other patients within this study and other 
studies within the sitravatinib program will be conducted using AUC0-t, AUC(0-∞), Cmax, 
Tmax, t1/2, and steady state PK exposure parameters.  Descriptive statistics will be used to 
summarize patient characteristics, treatment administration and safety variables.  Details 
of this analysis will be provided in the PKAP. 


 
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APPENDIX 8.  CONTINGENT STUDY COHORTS IN PATIENTS PREVIOUSLY 
RECEIVING TREATMENT WITH AN ANTIBODY-DRUG 
CONJUGATE 
In the event that results in the initial study cohorts are of high interest for efficacy, one or 
more cohorts in patients with documented disease progression on or after a PD-(L)1 
checkpoint inhibitor therapy and an antibody-drug conjugate (ADC; e.g. enfortumab 
vedotin, sacituzumab govitecan), in any order or in combination together.  Decisions for 
implementation of additional cohorts in the study will be made in collaboration with the 
Investigators and documented for Regulators and Institutional Review Boards by an 
Administrative Letter to Investigators. 
Based on the evolving treatment landscape of urothelial carcinoma in particular with the 
clinical activity of ADCs, and early efficacy and safety results from active study cohorts, 
and in consult with Investigators, both Cohort 7 and Cohort 8 described in this appendix 
were implemented by an Administrative Letter dated September 2019. 
The following lists sections of the main protocol and describes any changes to be 
implemented in cohorts of patients that have received checkpoint inhibitor and ADC 
therapy. 
Study Objectives – See main protocol. 
Study Endpoints – See main protocol. 
Study Design – Unchanged with the exception of the description of the populations to be 
enrolled into new cohorts.  The population will be stratified into 2 cohorts: 
• Cohort 7: Patients with documented disease progression on or after a previous 
anti-PD-(L)1 and ADC (in combination or separately, and in any order), and who 
were previously treated with a platinum-based chemotherapy.. 
• Cohort 8: Patients with documented disease progression on or after a previous 
anti-PD-(L)1 and ADC (in combination or separately, and in any order), and 
considered ineligible for platinum-based chemotherapy.  
Enrollment Criteria – See main protocol (inclusion and exclusion criteria changes 
specific to Cohorts 7 and 8 under Appendix 8 are noted as such in Section 4.1 and 
Section 4.2). 
Study Assessments and Procedures – See main protocol. 
Statistical Design – Changes to statistical design, hypothesis and sample size. 


 
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Hypothesis and Sample Size 
The ORR using taxanes in the population of advanced/metastatic urothelial carcinoma 
who have previously received treatment with a checkpoint inhibitor therapy and ADC is 
assumed to be 10%; thus, this rate is considered uninteresting.  The design for Cohort 7 
and Cohort 8 will utilize a 95% confidence interval to exclude an ORR of 10%.  
Assuming sitravatinib in combination with nivolumab treatment will result in an ORR of 
at least 25% in this treatment setting, a sample size of approximately 55 evaluable 
patients would be sufficient for the lower bound of a 2-sided 95% confidence interval 
(Clopper-Pearson method) to exclude an ORR of 10%. 
The design will include a non-binding stopping rule for futility derived using East® 
software v6.5 to control the Type 2 error rate of 0.117.  The Type 2 error spending 
function is based on the Rho family with parameter 2.0.  The futility analysis will be 
conducted when approximately 17 evaluable patients (approximately 30% of the total 
number of patients) are available for the response assessment.  The futility bound will be 
1 or fewer observed responses among the first 17 patients. 


 
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APPENDIX 9.  CONTINGENT STUDY COHORTS EVALUATING 
SITRAVATINIB COMBINATION WITH A CHECKPOINT 
INHIBITOR AND AN ANTIBODY-DRUG CONJUGATE 
In the event that results in the initial study cohorts are of high interest for efficacy, one or 
more cohorts in patients for treatment with sitravatinib in combination with 
pembrolizumab and enfortumab may be added to the study.  Decisions for 
implementation of additional cohorts in the study will be made in collaboration with the 
Investigators and documented for Regulators and Institutional Review Boards by an 
Administrative Letter to Investigators.  
Based on the evolving treatment landscape of urothelial carcinoma in particular with the 
clinical activity of ADCs, and early efficacy and safety results from active study cohorts, 
and in consult with Investigators, Cohort 9 described in this appendix is considered 
implemented of this protocol Version 4.0.  Cohort 10 also described in this appendix is 
pending implementation. 
The following lists sections of the main protocol and describes any changes to be 
implemented in cohorts of patients that will receive treatment with sitravatinib in 
combination with pembrolizumab and enfortumab. 
Background and Rationale – See main protocol. 
Study Objectives – See main protocol. 
Study Endpoints – See main protocol. 
Study Design – Design details specific to Cohort 9 (including lead-in dose escalation and 
dose expansion portions) and Cohort 10 under Appendix 9 are described below including 
description of the populations to be enrolled into these contingent cohorts evaluating the 
triple combination of sitravatinib, pembrolizumab and enfortumab, the study design and 
dose-limiting toxicities (DLTs) as applicable. 
Initially, the lead-in dose escalation portion of Cohort 9 will evaluate sitravatinib 
administered in combination with pembrolizumab and enfortumab in patients who have 
previously received a PD-(L)1 checkpoint inhibitor and a platinum-based chemotherapy.  
If a tolerable dose is identified for sitravatinib in combination with pembrolizumab and 
enfortumab, the recommended dose regimen of sitravatinib in combination with 
pembrolizumab and enfortumab may be further evaluated in as many as 2 populations 
including in patients who have previously received a PD-(L)1 checkpoint inhibitor and a 
platinum-based chemotherapy (dose expansion portion of Cohort 9), and in patients with 
previously untreated locally advanced or metastatic urothelial cancer (Cohort 10).  
Depending on the results in previous cohorts, only one or more of Cohort 9 and Cohort 
10 may be implemented.  Description of the populations to be enrolled into Cohort 9 and 
Cohort 10 evaluating the triple combination of sitravatinib, pembrolizumab and 
enfortumab are described below. 


 
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• Cohort 9 (including lead-in dose escalation and dose expansion portions): Patients 
who have previously received a PD-(L)1 checkpoint inhibitor and a 
platinum-containing chemotherapy. 
• Cohort 10: Patients with previously untreated unresectable, locally advanced or 
metastatic urothelial cancer. 
Lead-In Dose Escalation Portion of Cohort 9 Evaluating Sitravatinib in 
Combination with Pembrolizumab and Enfortumab 
This portion of the study will begin with the lead-in dose escalation portion of Cohort 9 
of up to three dose levels of sitravatinib in combination with up to two dose levels of 
pembrolizumab and enfortumab combination regimen, in patients who have previously 
received a PD-(L)1 checkpoint inhibitor and a platinum-based chemotherapy.  
Sitravatinib starting dose levels using the malate formulation are shown in Table 14, 
whereas the starting doses for pembrolizumab and enfortumab are shown in Table 15.  
Dosing will begin at 35 mg QD of sitravatinib in combination with the recommended 
doses of pembrolizumab and enfortumab combination regimen.  This starting dose for 
sitravatinib represents three dose levels below the dose administered as a single agent and 
in combination (with nivolumab) Phase 2 and 3 trials.  Dose Level 3 in Table 14 is the 
dose used in single agent and combination Phase 2 and 3 trials.  The starting doses for 
pembrolizumab and enfortumab (labeled as Dose Level 1 in Table 15) represent the 
recommended doses from the EV-103 Phase 2 trial and the EV-302 Phase 3 trial of 
pembrolizumab and enfortumab used in combination (Rosenberg-2020; Hoimes-2019).  
It is of note that the EV-302 Phase 3 trial also uses these recommended doses of 
pembrolizumab and enfortumab in the triple combination investigation arm combining 
pembrolizumab and enfortumab with the platinum-chemotherapy agents cisplatin or 
carboplatin.  In addition, a dose de-escalation step for enfortumab may be undertaken as 
appropriate (labeled as Dose Level -1 in Table 15).  Throughout the study, 
pembrolizumab and enfortumab will be administered in accordance with approved 
labeling.  Guidance for adverse event management and associated pembrolizumab 
treatment modifications are provided in product labeling.   
Table 14: 
Sitravatinib Starting Dose Levels for Lead-In Dose Escalation 
Cohort 9 (Malate Formulation) 
Sitravatinib Dose Level 
Sitravatinib Daily Dose 
1 
35 mg PO QD 
-21 
50 mg PO QD 
2 
70 mg PO QD 
3 
100 mg PO QD 
Abbreviations: PO = orally; QD = once daily. 
1  The 50 mg dose level will be enrolled only if de-escalation is needed after assessment of the next 
higher dose level (70 mg). 


 
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Table 15: 
Pembrolizumab and Enfortumab Dose Levels 
Combination 
Regimen Dose Level 
Pembrolizumab1 
Enfortumab1 
-12 
200 mg IV Q3W 
1 mg/kg IV on days 1 and 8 of Q3W 
1 
200 mg IV Q3W 
1.25 mg/kg IV on days 1 and 8 of 
Q3W 
Abbreviations: IV = intravenous; Q3W = every 3 weeks. 
1  Pembrolizumab and enfortumab should be administered according to USPI and standard care. 
2  The 1 mg/kg dose level of enfortumab will be enrolled only if de-escalation is needed after assessment 
of the next higher dose level (1.25 mg/kg). 
Dose-Limiting Toxicities (DLTs) in Cycle 1 for the Lead-In Dose Escalation Portion 
of Cohort 9 
DLTs are only defined for patients in the lead-in dose escalation portion of Cohort 9.  
The definition of DLT for the purpose of dose escalation decisions includes any of the 
following events considered to be causally related to treatment with sitravatinib in 
combination with pembrolizumab and enfortumab that occurs from Cycle 1 Day 1 
through pre-dose Cycle 2 Day 1: 
Hematological DLTs: 
• Grade 4 neutropenia, if it lasts more than 7 days. 
• ≥ Grade 3 febrile neutropenia. 
• ≥ Grade 3 neutropenia with significant clinical sequelae. 
• Grade 4 thrombocytopenia. 
• Grade 3 thrombocytopenia associated with clinically significant bleeding. 
• Any requirement for a platelet transfusion. 
• Grade 4 anemia unexplained by underlying disease. 
Non-hematological DLTs: 
• ≥ Grade 4 infusion related reaction. 
• Grade 3 infusion related reaction that does not resolve within 24 hours. 
• Any ≥ Grade 4 non-hematological toxicity. 
• Grade 3 hypertension that cannot be controlled with medical therapy, including: 


 
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− Severe hypertension with systolic blood pressure ≥180 mmHg or diastolic 
blood pressure ≥120 mmHg, on more than one occasion. 
− Sustained uncontrolled hypertension, with systolic blood pressure 
≥160 mmHg (but <180 mmHg) or diastolic blood pressure ≥100 mmHg (but 
<120 mmHg) lasting for ≥14 days or causing treatment delay for ≥4 days. 
• Other Grade 3 non-hematologic toxicity lasting for >3 days despite optimal 
supportive care, with the following exceptions: 
− Endocrine disorder (thyroid, pituitary, and/or adrenal insufficiency) that can 
be effectively managed with hormone replacement therapy. 
− Fatigue that persists for ≤7 days. 
− Rash that resolves to Grade ≤1 within 3 weeks. 
− Tumor flare (defined as local pain, irritation, or rash localized at sites of 
known or suspected tumor). 
• Grade 2 pneumonitis or colitis that does not resolve to ≤ Grade 1 as indicated by 
symptoms within 3 days after onset of the event despite optimal medical 
management with or without corticosteroids. 
• ≥ Grade 3 non-hematological laboratory abnormalities with clinical consequences 
that do not resolve within 24 hours. 
• ALT > 3 x ULN with bilirubin > 2 x ULN. 
• Any other related toxic effect during the first 3 weeks may be assessed as a DLT 
if, upon review by the Investigators and Sponsor, it is agreed that the toxicity was 
of sufficient severity to be considered dose limiting. 
• Any toxicity that requires suspension of sitravatinib for more than 1 week. 
• A patient did not receive at least 1 dose of pembrolizumab and at least 2 doses of 
enfortumab up to and including Cycle 2 Day 1 due to tolerability issues (i.e., other 
related AEs not attributed as DLTs). 
Patients from the lead-in dose escalation portion of Cohort 9 are considered DLT 
evaluable if they experience a DLT during the first cycle of treatment or if they clear the 
DLT period.  Patients who received prohibited therapy during Cycle 1 (refer to Section 
5.7.2), or who did not take at least 80% of the planned dose of sitravatinib, the 1 planned 
dose of pembrolizumab and 2 planned doses of enfortumab in Cycle 1 will be ineligible 
for DLT evaluation and will be replaced unless they experience a DLT event.  Initially, at 
least 3 patients will be enrolled at each new dose level.  The first patient to be treated at 


 
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each new dose level will be observed for at least one week prior to enrollment of 
subsequent patients at that dose level.  Decision making for dose level expansion and 
dose escalation or de-escalation will be in accordance with the mTPI-2 method 
(Dose-Finding Spreadsheet presented in Appendix 11), and will be made in collaboration 
with the Investigators and documented for Regulators and Institutional Review Boards by 
an Administrative Letter to Investigators.  To ensure sufficient patient experience at the 
dose regimen to be used in the dose expansion portion of Cohort 9 and contingent 
Cohort 10, enrollment at any dose regimen under consideration may be expanded to 
include at least 6 patients. 
For the lead-in dose escalation evaluation, no dose reductions of any investigational 
product are allowed during Cycle 1. 
Selection of Phase 2 Dose Regimen for Sitravatinib Combination with 
Pembrolizumab and Enfortumab (for Dose Expansion Portion of Cohorts 9 and for 
Cohort 10) 
The RP2Ds identified in lead-in dose escalation portion of Cohort 9 will be selected for 
the dose expansion portion of Cohort 9 and the contingent Cohort 10.  A dose regimen 
below the MTD may be selected. 
Once RP2Ds are identified, patients from lower dose levels who continue to receive study 
treatment may be permitted to dose escalate to the recommended dose regimen. 
Dose Expansion Portion of Cohort 9 and Contingent Cohort 10 
Following completion of the lead-in dose escalation portion of Cohort 9, and in the event 
that a tolerable dose regimen is identified for sitravatinib in combination with 
pembrolizumab and enfortumab, as many as 2 cohorts will evaluate the recommended 
dose regimen of sitravatinib in combination with pembrolizumab and enfortumab in 
patients who have previously received a PD-(L)1 checkpoint inhibitor and a platinum-
based chemotherapy (dose expansion portion of Cohort 9), and in patients with 
previously untreated locally advanced or metastatic urothelial cancer (Cohort 10). 
Enrollment Criteria – See main protocol (inclusion and exclusion criteria changes 
specific to Cohorts 9 and 10 under Appendix 9 are noted as such in Section 4.1 and 
Section 4.2). 
Study Assessments and Procedures – See main protocol. 
Statistical Design – Changes to statistical design, hypothesis and sample size. 
Hypothesis and Sample Size 
Lead-In Dose Escalation Evaluation for Sitravatinib Combination with 
Pembrolizumab and Enfortumab (Cohort 9) 


 
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Up to 30 patients may be enrolled into the lead-in dose escalation portion of Cohort 9.   
The mTPI-2 design (Guo-2017) will be employed in decision making of dose escalation 
within each regimen investigated.  The mTPI-2 design is based on the following 
assumptions: 
• the maximum tolerated dose (MTD) is the dose associated with probability of 
dose limiting toxicity in 30% of patients during the first treatment cycle; and 
• the acceptable variance around the MTD is - 0.05 to + 0.03 (i.e., the region of the 
MTD is 25% to 33% incidence of dose limiting toxicity). 
Refer to Appendix 11 for the dose escalation decision table using the mTPI-2 method. 
Dose Expansion Portion of Cohort 9 and Cohort 10 
Simon 2-stage optimal designs (Simon-1989) will be used to establish stopping rules for 
futility for the dose expansion portion of Cohort 9 and for Cohort 10.  The dose 
expansion portion for Cohort 9 will also include patients from the lead-in dose escalation 
portion of Cohort 9 who had similar starting doses to the recommended starting doses for 
the sitravatinib combination with pembrolizumab and enfortumab. 
• For the dose expansion portion of Cohort 9, the null hypothesis for ORR is 45%; 
the alternative hypothesis for ORR is 70%.  The first stage of patient enrollment 
will include 15 patients evaluable for response.  If 8 or more patients achieve an 
objective response, enrollment will continue to approximately 35 patients; if at 
least 21 objective responses are observed from both stages, further investigation 
will be considered warranted.  If the true ORR is 45% (null hypothesis), the 
probability of early termination during the study is 65.4%; the Type 1 error is 
0.048, and the power is 90.0%. 
• For Cohort 10, the null hypothesis for ORR is 45%; the alternative hypothesis for 
ORR is 65%.  The first stage of patient enrollment will include 19 patients 
evaluable for response.  If 10 or more patients achieve an objective response, 
enrollment will continue to approximately 49 patients; if at least 28 objective 
responses are observed from both stages, further investigation will be considered 
warranted.  If the true ORR is 45% (null hypothesis), the probability of early 
termination during the study is 67.1%; the Type 1 error is 0.05, and the power is 
85%. 


 
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APPENDIX 10.  EXAMPLES OF PROHIBITED P-GP INHIBITORS AND 
STRONG CYP3A4 INHIBITORS DURING TREATMENT WITH 
ENFORTUMAB 
Patients must have discontinued treatment with any of the following for at least 2 weeks 
prior to the first dose date of enfortumab.  There could also be additional new drugs and 
marketed drugs that could be identified as inducers/inhibitors with continued research.  
Use of any concomitant medication known to be a P-gp inducer/inhibitor and/or a strong 
CYP3A4 inhibitor with enfortumab is not permitted. 
Strong 
CYP3A4 
Inhibitors 
Boceprevir, clarithromycin, cobicistat, conivaptan, danoprevir/ritonavir, diltiazem, 
elvitegravir/ritonavir, grapefruit juice, idelalisib, indinavir/ritonavir, itraconazole, 
ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, 
paritaprevir/ritonavir/ombitasvir plus dasabuvir, posaconazole, ritonavir, 
saquinavir/ritonavir, telaprevir, tipranavir/ritonavir, telithromycin, troleandomycin, 
voriconazole. 
P-gp 
Inhibitors 
Azithromycin, captopril, carvedilol, clarithromycin, conivaptan, cyclosporine, 
diltiazem, dronedarone, erythromycin, felodipine, itraconazole, ketoconazole, 
lopinavir, ritonavir, quercetin, quinidine, ranolazine, ticagrelor, verapamil. 
P-gp 
Inducers 
Avasimibe, carbamazepine, phenytoin, rifampin, St John’s wort, tipranavir/ritonavir. 
Note: Any additional P-gp inducers/inhibitors or strong CYP3A4 inhibitors that are identified or become 
commercially available while the clinical trial is ongoing are also prohibited. 


 
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APPENDIX 11.  DOSE DE-ESCALATION DECISION TABLE USING THE mTPI 
METHOD 
The table below will be used for decision making with regards to potential starting dose 
escalations in subsequent patients.  The assessment is based on the number of patients 
with toxicity at a given dose regimen of sitravatinib in combination with pembrolizumab 
and enfortumab in the lead-in dose escalation evaluation (Cohort 9) as defined in 
Appendix 9 and assumes a maximum toxicity level of no more than 30% at the tolerated 
dose.  The letters in different colors are computed based on the decision rules under the 
mTPI-2 method (Guo-2017) and represent different dose-finding actions which include: 
E = Escalate to next higher dose; S = Stay at the current dose; D = De-escalate to the next 
lower dose; and U = The current dose in unacceptably toxic. 
 
 
Number of Patients Treated at Current Dose 
 
 1 2 
3 
4 
5 
6 
7 
8 
9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 
Number of Toxicities 
0 E E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
1 D D 
D 
S 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
2  DU D 
D 
D 
D 
S 
S 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
3  
 DU DU D 
D 
D 
D 
D 
S 
S 
S 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
4  
 
 DU DU DU D 
D 
D 
D 
D 
D 
S 
S 
S 
S 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
5  
 
 
 DU DU DU DU DU D 
D 
D 
D 
D 
D 
S 
S 
S 
S 
S 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
6  
 
 
 
 
DU DU DU DU DU DU D 
D 
D 
D 
D 
D 
D 
S 
S 
S 
S 
S 
S 
E 
E 
E 
E 
E 
E 
7  
 
 
 
 
 DU DU DU DU DU DU DU D 
D 
D 
D 
D 
D 
D 
D 
S 
S 
S 
S 
S 
S 
S 
E 
E 
8  
 
 
 
 
 
 DU DU DU DU DU DU DU DU DU D 
D 
D 
D 
D 
D 
D 
D 
S 
S 
S 
S 
S 
S 
9  
 
 
 
 
 
 
 
DU DU DU DU DU DU DU DU DU DU DU D 
D 
D 
D 
D 
D 
D 
D 
S 
S 
S 
10  
 
 
 
 
 
 
 
 DU DU DU DU DU DU DU DU DU DU DU DU D 
D 
D 
D 
D 
D 
D 
D 
D 
11  
 
 
 
 
 
 
 
 
 DU DU DU DU DU DU DU DU DU DU DU DU DU DU D 
D 
D 
D 
D 
D 
12  
 
 
 
 
 
 
 
 
 
 
DU DU DU DU DU DU DU DU DU DU DU DU DU DU DU DU D 
D 
D 
13  
 
 
 
 
 
 
 
 
 
 
 DU DU DU DU DU DU DU DU DU DU DU DU DU DU DU DU DU D 
14  
 
 
 
 
 
 
 
 
 
 
 
 DU DU DU DU DU DU DU DU DU DU DU DU DU DU DU DU DU 
15  
 
 
 
 
 
 
 
 
 
 
 
 
 
DU DU DU DU DU DU DU DU DU DU DU DU DU DU DU DU 
16  
 
 
 
 
 
 
 
 
 
 
 
 
 
 DU DU DU DU DU DU DU DU DU DU DU DU DU DU DU 
17  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 DU DU DU DU DU DU DU DU DU DU DU DU DU DU 
18  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DU DU DU DU DU DU DU DU DU DU DU DU DU 
19   E = Escalate to the next higher dose 
 S = Stay at the current dose 
 D = De-escalate to the next lower dose 
 U = The current dose is unacceptable toxic 
 MTD = 0.30 
 Sample size = 30 
 Epsilon1 (ɛ1) = 0.05 
 Epsilon1 (ɛ2) = 0.03 
 
 DU DU DU DU DU DU DU DU DU DU DU DU 
20  
 
 
 DU DU DU DU DU DU DU DU DU DU DU 
21  
 
 
 
 
DU DU DU DU DU DU DU DU DU DU 
22  
 
 
 
 
 DU DU DU DU DU DU DU DU DU 
23  
 
 
 
 
 
 DU DU DU DU DU DU DU DU 
24  
 
 
 
 
 
 
 
DU DU DU DU DU DU DU 
25  
 
 
 
 
 
 
 
 DU DU DU DU DU DU 
26  
 
 
 
 
 
 
 
 
 DU DU DU DU DU 
27  
 
 
 
 
 
 
 
 
 
 
DU DU DU DU 
28  
 
 
 
 
 
 
 
 
 
 
 DU DU DU 
29  
 
 
 
 
 
 
 
 
 
 
 
 DU DU 
30  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DU 
 


 
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APPENDIX 12.  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); 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 
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. 
Patients should not be enrolled into the lead-in dose escalation portion of Cohort 9 unless 
they are able to meet the protocol defined assessments and procedures including adhering 
visit windows. 
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. 
• 
Visit windows of +/- 3 days are allowed for Day 8 clinic visits 
(for dose expansion portion of Cohort 9 and Cohort 10). 
Clinic Visits 
• 
Clinic visits may be conducted remotely by telephone/video 
conference; any missed assessments or procedures (e.g., tumor 
assessment, laboratory assessments, vital signs, study drug 
administration, etc.) should be documented as Protocol 
Deviations. 
• 
Clinic visits may be conducted at the patient’s residence by 
qualified home health care professionals; any missed assessments 
or procedures (e.g., 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. 
Nivolumab Dosing (for 
Cohorts 1 through 8) 
In order to reduce the need for Day 15 visits, Investigators should: 
• 
Consider switching all patients who are on the Q2 week 240 mg 
nivolumab regimen to the Q4 week 480 mg regimen instead, as 
possible. 
• 
Start all newly enrolled patients on the Q4 week 480 mg regimen. 
Day 15 Sample Collection for 
PK and Other Exploratory 
Tests (for Cohorts 1 through 8)  
In order to eliminate the Day 15 clinic visit (for Cohorts 1 through 8):   
• 
C1D15 PK samples, PD samples (TCR sequencing, flow 
cytometry, protein and cytokine biomarkers), and triplicate ECG 
may be collected at C2D1 instead. 
• 
C2D15 PD samples (flow cytometry, protein and cytokine 
biomarkers) may be collected at C3D1 instead.  


 
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Assessment/Procedure 
Change During COVID-19 Pandemic 
PK Sample Collections 
For Cohorts 1 through 8: 
• 
The PK collection required post-dose at 7 hours (5-9 hours) on 
C1D1 and C1D15 may not be collected in order to reduce the 
time that patients need to remain in the clinic for the blood draw 
and ECGs. 
For dose expansion portion of Cohort 9 and Cohort 10: 
• 
The PK collection required post-dose at 7 hours (5-9 hours) on 
C1D1 and C2D1 may not be collected in order to reduce the time 
that patients need to remain in the clinic for the blood draw and 
ECGs. 
PK sub-study for patients with 
renal impairment (for 
Cohorts 1 through 8) 
Temporarily suspended for new patients to reduce the time patients 
need to remain in the clinic or hospital for blood draws. 
Action and Reporting in the Event of Documented or Suspected COVID-19 
Infection 
Study Treatment 
• Patients in Screening for Study Entry – Patients who exhibit symptoms consistent 
with COVID-19 infection or have recent COVID-19 test results consistent with 
active viral replication should delay study entry and start of study treatment until 
resolution of symptoms and evaluation by the Investigator.  Questions should be 
directed to the Sponsor’s Medical Monitor. 
• Patients in Study Treatment – For patients on study treatment exhibiting 
symptoms consistent with COVID-19 infection, contact the Sponsor’s Medical 
Monitor as soon as feasible. 

SAP_001.pdf: 
Protocol Number: 516-003
Official Title: A Phase 2 Study of Sitravatinib in Combination with PD-(L)1 Checkpoint Inhibitor 
Regimens in Patients with Advanced or Metastatic Urothelial Carcinoma 
NCT Number: NCT03606174 
Document Date: 15-Mar-2022


Statistical Analysis Plan 
MRT51603-51603X 
Version Date: 15-Mar-2022 
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Statistical Analysis Plan 
 
Sponsor: 
Mirati Therapeutics, Inc 
Protocol No: 
516-003 
PRA Project Id: 
MRT51603-51603X 
Version Date: 
22-Jun-2020 
Version No.: 
4.0 
 
Title: 
A Phase 2 Study of Sitravatinib in Combination with PD-(L)1 Checkpoint 
Inhibitor Regimens in Patients with Advanced or Metastatic Urothelial 
Carcinoma 
CRF Version 
No./Date: 
5.0/29-Oct-2020  
SAP No. 
V3.0 / 15-Mar-2022 
 
1.0 Approvals 
Sponsor 
Sponsor Name: 
Mirati Therapeutics, Inc. 
Representative/Title: 
/Manager of Biostatistics  
Signature/Date: 
Representative/Title: 
/Medical Director, Clinical Development 
Signature/Date: 
PRA 
Biostatistician/Title 
(Owner): 
/Senior Principal Biostatistician 
Signature/Date: 
 
 
 
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2.0 Change History 
Version/Date 
Change Log 
1.0/04Jun2021 
Created as new 
2.0/09Dec2021 
Incorporate the client’s comments to SAP v1.0 and finalize the SAP 
3.0/15Mar2022 
Add rule for the imputation of completely missing anti-cancer therapy dates. 
Add a definition for extent of follow-up. 
Revise the censoring rules for DoR and PFS as such: 
• 
add the derivation of last evaluable assessment, 
• 
add cohort-specific details to rule for patients lacking evaluation of disease 
after first study treatment, 
• 
add rule for patients that start a new anti-cancer therapy prior to PD or 
death. 
Add a definition of "on-treatment" to the Safety Analysis Section. 
Add definition of last evaluable assessment 
Remove repeated block of text from the irAE Section. 
Revise the definition of TEAEs to coincide with the MRT51605 study. 
Correct WHO Drug Dictionary Version to: 2018MAR01 DDE+HD B3 
Added cut for end date of defining concomitant medications 
Remove Cis from BOR 
 
 
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Table of Contents 
 
1.0 Approvals ............................................................................................................................. 1 
2.0 Change History .................................................................................................................... 2 
3.0 Purpose ............................................................................................................................... 5 
4.0 Scope ................................................................................................................................... 5 
5.0 Introduction .......................................................................................................................... 5 
6.0 Study Objectives and Endpoints ........................................................................................... 5 
6.1 Objectives ....................................................................................................................................................................... 5 
6.1.1 Primary Objective ............................................................................................................................................... 5 
6.1.2 Secondary Objectives ........................................................................................................................................ 5 
6.1.3 Exploratory Objectives ..................................................................................................................................... 6 
6.2 Endpoints ........................................................................................................................................................................ 6 
6.2.1 Primary Endpoint ............................................................................................................................................... 6 
6.2.2 Secondary Endpoints......................................................................................................................................... 6 
6.2.3 Exploratory Endpoints ..................................................................................................................................... 6 
7.0 Study Design ........................................................................................................................ 6 
7.1 Initial and Contingent Study Cohorts .................................................................................................................. 7 
7.1.1 Initial Study Cohorts .......................................................................................................................................... 7 
7.1.2 Contingent Study Cohorts ............................................................................................................................... 8 
7.1.3 Study Treatments ............................................................................................................................................. 18 
7.1.4 Contingent PK Evaluation in Patients with Renal Impairment ...................................................... 19 
7.1.5 Hypothesis and Sample Size Considerations ......................................................................................... 19 
7.2 Randomization ........................................................................................................................................................... 24 
7.3 COVID-19 Pandemic Changes to Study Conduct .......................................................................................... 24 
8.0 Analysis Populations ...........................................................................................................26 
8.1 Screened Population ................................................................................................................................................ 26 
8.2 Enrolled Population ................................................................................................................................................. 26 
8.3 Full Analysis Set (FAS) ............................................................................................................................................ 26 
8.4 Clinical Activity Evaluable Population .............................................................................................................. 26 
8.5 Safety Population ...................................................................................................................................................... 26 
8.6 Molecular Marker Evaluable Population ......................................................................................................... 26 
8.7 Pharmacokinetic Evaluable Population ........................................................................................................... 26 
8.8 Pharmacodynamic Evaluable Population ....................................................................................................... 27 
8.9 DLT Evaluable Population (only applicable to lead-in dose escalation portion of Cohort 9) ... 27 
9.0 Data Handling .....................................................................................................................27 
9.1 Imputation of AEs or Concomitant Medications .......................................................................................... 27 
9.2 Imputation of Alternative Cancer Treatment Start Date .......................................................................... 28 
9.3 Imputation of Laboratory Values with Character Symbol ....................................................................... 29 
9.4 Protocol Deviations .................................................................................................................................................. 29 
10.0 Interim Analyses ................................................................................................................29 
11.0 Statistical Methods ............................................................................................................29 
11.1 Patient Disposition ................................................................................................................................................. 29 
11.2 Important Protocol Deviations ......................................................................................................................... 29 
11.3 Demographic and Baseline Characteristics ................................................................................................. 30 
11.3.1 Baseline Bellmunt Score .............................................................................................................................. 30 
11.4 Prior and Concomitant Medications ............................................................................................................... 30 
11.5 Medical History........................................................................................................................................................ 31 
11.6 Efficacy Analyses and Efficacy Variables ...................................................................................................... 31 
11.6.1 Objective Response Rate (ORR) ............................................................................................................... 31 
11.6.2 Duration of Response (DOR) ..................................................................................................................... 33 
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11.6.3 Overall Survival (OS) .................................................................................................................................... 33 
11.6.4 Extent of Follow-up ....................................................................................................................................... 33 
11.6.5 Progression-Free Survival (PFS) ............................................................................................................. 33 
11.6.6 Clinical Benefit Rate (CBR) ......................................................................................................................... 34 
11.6.7 Subgroup Analyses, including Prior Clinical Benefit (PCB) and No Prior Clinical Benefit 
(NPCB) Endpoints ........................................................................................................................................................ 35 
11.7 Safety Analyses ........................................................................................................................................................ 35 
11.7.1 Extent of Study Drug Exposure and Exposure Variables ............................................................... 35 
11.7.2 Adverse Events ................................................................................................................................................ 37 
11.7.3 Deaths and Serious Adverse Events ....................................................................................................... 38 
11.7.4 Laboratory Data .............................................................................................................................................. 38 
11.7.5 Vital Signs .......................................................................................................................................................... 40 
11.7.6 Physical Examinations, ECGs, and Other Observations Related to Safety .............................. 41 
11.8 Other Endpoints ...................................................................................................................................................... 43 
12.0 References ........................................................................................................................43 
Appendix 1 Glossary of Abbreviations .......................................................................................44 
Appendix 2 Dose De-Escalation Decision Table Using the mTPI Method .................................46 
Appendix 3 Abbreviated Presentation of RECIST Version 1.1 Guidelines .................................48 
 
 
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3.0 Purpose 
The statistical analysis plan (SAP) describes the statistical methods to be used during the reporting and 
analyses of data collected under Mirati Therapeutics, Inc Protocol 516-003. 
4.0 Scope 
This plan is a living document that supplements the study protocol for statistical analysis-related aspects. 
The SAP outlines the following: 
• 
Study objectives and endpoints 
• 
Study design 
• 
Analysis populations 
• 
Endpoint and variable definitions 
• 
Data handling 
• 
Data review 
• 
Statistical methods 
Deviations from the statistical analysis plan will be described in the Clinical Study Report (CSR). 
5.0 Introduction 
This SAP describes the statistical methods to be used during the analysis and reporting of data collected 
under Mirati Therapeutics, Inc. Protocol 516-003. 
This SAP should be read in conjunction with the study protocol and case report form (CRF). This version 
of the plan has been developed using the protocol version 4.0 dated 22 June 2020 and CRF version 5.0 
dated 29 Oct 2020. Any further changes to the protocol or CRF may necessitate updates to the SAP. 
The SAP will be developed in two stages. An initial SAP, known as the SAP, will be finalized based on the 
current protocol and CRF, so that programming may be created. Changes following approval of the SAP 
will be tracked in the SAP Change Log and an amended SAP will be finalized prior to database lock. 
6.0 Study Objectives and Endpoints 
6.1 Objectives 
6.1.1 Primary Objective 
• 
To evaluate the clinical activity of sitravatinib in combination with PD-(L)1 checkpoint inhibitor 
regimens in patients with advanced or metastatic urothelial carcinoma. 
6.1.2 Secondary Objectives 
• 
To evaluate the safety and tolerability of the combination regimen in the selected population. 
• 
To evaluate secondary efficacy endpoints of the combination regimen in the selected population. 
• 
To evaluate the pharmacokinetics (PK) of sitravatinib administered in combination regimens. 
• 
To evaluate the PK of sitravatinib in patients with renal impairment, to be implemented in selected 
study sites contingent upon early results in the study or sitravatinib program. 
• 
Cohort 9 only: To identify recommended Phase 2 combinatorial doses (RP2Ds) of sitravatinib, 
pembrolizumab and enfortumab combination treatment. 
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6.1.3 Exploratory Objectives 
• 
To assess the effect of the combination regimen on circulating PD-L1, immune cell populations and 
cytokines. 
• 
To assess the effect of the combination regimen on tumor cell PD-L1 expression, tumor infiltrating 
immune cell populations and gene expression signatures. 
• 
To assess the correlation of tumor PD-L1 protein expression and gene alterations in circulation and 
in tumor tissue with treatment outcome. 
6.2 Endpoints 
6.2.1 Primary Endpoint 
The primary endpoint is the Objective Response Rate (ORR) as defined by Response Evaluation Criteria 
in Solid Tumors version 1.1 (RECIST 1.1) as per local Physicians in all other Cohorts. 
6.2.2 Secondary Endpoints 
• 
Safety characterized by type, incidence, severity, timing, seriousness and relationship to study 
treatment of adverse events, and laboratory abnormalities. 
• 
Secondary efficacy endpoints 
o 
Duration of Response (DOR) 
o 
Clinical Benefit Rate (CBR) 
o 
Progression-Free Survival (PFS) 
o 
1-Year Survival Rate 
o 
Overall Survival (OS) 
• 
Blood plasma concentrations of sitravatinib. 
• 
Lead-in dose escalation portion of Cohort 9 only: Dose-limiting toxicities (DLTs). 
6.2.3 Exploratory Endpoints 
• 
Circulating PD-L1 concentration 
• 
Circulating immune cell populations 
• 
Circulating cytokine concentrations 
• 
Circulating tumor deoxyribonucleic acid (ctDNA) 
• 
T-Cell Receptor sequencing 
• 
Tumor PD-L1 expression 
• 
Immune cell populations in the tumor 
• 
Gene expression signatures in the tumor 
• 
Tumor gene alterations 
7.0 Study Design 
Study 516-003 is an open-label, Phase 2 evaluation of the investigational agent sitravatinib in 
combination with PD-(L)1 checkpoint inhibitor regimens in patients with locally advanced or metastatic 
urothelial carcinoma.  The study will evaluate sitravatinib in combination with the PD-1 checkpoint 
inhibitor nivolumab, and sitravatinib in combination with the PD-1 checkpoint inhibitor pembrolizumab and 
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the antibody-drug conjugate (ADC) enfortumab.  An initial lead-in dose escalation evaluation may be 
initiated followed by further evaluation of clinical activity in 2 populations if a tolerable dose regimen for 
this combination is identified. 
The primary objective is to evaluate the clinical activity of the combination regimens using ORR in 
accordance with RECIST 1.1.  Secondary objectives include evaluation of safety, secondary efficacy 
endpoints, PK of sitravatinib, and (for lead-in dose escalation portion of Cohort 9 (35mg, 70mg, and 
100mg) DLTs for Cohort 9.  The Schedule of Assessments to be performed in the study are presented in 
Table 1 and 
.  The schedule for collection of pharmacokinetic and pharmacodynamic samples and ECG assessment 
time points are presented in Table 2 and Table 4. 
7.1 Initial and Contingent Study Cohorts 
Initial cohorts will be used to refer to the first two cohorts (cohort 1 and cohort 2) in which patients with 
documented disease progression on or after checkpoint inhibitor therapy as the most recent treatment will 
be enrolled. 
Contingent cohorts will be used to refer to one or more cohorts (cohort 3, 4 and up to cohort 9) that may be 
added to the study on a contingent basis. Cohorts 3 and 4 will enroll patients previously receiving treatment 
with selected immunotherapies, including anti-CTLA-4, anti-OX40 or anti–CD137 therapy. Cohorts 5 and 6 
will enroll patients who have not previously received checkpoint inhibitor therapy (CIT-naïve). Cohort 7 will 
enroll patients with documented disease progression on or after a previous anti-PD-(L)1 and ADC (in 
combination or separately, and in any order), and who were previously treated with a platinum-based 
chemotherapy. Cohort 8 will enroll patients with documented disease progression on or after a previous 
anti-PD-(L)1 and ADC (in combination or separately, and in any order), and considered ineligible for 
platinum-based chemotherapy. Cohort 9 (including lead-in dose escalation) will enroll patients who have 
previously received a PD-(L)1 checkpoint inhibitor and a platinum-based chemotherapy. 
7.1.1 Initial Study Cohorts 
The initial study population will include patients with documented disease progression on or after a PD-
(L)1 checkpoint inhibitor therapy as the most recent treatment [anti-PD-(L)1 refractory cohorts], stratified 
into 2 cohorts based on whether patients were previously treated with or ineligible for platinum-based 
chemotherapy, as depicted in Figure 1. 
• 
Cohort 1: Patients with documented disease progression on or after previous anti-PD-(L)1 as most 
recent treatment, and who were previously treated with a platinum-based chemotherapy.   
• 
Cohort 2: Patients with documented disease progression on or after previous anti-PD-(L)1 as most 
recent treatment, and considered ineligible for platinum-based chemotherapy.  
Enrollment will occur in 3 stages. Stage 1 of enrollment will include a minimum of 9 evaluable patients in 
each cohort.  Patients included in the evaluable population will have received treatment with both 
sitravatinib and nivolumab and have at least one on-study disease assessment prior to discontinuation. 
The exact stopping rules will be calculated based on the Predictive Probability Design (Lee-2008), once 
the exact number of patients evaluable at Stage 1 is known.  With exactly 9 evaluable patients at Stage 1, 
if at least 1 patient has an Objective Response, 8 additional evaluable patients will be enrolled in the 
treatment cohort, for a total sample size of 17 evaluable patients.  If at least 3 Objective Responses are 
observed in a treatment cohort, further investigation may be warranted.  If Stage 2 results in a cohort are 
of high interest for efficacy (in terms of examining the risk benefit ratio and not only in terms of ORR), 
enrollment may be expanded to as many as 40 patients in total in that cohort to narrow the 95% 
Confidence Interval (CI) around the ORR point estimate and to further characterize the durability of 
disease control. 
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7.1.2 Contingent Study Cohorts 
In the event that results in the initial cohorts are of high interest for efficacy, contingency plans are 
described in Appendix 5, Appendix 6, Appendix 8 and Appendix 9 of the Protocol to add one or more 
study cohorts.  Decisions for implementation of additional cohorts in the study will be made in 
collaboration with the Investigators and documented for Regulators and Institutional Review Boards by an 
Administrative Letter to Investigators. 
Appendix 5 of the Protocol describes addition of contingent Cohort 3 and Cohort 4 (other prior selected 
immunotherapy cohorts, including anti-CTLA-4, anti-OX40 or anti-CD137).  The statistical design for 
these cohorts will be the same as applied to Cohorts 1 and 2.  These contingent cohorts described below 
were implemented by Administrative Letter, as depicted in Figure 1. 
• 
Cohort 3: Patients with documented disease progression on or after a previous anti-PD-(L)1 as 
most recent treatment, who previously received (in combination or separately) other selected 
immunotherapies, and who were previously treated with a platinum-based chemotherapy.  
• 
Cohort 4: Patients with documented disease progression on or after a previous anti-PD-(L)1 as 
most recent treatment, who previously received (in combination or separately) other selected 
immunotherapies, and considered ineligible for platinum-based chemotherapy.  
Appendix 6 of Protocol describes addition of contingent Cohort 5 and Cohort 6 [anti-PD-(L)1 naïve 
cohorts].  The statistical design for these cohorts is described in the next section.  These contingent 
cohorts described below were implemented by Administrative Letter and still enrolling, as depicted in 
Figure 1.  
• 
Cohort 5: Patients who have not previously received an anti-PD-(L)1, and who were previously 
treated with a platinum-based chemotherapy.  
• 
Cohort 6: Patients who have not previously received an anti-PD-(L)1, and considered ineligible for 
platinum-based chemotherapy. 
Appendix 8 of Protocol describes addition of contingent Cohort 7 and Cohort 8 [post-ADC (antibody-drug 
conjugate) cohorts].  The statistical design for these new cohorts is described in the next section.  These 
contingent cohorts described below were implemented by Administrative Letter.  
• 
Cohort 7: Patients with documented disease progression on or after a previous anti-PD-(L)1 and 
ADC (in combination or separately, and in any order), and who were previously treated with a 
platinum-based chemotherapy.  
• 
Cohort 8: Patients with documented disease progression on or after a previous anti-PD-(L)1 and 
ADC (in combination or separately, and in any order), and considered ineligible for platinum-based 
chemotherapy. 
Appendix 9 of the Protocol describes addition of Cohort 9 to evaluate sitravatinib in combination with 
pembrolizumab and enfortumab.  The next section describes the initial lead-in dose escalation followed 
by further evaluation of clinical activity in 2 populations if a tolerable dose regimen is identified.  Cohort 9 
is introduced and implemented with this protocol Version 4.0. 
• 
Cohort 9 (including lead-in dose escalation): Patients who have previously received a PD-(L)1 
checkpoint inhibitor and a platinum-based chemotherapy. 
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Table 1 Schedule of Assessments: Cohorts 1 through 8 
Assessments 
Screen/Baseline 
Cycles 1, 2, and 3 
≥ Cycle 4 
End of Treatment 
Within 28 days 
Day 1 
(± 2 days for 
Cycles 2 & 3) 
Day 15 
(± 2 days) 
Day 1 
(± 2 
days) 
Day 15 
(± 2 days) 
End of 
Treatment/ 
Withdrawal14 
Post 
Treatment 
Follow Up 
Study Participation Informed 
Consent1 
Before study 
specific 
assessments 
  
  
  
  
  
  
Tumor Tissue Collection for 
PD-L1 Expression, Immune 
Cell Populations and Tumor 
Gene Alterations2 
X2 
  
X (Cycle 2 
only) 
Optional2 
  
  
  
  
Medical History, Disease 
History, Prior Therapy  
X 
  
  
  
  
  
  
ECOG Performance Status 
X 
  
  
  
  
  
  
Physical Exam3 
X 
  
  
  
  
X 
  
Abbreviated Physical Exam3 
  
X 
X 
X 
X if 
nivolumab 
Q2W 
  
  
Vital Signs4 
X 
X 
X 
X 
X if 
nivolumab 
Q2W 
X 
  
Pregnancy Test5 
X 
As clinically indicated 
  
Hematology6, 7 
X 
X 
X 
X 
  
X 
  
Coagulation6, 7 
X 
As clinically indicated 
  
Urinalysis6, 7 
X 
As clinically indicated 
  
Serum Chemistry6, 7 
X 
X 
X 
X 
  
X 
  
Thyroid Function Test6, 7 
X 
X 
  
X 
  
X 
  
Blood for Sitravatinib 
Pharmacokinetics8 
  
See Table 2 
  
 
 
 
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Assessments 
Screen/Baseline 
Cycles 1, 2, and 3 
≥ Cycle 4 
End of Treatment 
Within 28 days 
Day 1 
(± 2 days for 
Cycles 2 & 3) 
Day 15 
(± 2 days) 
Day 1 
(± 2 
days) 
Day 15 
(± 2 days) 
End of 
Treatment/ 
Withdrawal14 
Post 
Treatment 
Follow Up 
ctDNA blood sample9 
X 
At assessment for confirmation of disease response (PR or 
CR) 
X 
  
Single 12-Lead ECG10 
X 
As clinically indicated 
X 
  
Triplicate 12-Lead ECG10 
  
See Table 2 
  
Echocardiogram or MUGA 
X (Within 35 
days) 
Cycle 3 only 
  
As 
clinically 
indicated 
after C3 
  
X 
  
(± 7 days) 
Disease Evaluation11 
X 
Every 8 weeks (± 10 days) for ~12 months 
  
and then every 16 weeks 
Sitravatinib Dispensing and/or 
Reconciliation 
  
X 
  
X 
  
  
  
Nivolumab Administration 
  
Throughout as directed in protocol 
  
  
Adverse Events12 and 
Concomitant Medications 
SAEs only 
Throughout 
  
Long Term Follow-up13 
  
  
  
  
  
  
X 
1  Study Participation Informed Consent: May be performed more than 28 days prior to the first dose of study treatment and must be completed 
prior to initiation of any study specific assessments. 
2  Tumor Testing for PD-L1 Expression, Tumor Immune Cell Populations, and Tumor Gene Alterations: 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.  An optional tumor tissue collection after and as close as possible to C2D15 is desirable for all patients and is not dependent 
on the type of tumor tissue submitted at screening.  A urinalysis should be performed prior to any study-related biopsy involving the 
genitourinary tract.  If the results are consistent with a urinary tract infection, tumor lesions in other anatomical areas should be selected, if 
present. 
3  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. 
4  Vital Signs: Weight, temperature, blood pressure, and pulse rate to be assessed prior to dosing as indicated. 
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5  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.  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. 
6  Selected Day 1 Assessments: Repeat assessment not required if screening assessment performed within 7 days before the first dose. 
7    Safety Laboratory Assessments: Hematology, coagulation, chemistry, thyroid function and urinalysis evaluations (Table 8) will be performed by 
local laboratories. 
8    Pharmacokinetic Samples: Blood samples to be collected following ECGs and assessment of vital signs as scheduled in Table 2.  
9    Blood samples for ctDNA analysis:  Blood will be collected in two 10 mL Streck brand Cell-Free DNA Blood Collection tubes allowing shipping 
and stability at ambient temperatures. 
10 12-Lead ECGs: 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. 
11  Disease Evaluations: To be performed at screening (28-day window allowed) and every 8 weeks from Cycle 1 Day 1(± 10-day window for all 
other assessments except screening) until week 49 (~12 months) and then every 16 weeks.  All on-study disease evaluations should be 
based on a calendar beginning from the first day of dosing. At screening/baseline, assessments are to include CT with contrast of the chest, 
CT or MRI of the abdomen and pelvis, as well as brain Magnetic Resonance Imaging (MRI) with and without gadolinium or CT with contrast, a 
whole-body bone scan (or PET or PET/CT if local standard for clinical trials) and evaluation of any superficial lesions.  Subsequent disease 
assessments should include all sites of disease identified at baseline or suspected to have developed; bone scans may be performed half as 
often (every 16 weeks) as other radiology evaluations and should be performed during assessment for confirmation of disease response.  
More detailed guidance on exceptional circumstances is provided in the protocol.  Patients who discontinued the study for reasons other than 
objective disease progression will continue to have disease assessments at the same frequency until patient has radiologically confirmed 
progression, initiates a new anticancer therapy, or death. 
12  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.   
13  Long Term 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.  Follow-up may be performed by telephone contact or email. 
14  End of Treatment: Perform within 7-14 days of decision to permanently discontinue all study treatment.  Assessments that have been 
completed in the previous 4 weeks do not need to be repeated (8 or 16 weeks for tumor assessments in accordance with schedule).  
 
 
 
 
 
 
 
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Table 2 Sitravatinib Schedule of PK, Biomarker Samples and Triplicate ECG Assessments: Cohorts 1 through 8 
 
Screen/ 
Baseline 
Cycle 1 Day 1 
Cycle 1 Day 15  
(± 2 days) 
Cycle 2, 3, 5  
Day 1 only 
Cycle 2  
Day 15 only 
Collection Time 
and Allowable 
Window 
Within 28 
days 
Pre-dose 
(-0.5-0 hour) 
30 min 
(± 10 
min) 
7 hour5 
(5-9 
hour) 
Pre-dose 
(-0.5-0 
hour) 
7 hour5 
(5-9 hour) 
Pre-dose 
(-0.5-0 hour) 
Pre-dose 
(-0.5-0 hour) 
PK Sample1,2 
 
X 
X 
X 
X 
X 
X 
 
TCR Sequencing3 
 
X 
 
 
X 
 
 
 
Flow Cytometry3 
X 
X 
 
 
X 
 
 
X 
Protein and Cytokine 
Biomarkers3 
 
X 
 
 
X 
 
 
X 
Triplicate ECG4 
 
X 
(-1 hour) 
X 
(-0.5 hour) 
 
X 
X 
X 
X 
 
1  Scheduled vital signs and triplicate ECGs precede PK sample collection in all cases.  Sitravatinib dosing and sampling should precede 
nivolumab infusion.  Post-dose PK sample collections are not required for visits where sitravatinib dose is held but should be subsequently 
collected at the next visit following at least 7 days of sitravatinib intake.  Alternatively, both pre-dose and post-dose PK collections are not 
required for visits preceded by more than 4 days of sitravatinib hold but should be subsequently collected at the next visit following at least 7 
days of sitravatinib intake. 
2  In addition to the scheduled samples, an unscheduled PK blood sample should be drawn before a daily sitravatinib dose (trough sample) in 
the event of any of the following events: 1) as soon as possible after an SAE, 2) at a clinic visit at least one week following a dose modification 
of the investigational agent, and 3) as soon as possible after renal function declines by one Stage as defined in Appendix 2 of the Protocol, if 
the patient continues study treatment. 
3  The Day 1 blood samples for TCR sequencing, flow cytometry, protein and cytokine biomarker studies may be drawn up to 2 hours before 
dosing.  The screen/baseline sample should not be collected on the same day as the pre-dose Cycle 1 Day 1 sample. 
4  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 (e.g., 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: 
o 
Example for Cycle 1 Day 1 pre-dose ECGs/PK: ~-1.0 hr (Triplicate ECGs); ~-30 mins (Triplicate ECGs); ~-15 mins (Vitals/PK) 
o 
Example for all other pre-dose ECG/PK assessments: ~-30 mins (Triplicate ECGs); ~-15 mins (Vitals/PK) 
5  Timepoints changed in Version 3.0 of protocol to 7 hours (5-9 hours).  In preceding versions, these timepoints were 4 hours (2-6 hours). 
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Table 3 Schedule of Assessments: Cohort 9 
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 
Cycles 1, 2, and 3 
≥Cycle 4 
End of Treatment 
Within 28 
days 
Day 1 
(± 2 days for 
Cycles 2 & 3) 
Day 8 
(± 2 
days) 
Day 15 
(± 2 days) 
Only Lead-in 
Dose 
Escalation of 
Cohort 9 
Day 1 
(± 2 days) 
Day 8 
(± 2 days) 
End of 
Treatment/ 
Withdrawal14 
Post 
Treatment 
Follow Up 
Study Participation 
Informed Consent1 
Before study 
specific 
assessments 
 
 
 
 
 
 
 
Tumor Tissue Collection 
for PD-L1 Expression, 
Immune Cell 
Populations and Tumor 
Gene Alterations2 
X2 
X (Cycle 3 
only) 
Optional2 
 
 
 
 
 
 
Medical History, Disease 
History, Prior Therapy  
X 
 
 
 
 
 
 
 
ECOG Performance 
Status 
X 
 
 
 
 
 
 
 
Physical Exam3 
X 
 
 
 
 
 
X 
 
Eye Exam15 
X (Within ≤ 3 
months) 
As clinically indicated 
X 
 
Abbreviated Physical 
Exam3 
 
X 
X 
X 
X 
X 
 
 
Vital Signs4 
X 
X 
X 
X 
X 
X 
X 
 
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Assessments 
Screen/ 
Baseline 
Cycles 1, 2, and 3 
≥Cycle 4 
End of Treatment 
Within 28 
days 
Day 1 
(± 2 days for 
Cycles 2 & 3) 
Day 8 
(± 2 
days) 
Day 15 
(± 2 days) 
Only Lead-in 
Dose 
Escalation of 
Cohort 9 
Day 1 
(± 2 days) 
Day 8 
(± 2 days) 
End of 
Treatment/ 
Withdrawal14 
Post 
Treatment 
Follow Up 
Pregnancy Test5 
X 
As clinically indicated 
 
Hemoglobin A1c7 
X 
 
 
 
 
 
 
 
Hematology6, 7 
X 
X 
X 
X 
X 
X 
X 
 
Coagulation6, 7 
X 
As clinically indicated 
 
Urinalysis6, 7 
X 
As clinically indicated 
 
Serum Chemistry6, 7 
X 
X 
X 
X 
X 
X 
X 
 
Thyroid Function Test6, 7 
X 
X 
 
 
X 
 
X 
 
Blood for Sitravatinib 
PK8 
 
See Table 4 
 
ctDNA blood sample9 
X 
At assessment for confirmation of disease response (PR or CR) 
X 
 
Single 12-Lead ECG10 
X 
As clinically indicated 
X 
 
Triplicate 12-Lead 
ECG10 
 
See Table 4 
 
Echocardiogram or 
MUGA 
X (Within 
35 days) 
 
Cycle 3 
only 
(± 7 days) 
 
As clinically 
indicated 
after C3 
 
X 
 
Disease Evaluation11 
X 
Every 9 weeks (± 10 days) for ~12 months and then every 18 weeks 
 
Sitravatinib Dispensing 
and/or Reconciliation 
 
X 
 
 
X 
 
 
 
 
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Assessments 
Screen/ 
Baseline 
Cycles 1, 2, and 3 
≥Cycle 4 
End of Treatment 
Within 28 
days 
Day 1 
(± 2 days for 
Cycles 2 & 3) 
Day 8 
(± 2 
days) 
Day 15 
(± 2 days) 
Only Lead-in 
Dose 
Escalation of 
Cohort 9 
Day 1 
(± 2 days) 
Day 8 
(± 2 days) 
End of 
Treatment/ 
Withdrawal14 
Post 
Treatment 
Follow Up 
Enfortumab and 
Pembrolizumab 
Administration 
 
Throughout as directed in protocol 
(Note: pembrolizumab should be administered after sitravatinib, and 
enfortumab should be administered at least 30 minutes after 
pembrolizumab)  
 
 
Adverse Events12 and 
Concomitant 
Medications 
SAEs only 
Throughout 
 
Long Term Follow-up13 
 
 
 
 
 
 
 
X 
1  Study Participation Informed Consent: May be performed more than 28 days prior to the first dose of study treatment and must be completed 
prior to initiation of any study specific assessments. 
2  Tumor Testing for PD-L1 Expression, Tumor Immune Cell Populations, and Tumor Gene Alterations: 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.  An optional tumor tissue collection after and as close as possible to C3D1 is desirable for all patients and is not dependent 
on the type of tumor tissue submitted at screening.  A urinalysis should be performed prior to any study-related biopsy involving the 
genitourinary tract.  If the results are consistent with a urinary tract infection, tumor lesions in other anatomical areas should be selected, if 
present.  Nectin-4 testing by immunohistochemistry may be evaluated. 
3  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. 
4  Vital Signs: Weight, temperature, blood pressure, and pulse rate to be assessed prior to dosing as indicated. 
5  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.  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. 
6  Selected Day 1 Assessments: Repeat assessment not required if screening assessment performed within 7 days before the first dose. 
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7  Safety Laboratory Assessments: Hematology, coagulation, chemistry, thyroid function and urinalysis evaluations (see Table 11 of Protocol) 
will be performed by local laboratories.  If HbA1c is elevated (≥ 6.5 %), refer patient to appropriate provider during Cycle 1 for glucose 
management. 
8  Pharmacokinetic Samples: Blood samples to be collected following ECGs and assessment of vital signs as scheduled in Table 4 of Protocol.  
9  Blood samples for ctDNA analysis:  Blood will be collected in two 10 mL Streck brand Cell-Free DNA Blood Collection tubes allowing shipping 
and stability at ambient temperatures. 
10  12-Lead ECGs: Triplicate ECGs will accompany PK sampling as described in Table 4 of the Protocol. 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. 
11  Disease Evaluations: To be performed at screening (28-day window allowed) and every 9 weeks from Cycle 1 Day 1 (± 10-day window for all 
other assessments except screening) until week 49 (~12 months) and then every 18 weeks.  All on-study disease evaluations should be 
based on a calendar beginning from the first day of dosing. At screening/baseline, assessments are to include CT with contrast of the chest, 
CT or MRI of the abdomen and pelvis, as well as brain Magnetic Resonance Imaging (MRI) with and without gadolinium or CT with contrast, a 
whole-body bone scan (or PET or PET/CT if local standard for clinical trials) and evaluation of any superficial lesions.  Subsequent disease 
assessments should include all sites of disease identified at baseline or suspected to have developed; bone scans may be performed half as 
often (every 18 weeks) as other radiology evaluations and should be performed during assessment for confirmation of disease response.  
More detailed guidance on exceptional circumstances is provided in the protocol.  Patients who discontinued the study for reasons other than 
objective disease progression will continue to have disease assessments at the same frequency until patient has radiologically confirmed 
progression, initiates a new anticancer therapy, or death. 
12  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.   
13  Long Term 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.  Follow-up may be performed by telephone contact or email. 
14  End of Treatment: Perform within 7-14 days of decision to permanently discontinue all study treatment.  Assessments that have been 
completed in the previous 4 weeks do not need to be repeated (8 or 16 weeks for tumor assessments in accordance with schedule). 
15  Eye exam: Patients with recent ocular complaints (within ≤ 3 months of screening) must have a complete eye examination at Screening Visit 
performed by a qualified ophthalmologist or optometrist, including but not limited to: uncorrected, corrected and best corrected visual acuity, 
slit lamp, tonometry examination, and dilated fundus examination.  Prior ophthalmologic exam done within 3 months of screening is acceptable 
provided there are no new symptoms since that exam.  End of Treatment Visit slit lamp examinations are required for all patients who 
experience corneal adverse events during the study and must be performed ≥ 28 days from last dose of enfortumab.  Additional eye 
examinations are to be conducted as clinically indicated. 
 
 
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Table 4 Sitravatinib Schedule of PK, Biomarker Samples and Triplicate ECG Assessments: Cohort 9 
 
Screen/ 
Baseline 
Cycle 1 Day 1 
Cycle 2 Day 1  
(± 2 days) 
Cycle 2, 3, 6  
Day 8 only 
Cycle 3  
Day 1 only 
Collection Time 
and Allowable 
Window 
Within 28 
days 
Pre-dose 
(-0.5-0 hour) 
30 min 
(± 10 
min) 
7 hour5 
(5-9 
hour) 
Pre-dose 
(-0.5-0 
hour) 
7 hour5 
(5-9 hour) 
Pre-dose 
(-0.5-0 hour) 
Pre-dose 
(-0.5-0 hour) 
PK Sample1,2 
 
X 
X 
X 
X 
X 
X 
 
TCR Sequencing3 
 
X 
 
 
X 
 
 
 
Flow Cytometry3 
X 
X 
 
 
X 
 
 
X 
Protein and Cytokine 
Biomarkers3 
 
X 
 
 
X 
 
 
X 
Triplicate ECG4 
 
X 
(-1 hour) 
X 
(-0.5 hour) 
 
X 
X 
X 
X 
 
1  Scheduled vital signs and triplicate ECGs precede PK sample collection in all cases.  Sitravatinib dosing and sampling should precede 
nivolumab infusion.  Post-dose PK sample collections are not required for visits where sitravatinib dose is held but should be subsequently 
collected at the next visit following at least 7 days of sitravatinib intake.  Alternatively, both pre-dose and post-dose PK collections are not 
required for visits preceded by more than 4 days or sitravatinib hold but should be subsequently collected at the next visit following at least 7 
days of sitravatinib intake. 
2  In addition to the scheduled samples, an unscheduled PK blood sample should be drawn before a daily sitravatinib dose (trough sample) in 
the event of any of the following events: 1) as soon as possible after an SAE, 2) at a clinic visit at least one week following a dose modification 
of the investigational agent, and 3) as soon as possible after renal function declines by one Stage, if the patient continues study treatment. 
3  The Day 1 blood samples for TCR sequencing, flow cytometry, protein and cytokine biomarker studies may be drawn up to 2 hours before 
dosing.  The screen/baseline sample should not be collected on the same day as the pre-dose Cycle 1 Day 1 sample. 
4  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 (e.g., 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: 
o 
Example for Cycle 1 Day 1 pre-dose ECGs/PK: ~-1.0 hr (Triplicate ECGs); ~-30 mins (Triplicate ECGs); ~-15 mins (Vitals/PK) 
o 
Example for all other pre-dose ECG/PK assessments: ~-30 mins (Triplicate ECGs); ~-15 mins (Vitals/PK) 
5  Timepoints changed in Version 3.0 of protocol to 7 hours (5-9 hours).  In preceding versions, these timepoints were 4 hours (2-6 hours). 
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Figure 1 Study Schema (Note that Cohort 9 Expansion and Cohort 10 will not be opened) 
 
 
7.1.3 Study Treatments 
Throughout the study, nivolumab, pembrolizumab and enfortumab (where applicable) will be administered 
in accordance with approved labeling.  Nivolumab is to be administered by intravenous infusion, 240 mg 
Q2W or 480 mg Q4W.  Guidance for adverse event management and associated nivolumab treatment 
modifications are provided in product labeling.  Pembrolizumab is to be administered by intravenous 
infusion, 200 mg Q3W.  Guidance for adverse event management and associated pembrolizumab 
treatment modifications are provided in product labeling.  Enfortumab is to be administered by 
intravenous infusion, with a starting dose of 1.25mg/kg on days 1 and 8 of Q3W (a lower dose may be 
used if necessary; see Error! Reference source not found. of the protocol).  In addition, a dose de-
escalation step for enfortumab may be undertaken as appropriate.  Guidance for adverse event 
management and associated enfortumab treatment modifications are provided in product labeling.  Note: 
nivolumab (for Cohorts 1 through 8) or pembrolizumab (for Cohort 9) should be administered after 
sitravatinib (and specifically after the 30 minute PK sampling on applicable study visits), whereas 
enfortumab (for Cohort 9) should be administered at least 30 minutes after pembrolizumab. 
Sitravatinib capsules will be administered orally.  A starting dose of 120 mg QD of the free base capsule 
formulation (in 28-day cycles) was used for the sitravatinib and nivolumab combination cohorts under 
previous versions of this protocol.  Newly enrolled patients under Cohorts 1 through 6 will continue to 
receive the free base formulation with the starting dose of 120 mg QD.  For Cohorts 7 and 8, transition to 
use of an alternative formulation, sitravatinib malate capsule formulation, is being implemented with this 
protocol Version 4.0.  Newly enrolled patients in Cohorts 7 and 8 under this protocol Version 4.0 will 
receive a starting dose of 100 mg QD of the malate capsule formulation (an equivalent dose to 120 mg 
QD of the free base capsule formulation), based on the results of Study 516-006 described in Section 
Error! Reference source not found. of the protocol.  Patients who began treatment with the free base 
capsule formulation will remain on the free base capsule formulation throughout the duration of the study.  
A lead-in dose escalation will determine the starting dose of sitravatinib using the malate capsule 
formulation (21-day cycles) for sitravatinib combination with pembrolizumab and enfortumab Cohort 9.  
Guidelines for sitravatinib administration and dose reduction in the event of toxicity are provided in 
Section Error! Reference source not found. of the protocol. 
 
Detailed descriptions of the study treatments are presented in Section 5 of the protocol. 
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7.1.4 Contingent PK Evaluation in Patients with Renal Impairment 
In the event results in initial patient cohorts enrolled in this study or results emerging from other ongoing 
clinical trials of sitravatinib are of high interest for efficacy, the evaluation of the pharmacokinetics of 
sitravatinib in patients with mild or moderate renal impairment may be implemented. Appendix 7 of the 
protocol describes the plan for this assessment. Upon implementation of this study appendix, the 
evaluation of the PK of sitravatinib in at least 6 patients each having mild or moderate renal impairment at 
enrollment will be undertaken. Details of this analysis will be provided in the PKAP. 
7.1.5 Hypothesis and Sample Size Considerations 
This Phase 2 study will use Predictive Probability Designs (Lee-2008) for initial cohort 1 and 2. In 
summary, Cohorts 3 and 4 will also use Predictive Probability Designs with the same assumptions as the 
initial cohorts (Section 6.1), Cohorts 5 and 6 will use Predictive Probability Designs with revised 
assumptions, Cohorts 7 and 8 will use confidence interval method with the revised assumptions, the lead-
in dose escalation portion of Cohort 9 will use the mTPI-2 design (Guo-2017; Appendix 2). 
 
In creating the statistical designs, the Type 1 error (α) is constrained to <0.05 and Power (1-β) is constrained 
to ≥ 0.90. 
7.1.5.1 Cohort 1 and 2: 
ORR in accordance with RECIST v1.1 is the primary endpoint. The ORR using nivolumab in the population 
of advanced/metastatic urothelial carcinoma who experienced disease progression on or after treatment 
with a checkpoint inhibitor is assumed to be 5% (p0); thus, this rate is considered uninteresting. The target 
ORR using sitravatinib in combination with nivolumab in this study population is 30% (p1). Stage 1 of 
enrollment will include a minimum of 9 evaluable patients in each cohort. Patients included in the evaluable 
population will have at least one on-study disease assessment prior to discontinuation; patients who 
discontinue treatment due to adverse events or withdrawal of consent prior to the first on-study disease 
assessment will not be included in the evaluable population. With exactly 9 evaluable patients at Stage 1, 
if at least 1 patient has an Objective Response, 8 additional evaluable patients will be enrolled in the 
treatment cohort, for a total sample size of 17 evaluable patients. If at least 3 Objective Responses are 
observed in a treatment cohort, further investigation may be warranted. If the true ORR is 5% (null 
hypothesis), the probability of early termination during the study is 0.63; the Type 1 error is equal to 0.0466 
and the power is equal to 0.9045. 
The exact stopping rules for futility for each cohort will be calculated based on the Predictive Probability 
Design, once the exact number of patients evaluable at Stage 1 is known. The aim is to include a minimum 
of 9 evaluable patients at Stage 1. If Stage 2 results in a cohort are of high interest for efficacy (in terms of 
examining the risk benefit ratio and not only in terms of ORR), enrollment may be expanded to as many as 
40 patients total in that cohort to narrow the 95% CI around the ORR point estimate and to further 
characterize the durability of disease control. 
 
Table 5 presents estimates of the 95% CI around the observed ORR for several potential outcomes using 
the sample size of 40 patients, and the Clopper-Pearson method. 
Table 5 Estimates of 95% CI Using Clopper-Pearson in After Enrollment of 40 Patients 
Number of  
Observed Responses  
Among 40 Patients 
ORR 
95% CI 
10 
25% 
(12.7%, 41.2%) 
12 
30% 
(16.6%, 46.5%) 
14 
35% 
(20.6%, 51.7%) 
16 
40% 
(24.9%, 56.7%) 
20 
50% 
(33.8%, 66.2%) 
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7.1.5.2 Cohort 3 and 4: 
In the event that results in the initial study cohorts are of high interest for efficacy, one or more cohorts in 
patients with documented disease progression on or after a PD-(L)1 checkpoint inhibitor therapy as the 
most recent treatment, and who previously received (in combination or separately) treatment with 
selected immunotherapies, including but not limited to anti-CTLA-4, anti-OX40 or anti–CD137 therapy, 
may be added to the study.  Decisions for implementation of additional cohorts in the study will be made 
in collaboration with the Investigators and documented for Regulators and Institutional Review Boards by 
an Administrative Letter to Investigators. 
Based on the evolving treatment landscape of urothelial carcinoma including regimens combining 
selected immunotherapies with checkpoint inhibitors, and in consult with Investigators, both Cohort 3 and 
Cohort 4 described in this appendix were implemented by an Administrative Letter dated January 2019. 
The statistical design is the same as cohort 1 and 2. 
7.1.5.3 Cohort 5 and 6: 
In the event that results in the initial study cohorts are of high interest for efficacy, one or more cohorts in 
patients who have not previously received checkpoint inhibitor therapy (CIT-naïve) may be added to the 
study.  Decisions for implementation of additional cohorts in the study will be made in collaboration with 
the Investigators and documented for Regulators and Institutional Review Boards by an Administrative 
Letter to Investigators. 
 
Based on the evolving treatment landscape of urothelial carcinoma and early efficacy and safety results 
from active study cohorts, and in consult with Investigators, both Cohort 5 and Cohort 6 described in this 
section were implemented by an Administrative Letter dated May 2019. 
 
The ORR using nivolumab in the population of advanced/metastatic urothelial carcinoma who have not 
previously received treatment with a checkpoint inhibitor therapy is assumed to be 20% (p0); thus, this rate 
is considered uninteresting. The target ORR using sitravatinib in combination with nivolumab in this study 
population is 40% (p1). Stage 1 of enrollment will include approximately 24 evaluable patients in each 
cohort. Patients included in the evaluable population will have received treatment with both sitravatinib and 
nivolumab and will have at least one on-study disease assessment prior to discontinuation; patients who 
discontinue treatment due to adverse events or withdrawal of consent prior to the first on-study disease 
assessment will not be included in the evaluable population. With exactly 24 evaluable patients at Stage 1, 
if at least 6 patients have Objective Responses, enrollment of 21 additional evaluable patients is needed in 
the treatment cohort, for a total sample size of 45 evaluable patients. If at least 14 Objective Responses 
are observed in a treatment cohort, further investigation may be warranted. If the true ORR is 20% (null 
hypothesis), the probability of early termination during the study is 0.66; the Type 1 error is equal to 0.0483 
and the power is equal to 0.9001. 
The exact stopping rules for futility for both cohorts will be calculated based on the Predictive Probability 
Design, once the exact number of patients evaluable at Stage 1 is known. The aim is to include 
approximately 24 evaluable patients at Stage 1. The Sponsor retains the option to take more than one look 
at the data when making decisions based on the PPD method to expand cohorts. 
7.1.5.4 Cohort 7 and 8: 
In the event that results in the initial study cohorts are of high interest for efficacy, one or more cohorts in 
patients with documented disease progression on or after a PD-(L)1 checkpoint inhibitor therapy and an 
antibody-drug conjugate (ADC; e.g. enfortumab vedotin, sacituzumab govitecan), in any order or in 
combination together.  Decisions for implementation of additional cohorts in the study will be made in 
collaboration with the Investigators and documented for Regulators and Institutional Review Boards by an 
Administrative Letter to Investigators. 
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Based on the evolving treatment landscape of urothelial carcinoma in particular with the clinical activity of 
ADCs, and early efficacy and safety results from active study cohorts, and in consult with Investigators, 
both Cohort 7 and Cohort 8 described in this section were implemented by an Administrative Letter dated 
September 2019. 
The ORR using taxanes in the population of advanced/metastatic urothelial carcinoma who have 
previously received treatment with a checkpoint inhibitor therapy and ADC is assumed to be 10%; thus, 
this rate is considered uninteresting.  The design for Cohort 7 and Cohort 8 will utilize a 95% confidence 
interval to exclude an ORR of 10%.  Assuming sitravatinib in combination with nivolumab treatment will 
result in an ORR of at least 25% in this treatment setting, a sample size of approximately 55 evaluable 
patients would be sufficient for the lower bound of a 2-sided 95% confidence interval (Clopper-Pearson 
method) to exclude an ORR of 10%. 
The design will include a non-binding stopping rule for futility derived using East® software v6.5 to control 
the Type 2 error rate of 0.117.  The Type 2 error spending function is based on the Rho family with 
parameter 2.0.  The futility analysis will be conducted when approximately 17 evaluable patients 
(approximately 30% of the total number of patients) are available for the response assessment.  The 
futility bound will be 1 or fewer observed responses among the first 17 patients.  
 
7.1.5.5 Cohort 9: 
In the event that results in the initial study cohorts are of high interest for efficacy, one or more cohorts in 
patients for treatment with sitravatinib in combination with pembrolizumab and enfortumab may be added 
to the study.  Decisions for implementation of additional cohorts in the study will be made in collaboration 
with the Investigators and documented for Regulators and Institutional Review Boards by an 
Administrative Letter to Investigators.  
Based on the evolving treatment landscape of urothelial carcinoma in particular with the clinical activity of 
ADCs, and early efficacy and safety results from active study cohorts, and in consult with Investigators, 
Cohort 9 described in this appendix is considered implemented of this protocol Version 4.0. 
Study Design – Design details specific to Cohort 9 (including lead-in dose escalation) are described 
below including description of the populations to be enrolled into these contingent cohorts evaluating the 
triple combination of sitravatinib, pembrolizumab and enfortumab, the study design and dose-limiting 
toxicities (DLTs) as applicable. 
Initially, the lead-in dose escalation portion of Cohort 9 will evaluate sitravatinib administered in 
combination with pembrolizumab and enfortumab in patients who have previously received a PD-(L)1 
checkpoint inhibitor and a platinum-based chemotherapy.  If a tolerable dose is identified for sitravatinib in 
combination with pembrolizumab and enfortumab, the recommended dose regimen of sitravatinib in 
combination with pembrolizumab and enfortumab may be further evaluated in as many as 2 populations 
including in patients who have previously received a PD-(L)1 checkpoint inhibitor. Depending on the 
results in previous cohorts, only one or more of Cohort 9 may be implemented.  Description of the 
populations to be enrolled into Cohort 9 evaluating the triple combination of sitravatinib, pembrolizumab 
and enfortumab are described below. 
Lead-In Dose Escalation Portion of Cohort 9 Evaluating Sitravatinib in Combination with 
Pembrolizumab and Enfortumab 
This portion of the study will begin with the lead-in dose escalation portion of Cohort 9 of up to three dose 
levels of sitravatinib in combination with up to two dose levels of pembrolizumab and enfortumab 
combination regimen, in patients who have previously received a PD-(L)1 checkpoint inhibitor and a 
platinum-based chemotherapy.  Sitravatinib starting dose levels using the malate formulation are shown 
in Table 6, whereas the starting doses for pembrolizumab and enfortumab are shown in Table 7.  Dosing 
will begin at 35 mg QD of sitravatinib in combination with the recommended doses of pembrolizumab and 
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enfortumab combination regimen.  This starting dose for sitravatinib represents three dose levels below 
the dose administered as a single agent and in combination (with nivolumab) Phase 2 and 3 trials.  Dose 
Level 3 in Table 6 is the dose used in single agent and combination Phase 2 and 3 trials.  The starting 
doses for pembrolizumab and enfortumab (labeled as Dose Level 1 in Table 7) represent the 
recommended doses from the EV-103 Phase 2 trial and the EV-302 Phase 3 trial of pembrolizumab and 
enfortumab used in combination (Rosenberg-2020; Hoimes-2019).  It is of note that the EV-302 Phase 3 
trial also uses these recommended doses of pembrolizumab and enfortumab in the triple combination 
investigation arm combining pembrolizumab and enfortumab with the platinum-chemotherapy agents 
cisplatin or carboplatin.  In addition, a dose de-escalation step for enfortumab may be undertaken as 
appropriate (labeled as Dose Level -1 in Table 7).  Throughout the study, pembrolizumab and 
enfortumab will be administered in accordance with approved labeling.  Guidance for adverse event 
management and associated pembrolizumab treatment modifications are provided in product labeling.   
Table 6 Sitravatinib Starting Dose Levels for Lead-In Dose Escalation Cohort 9 (Malate 
Formulation) 
Sitravatinib Dose Level 
Sitravatinib Daily Dose 
1 
35 mg PO QD 
-21 
50 mg PO QD 
2 
70 mg PO QD 
3 
100 mg PO QD 
Abbreviations: PO = orally; QD = once daily. 
1    The 50 mg dose level will be enrolled only if de-escalation is needed after assessment of the next 
higher dose level (70 mg). 
Table 7 Pembrolizumab and Enfortumab Dose Levels 
Combination 
Regimen Dose Level 
Pembrolizumab1 
Enfortumab1 
-12 
200 mg IV Q3W 
1 mg/kg IV on days 1 and 8 of Q3W 
1 
200 mg IV Q3W 
1.25 
mg/kg IV on days 1 and 8 of 
Q3W 
Abbreviations: IV = intravenous; Q3W = every 3 weeks. 
1  Pembrolizumab and enfortumab should be administered according to USPI and standard care. 
2  The 1 mg/kg dose level of enfortumab will be enrolled only if de-escalation is needed after 
assessment of the next higher dose level (1.25 mg/kg). 
Dose-Limiting Toxicities (DLTs) in Cycle 1 for the Lead-In Dose Escalation Portion of Cohort 9 
DLTs are only defined for patients in the lead-in dose escalation portion of Cohort 9.  The definition of 
DLT for the purpose of dose escalation decisions includes any of the following events considered to be 
causally related to treatment with sitravatinib in combination with pembrolizumab and enfortumab that 
occurs from Cycle 1 Day 1 through pre-dose Cycle 2 Day 1: 
Hematological DLTs: 
• 
Grade 4 neutropenia, if it lasts more than 7 days. 
• 
≥ Grade 3 febrile neutropenia. 
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• 
≥ Grade 3 neutropenia with significant clinical sequelae. 
• 
Grade 4 thrombocytopenia. 
• 
Grade 3 thrombocytopenia associated with clinically significant bleeding. 
• 
Any requirement for a platelet transfusion. 
• 
Grade 4 anemia unexplained by underlying disease. 
Non-hematological DLTs: 
• 
≥ Grade 4 infusion related reaction. 
• 
Grade 3 infusion related reaction that does not resolve within 24 hours. 
• 
Any ≥ Grade 4 non-hematological toxicity. 
• 
Grade 3 hypertension that cannot be controlled with medical therapy, including: 
o 
Severe hypertension with systolic blood pressure ≥180 mmHg or diastolic blood pressure 
≥120 mmHg, on more than one occasion. 
o 
Sustained uncontrolled hypertension, with systolic blood pressure ≥160 mmHg (but <180 
mmHg) or diastolic blood pressure ≥100 mmHg (but <120 mmHg) lasting for ≥14 days or 
causing treatment delay for ≥4 days. 
• 
Other Grade 3 non-hematologic toxicity lasting for >3 days despite optimal supportive care, with 
the following exceptions: 
o 
Endocrine disorder (thyroid, pituitary, and/or adrenal insufficiency) that can be effectively 
managed with hormone replacement therapy. 
o 
Fatigue that persists for ≤7 days. 
o 
Rash that resolves to Grade ≤1 within 3 weeks. 
o 
Tumor flare (defined as local pain, irritation, or rash localized at sites of known or suspected 
tumor). 
• 
Grade 2 pneumonitis or colitis that does not resolve to ≤ Grade 1 as indicated by symptoms 
within 3 days after onset of the event despite optimal medical management with or without 
corticosteroids. 
• 
≥ Grade 3 non-hematological laboratory abnormalities with clinical consequences that do not 
resolve within 24 hours. 
• 
ALT > 3 x ULN with bilirubin > 2 x ULN. 
• 
Any other related toxic effect during the first 3 weeks may be assessed as a DLT if, upon review 
by the Investigators and Sponsor, it is agreed that the toxicity was of sufficient severity to be 
considered dose limiting. 
• 
Any toxicity that requires suspension of sitravatinib for more than 1 week. 
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• 
A patient did not receive at least 1 dose of pembrolizumab and at least 2 doses of enfortumab up 
to and including Cycle 2 Day 1 due to tolerability issues (i.e., other related AEs not attributed as 
DLTs). 
Patients from the lead-in dose escalation portion of Cohort 9 are considered DLT evaluable if they 
experience a DLT during the first cycle of treatment or if they clear the DLT period.  Patients who received 
prohibited therapy during Cycle 1 (refer to Section Error! Reference source not found.), or who did not 
take at least 80% of the planned dose of sitravatinib, the 1 planned dose of pembrolizumab and 2 
planned doses of enfortumab in Cycle 1 will be ineligible for DLT evaluation and will be replaced unless 
they experience a DLT event.  Initially, at least 3 patients will be enrolled at each new dose level.  The 
first patient to be treated at each new dose level will be observed for at least one week prior to enrollment 
of subsequent patients at that dose level.  Decision making for dose escalation or de-escalation will be in 
accordance with the mTPI-2 method (Dose-Finding Spreadsheet presented in Appendix 2), and will be 
made in collaboration with the Investigators and documented for Regulators and Institutional Review 
Boards by an Administrative Letter to Investigators. 
For the lead-in dose escalation evaluation, no dose reductions of any investigational product are allowed 
during Cycle 1. 
Hypothesis and Sample Size 
Lead-In Dose Escalation Evaluation for Sitravatinib in Combination with Pembrolizumab 
and Enfortumab (Cohort 9) 
Up to 30 patients may be enrolled into the lead-in dose escalation portion of Cohort 9.   
The mTPI-2 design (Guo-2017) will be employed in decision making of dose escalation within each 
regimen investigated.  The mTPI-2 design is based on the following assumptions: 
• 
the maximum tolerated dose (MTD) is the dose associated with probability of dose limiting toxicity 
in 30% of patients during the first treatment cycle; and 
• 
the acceptable variance around the MTD is - 0.05 to + 0.03 (i.e., the region of the MTD is 25% to 
33% incidence of dose limiting toxicity). 
Refer to 02 of the protocol for the dose escalation decision table using the mTPI-2 method. 
7.2 Randomization 
Random assignment to treatment arm is not being used in this study. Enrollment decisions will be 
determined by the site where the patient is enrolled as described in Section 6.1 of the protocol. 
7.3 COVID-19 Pandemic Changes to Study Conduct 
Table 8 below summarizes temporary changes to specific protocol assessments and procedures that are 
allowable during the COVID-19 pandemic (FDA-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 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. 
Patients should not be enrolled into the lead-in dose escalation portion of Cohort 9 unless they are able to 
meet the protocol defined assessments and procedures including adhering visit windows. 
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Table 8 COVID-19 Pandemic Changes to Study Conduct 
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. 
Clinic Visits 
• 
Clinic visits may be conducted remotely by telephone/video 
conference; any missed assessments or procedures (e.g., 
tumor assessment, laboratory assessments, vital signs, 
study drug administration, etc.) should be documented as 
Protocol Deviations. 
• 
Clinic visits may be conducted at the patient’s residence by 
qualified home health care professionals; any missed 
assessments or procedures (e.g., 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. 
Nivolumab Dosing (for 
Cohorts 1 through 8) 
In order to reduce the need for Day 15 visits, Investigators 
should: 
• 
Consider switching all patients who are on the Q2 week 
240 mg nivolumab regimen to the Q4 week 480 mg 
regimen instead, as possible. 
• 
Start all newly enrolled patients on the Q4 week 480 mg 
regimen. 
Day 15 Sample Collection 
for PK and Other 
Exploratory Tests (for 
Cohorts 1 through 8)  
In order to eliminate the Day 15 clinic visit (for Cohorts 1 
through 8):   
• 
C1D15 PK samples, PD samples (TCR sequencing, flow 
cytometry, protein and cytokine biomarkers), and triplicate 
ECG may be collected at C2D1 instead. 
• 
C2D15 PD samples (flow cytometry, protein and cytokine 
biomarkers) may be collected at C3D1 instead.  
PK Sample Collections 
For Cohorts 1 through 8: 
• 
The PK collection required post-dose at 7 hours (5-9 hours) 
on C1D1 and C1D15 may not be collected in order to 
reduce the time that patients need to remain in the clinic for 
the blood draw and ECGs. 
PK sub-study for patients 
with renal impairment (for 
Cohorts 1 through 8) 
Temporarily suspended for new patients to reduce the time 
patients need to remain in the clinic or hospital for blood draws. 
Action and Reporting in the Event of Documented or Suspected COVID-19 Infection 
Study Treatment 
• 
Patients in Screening for Study Entry – Patients who exhibit symptoms consistent with COVID-19 
infection or have recent COVID-19 test results consistent with active viral replication should delay 
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study entry and start of study treatment until resolution of symptoms and evaluation by the 
Investigator.  Questions should be directed to the Sponsor’s Medical Monitor. 
• 
Patients in Study Treatment – For patients on study treatment exhibiting symptoms consistent 
with COVID-19 infection, contact the Sponsor’s Medical Monitor as soon as feasible. 
8.0  Analysis Populations 
8.1 Screened Population 
The Screened Population is defined as all patients who sign an informed consent for the study. 
8.2 Enrolled Population 
The enrolled population is defined as all patients who sign an informed consent form for the study and are 
determined by the investigator to meet all eligibility criteria during screening assessments. This population 
will be used to describe disposition and may include patients who have not received study treatment.   
8.3 Full Analysis Set (FAS) 
The full analysis set will include patients who receive at least one dose of each study treatment drug (i.e. 
at least one dose of both sitravatinib and nivolumab for Cohorts 1 through 8, or at least one dose each of 
sitravatinib, pembrolizumab and enfortumab for Cohort 9). 
This population will be used to present OS and PFS analyses and will also be the population set used for 
tumor assessment, tumor response and time to event listings. 
8.4 Clinical Activity Evaluable Population 
Patients included in the clinical activity evaluable population are patients who receive at least one dose of 
each study treatment drug and have an evaluable baseline tumor assessment and at least one post-
baseline tumor assessment.  
This population will be used to summarize tumor responses as well as to make decisions throughout the 
first two stages of the study on the Predictive Probability Design for Cohorts 1 through 6. 
8.5 Safety Population 
The safety population is defined as all patients who received at least 1 dose of any study treatment 
(sitravatinib, nivolumab, pembrolizumab or enfortumab).  The Safety population will be used for all safety 
analyses. 
8.6 Molecular Marker Evaluable Population 
The molecular marker evaluable population will consist of all patients who receive at least one dose of 
any study treatment (sitravatinib, nivolumab, pembrolizumab or enfortumab) and for whom PD-L1 
expression or circulating PD-L1 results are available. 
8.7 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 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. 
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8.8 Pharmacodynamic Evaluable Population 
The pharmacodynamic evaluable population will consist of all patients who receive at least one dose of 
any study treatment (sitravatinib, nivolumab, pembrolizumab or enfortumab) and for whom PD results are 
available. 
8.9 DLT Evaluable Population (only applicable to lead-in dose escalation portion 
of Cohort 9) 
The DLT evaluable population is defined as patients enrolled in the lead-in dose escalation portion of 
Cohort 9, who experienced a DLT or who cleared the DLT period.  Patients who received prohibited 
therapy during Cycle 1 (refer to Section Error! Reference source not found.), or who did not take at 
least 80% of the planned dose of sitravatinib, and 1 planned dose of pembrolizumab and 2 planned doses 
of enfortumab in Cycle 1 will be ineligible for DLT evaluation and will be replaced unless they experience 
a DLT event. The DLT evaluable population will be used for dose escalation decisions during the lead-in 
dose escalation evaluation. 
9.0 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. 
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. 
9.1 Imputation of AEs or Concomitant Medications 
Start Date 
If the start date of AE is completely missing (i.e., the day, month, and year are all unknown), the 
start date will be set to the date of first dose of study medication. No imputation will be performed 
for medications with completely missing start dates. 
Missing Day Only 
• 
If the month and year of the incomplete date are the same as the month and year of the 
first dose date, then the day of the first dose date will be assigned to the missing day.  
• 
If either the year is before the year of the first dose date or if years are the same but the 
month is before the month of the first dose date, then the last day of the month will be 
assigned to the missing day.  
• 
If either the year is after the year of the first dose date or if both years are the same but 
the month is after the month of the first dose date, then the first day of the month will be 
assigned to the missing day. 
Missing Month Only 
• 
The day will be treated as also missing and both month and day will be replaced according 
to the below procedure.  
Missing Day and Month 
• 
If the year of the incomplete date is the same as the year of the first dose date, then the 
day and month of the first dose date will be assigned to the missing fields. 
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• 
If the year of the incomplete date is not the same as the year of the first dose date, then 
January 1 will be assigned to the missing fields. 
• 
If the stop date is complete and the imputed start date is after the stop date, then the start 
date will be imputed using the stop date. 
 
Stop Date 
Missing Day Only 
• 
If the month and year of the incomplete date are the same as the month and year of the 
last visit date, then the day of the last visit date will be assigned to the missing day. 
• 
If either the year is before the year of the last visit date or if both years are the same but 
the month is before the month of the last visit date, then the last day of the month will be 
assigned to the missing day. 
• 
If either the year is after the year of the last visit date or if both years are the same but 
the month is after the month of the last visit date, then the first day of the month will be 
assigned to the missing day. 
Missing Month Only 
• 
The day will be treated as missing and both month and day will be replaced according to 
the below procedure. 
Missing Day and Month 
• 
If the year of the incomplete date is the same as the year of the last visit date, then the 
day and month of the last visit date will be assigned to the missing fields. 
• 
If the year of the incomplete date is before the year of the last visit date, then December 
31 will be assigned to the missing fields. 
• 
If the year of the incomplete date is after the year of the last visit date, then Jan 1 will be 
assigned to the missing fields. 
 
9.2 Imputation of Alternative Cancer Treatment Start Date 
If the start date is completely missing, given that the patient did receive the anti-cancer therapy. the start 
date will be set to last dose date + 1.  
 
Missing Day Only  
• 
If the month and year of the incomplete date are the same as the month and year of the last 
dose date, then the last dose date + 1 will be assigned to the missing day.   
• 
If the month and year of the incomplete date are after the month and year of the last dose 
date, then the first day of the month will be assigned to the missing day.  
   
Missing Month Only  
• 
The day will be set as missing and treated as missing Day and Month.  
   
Missing Day and Month  
• 
If the year of the incomplete date is the same as the year of the last dose date, then the 
last dose date + 1 will be assigned to the missing day and month.   
• 
If the year of the incomplete date is after the year of the last dose date, then Jan 1 will be 
assigned to the missing day and month.  
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9.3 Imputation of Laboratory Values with Character Symbol 
Missing laboratory data will not be imputed. However, laboratory values of the form of “< x” (i.e., below the 
lower limit of quantification) or “> x” (i.e., above the upper limit of quantification) will be imputed as “x” for 
the purpose of calculation of summary statistics and comparing to normal ranges. These values will still be 
displayed as “< x” or “> x” in the listings. 
9.4 Protocol Deviations 
Potential planned or unplanned protocol deviations noted during clinical monitoring will be documented by 
category (i.e., inclusion criteria, exclusion criteria, study drug, safety assessment, efficacy assessment, visit 
window, informed consent, prohibited medication, and other). All deviations will be reviewed, categorized, 
designated important or not important, and finalized prior to database lock. Important protocol deviations 
will be defined as those potentially impacting safety or efficacy assessments. Additional details of what will 
be considered important can be found in the Protocol Deviation Guidance document. 
10.0 Interim Analyses 
No interim statistical analysis is planned during this study. As detailed in Protocol Section 9.1, per the  
Predictive Probability Design, tumor responses in the clinical activity evaluable population will be reviewed 
and enrollment decisions will be documented. 
11.0 Statistical Methods 
All data collected during this study will be displayed in data listings, unless otherwise specified. Data listings 
will be sorted by cohort and patient identifier for safety and efficacy listings. In addition, listings will include 
all relevant derived variables. 
Descriptive statistics (mean, median, standard deviations [STD], first quartile [Q1], third quartile [Q3], 
minimum and maximum values) for continuous variables will be presented. Mean and median will be 
presented to 1 decimal more than original data. STD will be presented to 2 decimals more than original 
data. Minimum and maximum will match the decimal points in the original data. For categorical variables, 
summary measures will include the frequency and percentage (with 1 decimal place) of patients in each 
category. 
The summary tables will be presented by cohort (including initial and contingent cohorts) and for all cohorts 
combined. 
Unless otherwise noted, missing data will not be imputed or carried forward. 
All data summaries and tabulations will be prepared with SAS Version 9.4 or higher. 
11.1 Patient Disposition 
The number and percentage of patients enrolled and treated in the study will be presented. The number 
and percentage of patients and each population to which they belong will be presented as well as the 
number and percentage of patients who withdrew from the study and a breakdown of the corresponding 
reasons for withdrawal and the number and percentage of patients who discontinued nivolumab, 
sitravatinib, pembrolizumab, or enfortumab with the corresponding reasons. Summaries will be reported by 
cohort. The number of patients enrolled by site and across sites will be presented. Disposition will be 
summarized descriptively by cohort and for all cohorts combined. 
11.2 Important Protocol Deviations 
Important protocol deviations for patients in the Enrolled Population will be reported by category. Important 
protocol deviations will be listed. 
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11.3 Demographic and Baseline Characteristics 
Demographic and baseline data will be summarized descriptively by cohort and all cohorts combined for 
the initial and contingent cohorts for the Safety population. For continuous variables, descriptive statistics 
will include the mean, STD, median, Q1, Q3, and range. For categorical variables, descriptive statistics will 
include the number and percent. 
The term “baseline” is defined as the last pre-dose assessment, (includes screening and Cycle 1 Day 1 
pre-dose assessment which would represent a 29-day window), unless otherwise specified. Unscheduled 
visits assessments preceding C1D1 will be also considered for baseline. If assessment time is missing and 
there is no way to determine if the assessment occurred before or after study drug administration, Cycle 1 
Day 1 assessments will be considered for baseline. 
Demographic variables to be summarized include gender, reproductive status for female, race, ethnicity, 
age (years), baseline weight (kg), baseline height (m), baseline Eastern Cooperative Oncology Group 
(ECOG) status, and smoking history. Age is calculated from date of informed consent to date of birth. 
Primary disease history will be tabulated for the Safety population and will include the summary statistics 
(count and percentage) for Disease Location (Renal Pelvis, Ureter, Bladder, or Urethra), disease stage 
(Unresectable Locally-Advanced or Metastatic), and Clinical Stage (III, IIIA, IIIB, IV, IVA, IVB, Stage 
unknown). 
Demographic, primary disease history, and prior primary disease treatment data will be listed by patient. 
Prior primary disease treatment (systemic therapies including platinum therapies and checkpoint 
inhibitors; radiotherapy, and surgery) will be tabulated for the Safety population and include the summary 
statistics (count and percentage) for the following: 
• 
Prior platinum therapy - Platinum agent received (Cisplatin, Carboplatin, Other); Setting 
(Metastatic, Peri-operative); Disease Progression (Yes, No); Ineligible for platinum-based 
chemotherapy (Yes, No); 
• 
Prior systemic therapy - Type (Neo-adjuvant or Adjuvant, Advanced Disease Treatment 
Regimen, Other); 
• 
Prior checkpoint inhibitor – (Nivolumab, Pembrolizumab, Durvalumab, Atezolizumab, 
Avelumab, Other); Best Overall Response to prior Checkpoint inhibitor (CR, PR, SD, PD); 
• 
Prior antibody drug conjugate – antibody drug conjugate received (Enfortumab Vedotin, 
Sacituzumab Govitecan); 
• 
Prior radiotherapy – Type (Adjuvant, Palliative); 
• 
Prior surgery – Location (Renal Pelvis, Ureter, Bladder, Urethra, Lung, Liver, Bone, Lymph 
Node, Other). 
11.3.1 Baseline Bellmunt Score 
The Bellmunt prognostic risk factor score is a tool that is often used to predict treatment outcomes before 
initiating a secondline treatment regimen. Baseline Bellmunt Score will be computed as number or risk 
factor (0,1,2,or 3) out of the following: 
• 
ECOG PS ≥ 1 
• 
Hemoglobin concentration < 10 g/dL 
• 
Liver metasteses present 
11.4 Prior and Concomitant Medications 
Medications administered to study participants during the on-study period are captured on a log CRF page. 
Medications are considered prior medications if they have a start date prior to the date of first dose of study 
medication or a partial start date which indicates the medication was begun prior to the first dose of study 
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treatment. Medications with missing start dates will be considered prior medications. If medication with 
missing start dates but the end date is after first dose of study treatment, it will be considered as concomitant 
medication as well. Concomitant medications are defined as medications administered to study participants 
on or after the first dose of study treatment and before the last dose of study treatment. A medication can 
be considered both prior and concomitant. Collected prior and concomitant medications will be coded using 
the World Health Organization (WHO) Drug Enhanced (version: 2018MAR01 DDE+HD B3  medical 
dictionary. 
Prior and concomitant medications will be tabulated separately for the Safety population by Anatomical 
Therapeutic Chemical Classification and preferred drug name using counts and percentages. Summaries 
will be presented by cohort (including initial and contingent cohorts) and all cohorts combined. Prior and 
concomitant medications will be included in a patient data listing. 
11.5 Medical History 
Medical history will be tabulated by system organ class (SOC) and preferred term (PT) using counts and 
percentages for the Safety population. Medical history will be coded according to Medical Dictionary for 
Regulatory Activities (MedDRA, Version 21.0). Medical history will be listed by patient. 
Baseline Signs and Symptoms 
Signs and symptoms of the patient’s cancer diagnosis and/or comorbidities present prior to Day 1 of study 
treatment dosing are recorded in the CRF as primary disease history. 
11.6 Efficacy Analyses and Efficacy Variables  
11.6.1 Objective Response Rate (ORR) 
Disease assessments involving radiographic evaluations may be performed over the course of a few days. 
The date of response (Complete Response, CR; Partial Response, PR; Stable Disease, SD; or Not 
Evaluable, NE) will be recorded as the date of the last radiographic evaluation included in the series for that 
time point assessment. The date of progression (PD) will be recorded as the date of the first radiographic 
evaluation included in the series for that time point assessment to identify progression.  
ORR will be categorized in accordance with RECIST v1.1. (Appendix 3) Objective Response Rate (ORR) 
is defined as the percent of patients documented to have a confirmed CR or PR as defined in Table 9. 
Descriptive statistics (frequency and percentage) for ORR, CR, and PR will be presented.  The 95% exact 
Clopper-Pearson CI of these response rates will be calculated.  An exact test for single proportion (two-
sided α = 5%) will be performed to test H0: ORR ≤ 5% against H1: ORR > 5%. 
Best overall response (BOR) is defined as the best response among all overall responses (in the order 
CR, PR, SD, PD, and indeterminate NE) recorded from the start of study drug until disease progression/ 
recurrence, or start of anti-cancer therapy, whichever comes first.  
The status of best response of CR or PR must be confirmed by repeat tumor assessment within no less 
than 4 weeks according to RECIST version 1.1. If the status of CR or PR cannot be confirmed by repeat 
tumor assessment, the BOR of unconfirmed CR and PR will be determined per RECIST 1.1. The status of 
BOR of SD requires an on-study assessment after at least 42 days on treatment. Patients without a valid 
clinical response assessment will be assigned a best overall response of NE. No response will be 
counted after PD.  
Table 9 lists out the different scenarios of confirmed response based on subsequent assessment. The 
status of SD requires an on-study assessment at least 42 days on study. Patients without a valid clinical 
response assessment will be assigned a best overall response of NE. 
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Table 9 Confirmed Response Based on Subsequent Assessments* 
First Time Point 
Response** 
Second Time Point 
Response 
Confirmed Response 
(Best Response)* 
PD 
No further evaluation 
PD 
NE 
PD 
PD 
CR 
PD 
SD or PD (1) 
PR 
PD 
SD or PD (1) 
SD 
PD 
SD or PD (1) 
CR 
CR 
CR 
CR 
NE ** 
SD or NE (2) 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD (3)** 
SD 
PR 
NE ** 
SD or NE (2) 
SD 
CR 
SD 
SD 
PR 
SD 
SD 
SD 
SD 
SD 
NE 
SD or NE (2) 
First Time Point 
Response** 
Second Time Point 
Response 
Confirmed Response 
(Best Response)* 
NE 
CR 
SD 
NE 
PR 
SD 
NE 
SD 
SD 
NE 
NE 
NE 
* 
A Best Response of SD can only be made after the patient is on-study for a minimum of six (6) weeks (42 
days).If the patient is on-study less than six (6) weeks (42 days), any tumor assessment indicating stable 
disease before this time period will have a Best Response of NE unless PD is identified. 
** 
Subsequent documentation of CR may provide confirmation of a previously identified CR for patients where 
the second integrated response was NE.  Subsequent documentation of PR may provide confirmation of a 
previously identified PR for patients where the second integrated response was NE or SD.  If the third Time 
Point Response (TPR) confirms the CR (or PR) then the Confirmed Response will be CR (or PR).  For this 
study, only one (1) intervening NE is allowed between CRs/PRs. For example: CR NE CR = CR; PR NE PR 
= PR.  Additionally, one (1) SD is allowed between PRs (e.g., PR SD PR = PR). 
(1) 
Best response will be SD if the first TPR is after at least six (6) weeks (42 days) on-treatment.  Otherwise, the 
best response will be PD. 
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(2) 
Best response will be SD if the first TPR is after six (6) weeks (42 days) on-study.  Otherwise, the best 
response will be NE. 
(3) 
TPR is SD if the increase from the first to the second assessment does not qualify for PD. 
For patients with unconfirmed CR/PR and who subsequently drop off the study, the best overall response will be SD. 
Descriptive statistics (frequency, percentagefor best overall response (CR, PR, SD, PD, NE) based on 
response assessments by the investigator will be presented.  
The primary analysis will be conducted in the Full Analysis Population and supportive analysis will be 
presented in the Clinical Activity Evaluable population. 
11.6.2 Duration of Response (DOR) 
Duration of response (DOR) in months is defined as the time from date of the first documentation of 
confirmed objective response (CR or PR) to the first documentation of objective PD or to death due to any 
cause in the absence of documented PD (i.e., min [PD date, death date] – date of the first observation of 
response +1)/30.4375. Duration of response will only be calculated for the subgroup of patients achieving 
a confirmed CR or PR. 
DOR will be summarized descriptively using the Kaplan-Meier estimate. The median, 25th percentile, and 
75th percentile of DOR and their two-sided 95% CI (Brookmeyer & Crowley, 1982)  will be calculated where 
appropriate. In addition, minimum and maximum will also be displayed. Kaplan-Meier plots will be provided 
for DOR.  
DOR will be based on response assessments by Investigator. DOR will be conducted in the CAE population 
who have confirmed CR or PR. 
11.6.3 Overall Survival (OS) 
Overall survival (OS) is defined as the time from first dose of study drug to the date of death due to any 
cause. OS (in months) is calculated as (date of death − date of first dose of study drug +1)/30.4375. 
OS will be summarized descriptively using the Kaplan-Meier estimate. The median, 25th percentile, and 
75th percentile of OS and their two-sided 95% CI (Brookmeyer & Crowley, 1982) will be calculated where 
appropriate. In addition, minimum and maximum will also be displayed. Kaplan-Meier plots will be provided.  
The 1-year OS rate (proportion and 95% CI) will be analyzed using Kaplan-Meier methodology 
(Greenwood’s formula, (Kalbfleisch & Prentice, 1980)). 
Analysis will be performed on the FAS. 
Censoring Rules 
For patients who are continuing study at the time of analysis, lost to follow-up or who withdraw consent, the 
OS endpoint will be censored on the last date that patients were known to be alive. The date last known to 
be alive is derived from the CRF and may include the latest visit date for patients ongoing in the study or 
the latest Date of Contact on the Long-Term Follow-Up/Survival Status page, whichever occurs latest. For 
patients with no follow-up after first dose of study drug, OS will be censored at the date of first dose (Day 
1). 
11.6.4 Extent of Follow-up 
The extent of follow-up is defined as the time from the date of the first dose to the last known date that the 
patient was alive (for patients who are alive) or death date (for patients who died). 
The median extent of follow-up with 95% CI will be calculated and presented using a reverse KM approach. 
Analysis will be performed on the FAS. 
11.6.5 Progression-Free Survival (PFS) 
Progression-free survival (PFS) is defined as the time from the first dose of study drug to the date of PD or 
death due to any cause, whichever occurs first in the absence of documented PD. PFS (in months) will be 
calculated as (first event date – first dose date + 1)/30.4375. 
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PFS will be summarized descriptively using the Kaplan-Meier estimate. The median, 25th percentile, and 
75th percentile of PFS and their two-sided 95% CI (Brookmeyer & Crowley, 1982) will be calculated where 
appropriate. In addition, minimum and maximum will also be displayed. Kaplan-Meier plots will be provided 
for PFS.  
Analysis will be performed on the FAS. 
Censoring Rules for DoR and PFS 
The following censoring rules will apply to event dates for time-to-event endpoints that are based on 
radiographic evaluations, i.e., DOR and PFS: 
• 
Endpoints will be censored on the date of first dose (or randomization) with duration of 1 day under 
the following scenarios, unless patients die within 2 consecutive tumor assessments of first dose 
(on or prior to week 16, i.e. Cycle 5 Day 1 plus the 10 day window, which is Study Day 122 for 
Cohorts 1-8 or Day 136 for Cohort 9), , in which case they will be assessed as having an event on 
the date of death (apply to PFS only): 
o 
baseline disease assessment inadequate to apply RECIST1.1; 
o 
no disease assessments are performed during study treatment; or 
o 
all disease assessments performed during study treatment result in the conclusion of NE. 
• 
Endpoints will be censored on the date of the last evaluable disease assessment prior to the start 
of subsequent anti-cancer therapy under the following scenarios (apply to PFS and DOR). Last 
evaluable assessment date is defined as the last response assessment date on or after treatment 
start date with a response of CR, PR, or SD. 
o 
PD or death occur after ≥2 consecutive tumor assessments (i.e., ≥ 122 days of last 
evaluable tumor assessment for Cohorts 1-8 or ≥ 136 days for Cohort 9) that are missed 
or result in the conclusion of NE; 
o 
patient administered subsequent anti-cancer treatment prior to documented PD or death; 
o 
patient lost to follow-up; 
o 
patient withdrawal of consent for follow-up; or 
o 
patients alive and without PD at the time of analysis 
Date of death will be considered an event for DOR and PFS only if death occurred in the absence of 
receiving subsequent anti-cancer therapy, and under one of the following scenarios: 
• 
death occurs prior to PD and < 122 days for Cohorts 1-8 or < 136 days for Cohort 9 after the first 
dose of study treatment; or 
• 
death occurs < 122 days for Cohorts 1-8 or < 136 days for Cohort 9 after the last evaluable disease 
assessment 
 
11.6.6 Clinical Benefit Rate (CBR) 
Clinical benefit rate (CBR) response will be categorized in accordance with RECIST v1.1. CBR is defined 
as the percent of patients documented to have a confirmed CR, PR, or SD. 
Descriptive statistics (frequency and percentage) and 95% exact Clopper-Pearson CI for CBR rate will be 
presented for FAS and CAE. 
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11.6.7 Subgroup Analyses, including Prior Clinical Benefit (PCB) and No Prior 
Clinical Benefit (NPCB) Endpoints 
Baseline characteristics to be evaluated in subgroup analyses include most recent tumor PD-L1 
expression test result indicating high versus low expression and, for cohorts that have prior PD-(L)1 
checkpoint inhibitor therapy experience (i.e. Cohorts 1 through 4, and Cohorts 7 through 9) outcome of 
prior treatment with checkpoint inhibitor therapy, specifically prior clinical benefit versus no prior clinical 
benefit, defined as:  
• 
Prior clinical benefit (PCB): RECIST-defined partial or complete response or stable disease for at 
least 12 weeks (-2 week window permitted for radiograph scheduling) followed by radiographic 
progression of disease.  
• 
No prior clinical benefit (NPCB): does not meet criteria for PCB and has radiographic progression of 
disease ≤ 12 weeks after initiation of treatment (+2 week window permitted for radiograph 
scheduling). 
• 
Efficacy analyses will be presented descriptively per each subgroup listed above, for each cohort, 
as well as for all cohorts combined if deemed appropriate.  
11.7 Safety Analyses 
All safety summaries will be presented by cohort (including initial and contingent cohorts) and all cohorts 
combined.  With regard to safety summaries, the term “on-treatment” is the period from first dose until either 
last dose + 28 days or the start of subsequent anti-cancer therapy, whichever is earlier. 
11.7.1 Extent of Study Drug Exposure and Exposure Variables 
Study Treatment Duration 
Study treatment duration (weeks) is defined as (the last dose date – the first dose date +1)/7.  Weeks on 
treatment will be summarized separately for each study drug. 
Days on Sitravatinib 
Days on sitravatinib is defined as the total number of days patient received sitravatinib, after subtracting for 
interruptions or drug missed, that is: 
the [(latest Stop Date - the earliest Start Date captured on the Sitra Administration CRF page) – number of 
days with 0 mg dose + 1]. 
Cycles Started 
A patient is considered to have started a cycle if they received at least one dose of the study drug in that 
cycle, per the Study Drug Administration CRF page. 
Cumulative Dose Received 
• 
Cumulative dose received for nivolumab (mg) is defined as the total amount of nivolumab  a patient 
receives during the study as recorded on the Nivolumab Administration CRF forms. Nivolumab is 
planned to be administered as a 240 mg intravenous infusion over 30 minutes every 2 weeks. An 
alternative dosing regimen of 480 mg intravenous infusion over 30 minutes every 4 weeks may be 
introduced during the study. Dose modifications should be accounted for in the cumulative dose 
received calculations. 
• 
Cumulative dose received for sitravatinib (mg) is defined as the total amount of sitravatinib  a patient 
receives during the study, that is, Sum of [(Stop date – Start date + 1) x Total Dose (mg per 
administration) x Dose Frequency] as recorded on the Sitravatinib Administration CRF forms. Dose 
modifications should be accounted for in the cumulative dose received calculations 
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• 
Cumalative dose received for pembrolizumab (mg) is defined as total amount of pembrolizumab  a 
patient receives during the study as recorded on the Pembrolizumab Administration CRF forms. 
Pembrolizumab is planned to be administered as 200 mg intravenous infusion every 3 week. 
• 
Cumulative dose received for enfortumab is defined as total amount of enfortumab a patient 
receives during the study as recorded on the Enfortumab Administration CRF forms. Enfortumab 
is planned to be administered as 1 mg/kg infusions on Days 1 and 8, every 3 weeks for combination 
regimine dose level “-12” in Cohort 9. Enfortumab is planned to be administered as 1.25 mg/kg 
infusions on Days 1 and 8, every 3 weeks for combination regimine dose level “1” in Cohort 9.    
Compliance 
• 
Compliance is only applied to sitravatinib and is calculated as cumulative dose received (mg) / 
cumulative planned dose (mg) x 100, where the adjusted cumulative planned dose = (Planned dose 
in mg) * (study treatment duration in days - number of days on dose interruption due to AE - number 
of days on dose reduction due to AE) + ∑(planned reduced daily dose x number of days on dose 
reduction due to AE). 
Dose Intensity 
• 
Relative dose intensity for sitravatinib, nivolumab, pembrolizumab, enfortumab is defined as: 
o 
For sitravatinib: [cumulative dose received (mg) / cumulative planned dose (mg)] x 100, 
where cumulative planned dose is calculated as the starting daily dose multiplied by the 
study treatment duration in days, which does not take into account dose reduction or 
interruption. 
o 
For nivolumab: [cumulative nivolumab dose received (mg)] / [cumulative planned 
nivolumab dose (mg)] x 100, where cumulative planned dose is: 
𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟ቀ
𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑜𝑜𝑜𝑜 𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 𝑖𝑖𝑖𝑖 𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤 +2 𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤
2 𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤
ቁ× 240 𝑚𝑚𝑚𝑚, for patients who 
received 240 mg as last dose 
𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟ቀ
𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑜𝑜𝑜𝑜 𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 𝑖𝑖𝑖𝑖 𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤 +4 𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤
2 𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤
ቁ× 240 𝑚𝑚𝑚𝑚, for patients who 
received 480 mg as last dose 
Duration of nivolumab is last dose of nivolumab – first dose of nivolumab in weeks. 
o 
For pembrolizumab: [cumulative dose received (mg) / cumulative planned dose (mg)] x 
100, where cumulative planned dose is calculated as  
𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟൬𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑜𝑜𝑜𝑜 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑖𝑖𝑖𝑖 𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤+ 3 𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤
3 𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤
൰× 200 𝑚𝑚𝑚𝑚 
 
Duration of nivolumab is last dose of nivolumab – first dose of nivolumab in weeks. 
o 
For enfortumab: [cumulative dose received (mg) / cumulative planned dose (mg)] x 100, 
where cumulative planned dose is calculated as: 
𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟൬𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑜𝑜𝑜𝑜 𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒 𝑖𝑖𝑖𝑖 𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤+ 3 𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤
3 𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤
൰× min( 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑
× 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤ℎ𝑡𝑡 (𝑘𝑘𝑘𝑘) ,  𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑) × 2 (𝐷𝐷𝐷𝐷𝐷𝐷 1 𝑎𝑎𝑎𝑎𝑎𝑎 𝐷𝐷𝐷𝐷𝐷𝐷 8) 
Duration of enfortumab is last dose of enfortumab – first dose of enfortumab in weeks.  
Descriptive statistics will be provided separately for each study drug, for the duration of exposure (weeks), 
the total number of cycles started, number of days on sitravatinib , cumulative dose received (mg) and 
absolute and relative dose intensities as well as compliance. 
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Number and percentage of patients with at least 1 dose reduced and reason for dose reduction (only for 
sitravatinib), at least 1 dose interrupted and reasons for dose interruption will be presented separately for 
each study drug. 
Information regarding patients’ dosing regimens will be listed separately for each study drug. 
11.7.2 Adverse Events 
AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA, Version 21.0). Non-
serious AEs will be reported from the day of first dose of study treatment until at least 28 days after last 
administration of study drug treatment. Serious adverse events (SAEs) are reported from the time that the 
patient provides informed consent (i.e., prior to undergoing any study-specific procedure or assessment) 
until at least 28 days after last administration of study treatment.  All SAEs ongoing or occur on Day 28 
after the last dose should be followed until resolution or stabilization to a chronic condition, or 
administration of alternative cancer treatment, whichever is earlier. 
Treatment-Emergent AEs (TEAEs) 
Treatment emergent AEs (TEAEs) are AEs that begin after first dose of study treatment until 28 days after 
the last dose of study treatment and prior to the initiation of subsequent anti-cancer therapy.  
Baseline signs and symptoms that change attribution or severity during the on-study period are TEAEs. 
Any ongoing TEAEs that changes in attribution or severity is captured as a new AE. All SAEs ongoing or 
occur on Day 28 after the last dose should be followed until resolution or stabilization to a chronic condition, 
or administration of alternative cancer treatment, whichever is later. All AEs will be coded according to the 
MedDRA Version 21.0 dictionary by system organ class (SOC), preferred term (PT), and severity grade 
using NCI CTCAE Version 5.0 . 
Immune-related Adverse Event (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 alternate etiology. irAEs will be 
identified on the adverse events CRF page. 
All adverse event summary tables will be based on the safety population. An overall summary of TEAEs by 
cohort will be presented.  
A breakdown of the number and percentage of patients reporting each adverse event categorized by SOC 
and PT will be presented. Note that counting will be by patient not event and patients are only counted once 
within each SOC or PT at the highest grade. The following summaries will be presented: 
• 
Treatment-emergent adverse events 
• 
Treatment-related treatment-emergent adverse events 
• 
Treatment-emergent adverse events leading to all study drug discontinuation 
• 
Treatment-emergent serious adverse events 
• 
Treatment-emergent adverse events resulting in death 
• 
Treatment-emergent adverse events with maximum CTCAE severity grade ≥ 3 
All summaries will also be presented by: 
• 
Sitravatinib-related treatment-emergent adverse events 
• 
Nivolumab-related treatment-emergent adverse events 
• 
Sitravatinib- or Nivolumab-related treatment-emergent adverse events 
• 
Pembrolizumab-related treatment-emergent adverse events 
• 
Enfortumab-related treatment-emergent adverse events 
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• 
Sitravatinib- or Pembrolizumab- or Enfortumab-related treatment-emergent adverse events 
TEAEs will be presented by PT in descending order of frequency. In addition, TEAEs in the Safety 
population will be presented by grouped grade(Grade 1/2, Grade 3/4, Grade 5 and any) and PT in 
descending order of frequency. 
Immune-related AEs will be summarized separately by SOC, PT, and cohort. 
All AEs (including non-treatment-emergent events and serious events) recorded on the CRF will be listed 
using the all Enrolled Population. A listing of treatment-emergent adverse events leading to dose reduction, 
interruption or discontinuation of either study drug will be presented separately. 
11.7.3 Deaths and Serious Adverse Events 
TEAEs that lead to death and SAEs will be summarized by SOC and PT. The following summaries will be 
presented for TEAEs leading to death and SAEs: 
• 
Treatment-related treatment-emergent adverse events 
• 
Sitravatinib-related treatment-emergent adverse events 
• 
Nivolumab-related treatment-emergent adverse events 
• 
Sitravatinib- or Nivolumab-related treatment-emergent adverse events 
• 
Pembrolizumab-related treatment-emergent adverse events 
• 
Enfortumab-related treatment-emergent adverse events 
• 
Sitravatinib- or Pembrolizumab- or Enfortumab-related treatment-emergent adverse events 
A listing of patients with TEAEs that led to death will be presented. A listing of patients who experience an 
SAE will also be presented. 
11.7.4 Laboratory Data 
All laboratory data will be summarized in International System (SI) units, with certain parameters (creatinine, 
BUN, bilirubin, phosphate, and calcium) repeated using British imperial units commonly used in the US. 
The conversion factors from conventional to SI units will be documented in the Local Lab Conventions 
document for this study. In general, laboratory data will be presented by visit.  
Selected parameters will be presented in shift tables of baseline against worst grade test result. The shift 
from baseline to worst post baseline (including unscheduled visit) NCI CTCAE Version 5.0 grade will be 
presented by cohort and overall cohort combined for albumin (albumin increased), AST (AST increased), 
ALT (ALT increased), bilirubin (bilirubin increased), creatinine (creatinine increased), hemoglobin (anemia), 
neutrophils (neutrophil count decreased), platelets (platelet count decreased), sodium (hyponatremia and 
hypernatremia), potassium (hypokalemia and hyperkalemia), calcium (hypocalcemia and hypercalcemia), 
and uric acid (hyperuricemia). 
For sodium, potassium, and calcium, separate grading criteria exist depending whether the analyte is high 
or low. For the purpose of shift tables, all low values will be included in the Grade 0 group in the shift tables 
for high values, and vice versa (all high values should be included in the Grade 0 group in the shift tables 
for low values). 
Patients with at least 1 on-study measurement for each laboratory parameter will be included, regardless 
of whether or not a baseline assessment is present. 
Clinical laboratory results will be listed by subject. Laboratory values that meet Grade 3 or 4 criteria 
according to NCI CTCAE Version 5.0 will also be listed separately. 
Clinical laboratory parameters to be collected routinely on-study are listed in Table 10 below. 
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Table 10 Laboratory Safety Parameters 
Hematology Panel 
Blood Chemistry Panel 
Hemoglobin 
Aspartate aminotransferase (AST) 
Platelet count 
Alanine aminotransferase (ALT) 
White blood cell count (WBC) 
Alkaline phosphatase 
Neutrophil count 
Total bilirubin 
Lymphocyte count 
Direct bilirubin 
 
Indirect bilirubin 
Coagulation 
Lipase 
International normalized ration (INR) 
Amylase 
Partial thromboplastin time (PTT) 
Sodium 
 
Potassium 
Urinalysis (dip stick) 
Chloride 
Blood 
Bicarbonate [CO2] 
Protein 
Blood urea nitrogen (BUN) 
 
Creatinine 
Thyroid Function Test 
Albumin 
Thyroid stimulating hormone (TSH) 
Total calcium 
 
Magnesium 
 
Uric acid 
 
Hemoglobin A1C (HgBA1c) 
 
Pregnancy Testing: For patients of childbearing potential, a serum or urine pregnancy test will be 
performed by the local laboratory at screening. Pregnancy tests will also be done whenever pregnancy is 
suspected during the study. 
11.7.4.1 Hematology  
Hematology parameters include hemoglobin, platelet count, WBC count, lymphocytes, and neutrophils. The 
coagulation parameters include partial thromboplastin time (PTT), and international normalized ratio (INR). 
Descriptive statistics will be provided for each test result and for change from baseline by cycle. Multiple 
measurements taken during the visit for a patient will be represented by the most severe value for each 
hematology test. The most severe value will be determined first by the value closest to the upper or lower 
limit of the normal limits (dependent on which direction is considered severe) if the value is within the normal 
limits. If the value is outside the normal limits, the value furthest from the upper or lower limit will be selected 
(dependent on which direction is considered severe). In the event that this algorithm does not allow for 
determining the most severe (e.g., a tie, etc.) the first chronological value will be selected. Low values are 
considered the most severe for all hematology parameters. Shift tables (for hemoglobin (anemia), 
neutrophils (neutrophil count decreased), platelets (platelet count decreased)), summarizing the shift from 
baseline grade to each post-baseline visit, maximum post-baseline CTCAE grade including unscheduled 
visits, and last assessment on study will be presented. Patients who develop a ≥ Grade 3 toxicity will be 
listed. 
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11.7.4.2 Chemistry  
Serum chemistry parameters include ALT, AST, alkaline phosphatase, total bilirubin, direct bilirubin, indirect 
bilirubin, lipase, amylase, creatinine, uric acid, BUN, albumin, sodium, potassium, chloride, magnesium, 
calcium and bicarbonate. 
Descriptive statistics will be provided for each test result and for change from baseline by cycle. Multiple 
measurements taken during the visit for a patient will be represented by the most severe value as noted in 
Section 12.7.4.1. For all chemistry analytes, the most severe value is the highest value, with the exception 
of albumin, chloride, and bicarbonate. The most severe could be in either direction for potassium, sodium, 
and calcium. For these analytes, if within the normal limits, then the value closest to the normal limit (either 
direction) will be selected. If outside the normal limits, then the value most distant from the normal limit 
(either direction) will be used. Shift tables (for AST (AST increased), ALT (ALT increased), creatinine 
(creatinine increased), sodium (hyponatremia and hypernatremia), potassium (hypokalemia and 
hyperkalemia), and uric acid (hyperuricemia), summarizing the shift from baseline grade to each post-
baseline visit, maximum post-baseline CTCAE grade including unscheduled visits, and last assessment on 
study will be presented. Patients who develop a ≥ Grade 3 toxicity will be listed. 
11.7.4.3 Urinalysis 
Urinalysis results for the parameters blood and protein will be listed. 
11.7.4.4 Thyroid 
Results will be listed for Thyroid stimulating hormone (TSH). 
11.7.4.5 CTCAE Coding of Laboratory Data 
Where laboratory values are categorized into NCI CTCAE Version 5.0 grades, the categories are defined 
according to the criteria available on the following website: http://evs.nci.nih.gov/ftp1/CTCAE/About.html. 
Note that grades are applied based only on the numeric SI value of the parameter assessed; clinical signs 
and symptoms are not considered. Where categories are only distinguished by clinical signs or symptoms, 
the lowest of the possible grades will be assigned. 
NCI CTCAE grades will be applied for the following lab parameters:  
• 
Hematology: hemoglobin, WBC, lymphocyte, neutrophils, and platelets. 
• 
Chemistry: ALT, albumin, Alkaline phosphatase, AST, total bilirubin, calcium, creatinine, 
magnesium, potassium, sodium, uric acid. 
Laboratory measurements that are within their institutional limits of normal and are not graded as 1-4, per 
the CTCAE, will be summarized as “Grade 0,” which is defined as normal. 
11.7.4.6 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 (i.e., 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. 
A figure displaying patients who are at risk for a drug induced liver injury according to Hy’s law will be 
presented. A listing of patients at risk will also be presented. 
11.7.5 Vital Signs 
Clinically significant findings noted during screening will be reflected on the medical history CRF, while 
those noted during study treatment will be collected on the AE CRFs. The following vital signs will be 
summarized: pulse rate (beats/min), systolic blood pressure (SBP; mmHg), diastolic blood pressure (DBP; 
mmHg), body temperature (C), Height (cm) and weight (kg). Height will be recorded at screening only.  
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Vital signs and change from baseline will be summarized. All vital signs and change from baseline through 
the last Cycle will be summarized by cohort and all cohorts combined. This will include a summary of the 
maximum and minimum values observed while the patient was on treatment and change from baseline to 
that observed value. 
Potentially clinically important vital sign results will be summarized separately. These criteria are defined 
as increases in blood pressure and weight changes: 
• 
SBP (≥160 mmHg, ≥180 mmHg, ≥ 200 mmHg)   
• 
DBP (≥100 mmHg, ≥120 mmHg) 
• 
Weight increased ≥5% from baseline 
• 
Weight decreased ≥10% from baseline 
All vital signs will be listed. 
11.7.6 Physical Examinations, ECGs, and Other Observations Related to Safety 
11.7.6.1 Physical Examination 
A physical examination including all major body systems is mandated at Screening and End of Treatment 
Visits only. During study treatment, symptom-directed physical examinations are performed. 
Complete physical examinations will be conducted during screening and at the End of Treatment visit. 
Abbreviated physical examinations will be performed on Day 1 and Day 15 of all cycles. Any new 
abnormal physical exam findings will be collected as AEs. Physical Examination data will be listed for the 
Safety population 
11.7.6.2 Eye Exam (Cohort 9 only) 
Patients with recent ocular complaints (within ≤ 3 months of screening) must have a complete eye 
examination at Screening Visit performed by a qualified ophthalmologist or optometrist, including but not 
limited to: uncorrected, corrected and best corrected visual acuity, slit lamp, tonometry examination, and 
dilated fundus examination.  Prior ophthalmologic exam done within 3 months of screening is acceptable 
provided there are no new symptoms since that exam.  End of Treatment Visit slit lamp examinations are 
required for all patients who experience corneal adverse events during the study and must be performed 
≥ 28 days from last dose of enfortumab.  Additional eye examinations are to be conducted as clinically 
indicated. 
 
Eye exam data will be presented as Listings including values obtained on visual acuity tests within 3 
months of screening, and End of Treatment Visit (as applicable), and any additional eye measurements 
(as needed), and corneal Adverse Events. 
 
Eye exam Table will include patient id, baseline visual acuity values, change in visual actuiy value by test, 
and percent change of visual acuity test value till End of Treatment. 
Another eye exam Table will include Number of Corneal Adverse Events (absolute and by percentage) by 
Cohort and for Total. 
11.7.6.3 Electrocardiograms 
Single and triplicate 12-Lead electrocardiogram (ECG) parameters will be collected. The following will be 
assessed: rhythm (sinus or other), heart rate (bpm), QRS, QT, RR, and the investigator interpretation. The 
QT interval corrected for heart rate by the Fridericia’s formula (QTcF) will be manually calculated in the 
database. 
A summary of ECG parameters including heart rate (beats/min), QT interval (msec), QTcF (msec), rhythm, 
and RR interval (msec) and change from baseline will be presented for each planned visit as well as the 
minimum, maximum, and last observation on-treatment.  
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For each planned visit for which a triplicate ECG is obtained, the average the 3 values should be calculated 
for each parameter at each timepoint.  The average values will be used for the ECG tables.  
The baseline to be used in the calculation of changes over time will be the mean of the 6 pre-dose values, 
i.e., the triplicate values at -1 hour and -0.5 hours pre-dose. 
In addition, listings and summaries will be generated for patients by Maximum ICH E14 Category with QTcF 
increased to value ≥480 and <500 msec, and value ≥500 msec, and patients with change from baseline 
QTcF increased by ≥30 to <60 msec, and by ≥60 msec. Patients with PR value >220 msec and change 
from baseline >25% as well as patients with QRS >110 msec and change from baseline >25% will also be 
summarized and presented in Listings. A shift from baseline to worst CTCAE grade summary will also be 
presented. 
A shift from baseline to worst CTCAE (v5.0) grade for QTcF values will also be presented.  
QTcF will be graded per CTCAE v5.0. the grades are as follows: 
• 
Grade 0: value <450 msec 
• 
Grade 1: value 450 to 480 msec 
• 
Grade 2: value >480 to 500 msec 
• 
Grade 3: value >500 or increase from baseline >60 msec 
Descriptive summaries for patients meeting the following ECG thresholds (based on the average of triplicate 
measurements at each time point), will also be provided: 
• 
Absolute QTc ≤450 msec,  >450 to ≤480 msec, >480 to ≤500 msec, >500 msec 
• 
Change from baseline QTc ≤30 msec,  >30 to ≤60 msec,  >60 msec 
• 
PR >220 msec and change from baseline >25% 
• 
QRS >110 msec and change from baseline >25% 
A separate listing of the ECG results along with the overall interpretation will be presented. 
11.7.6.4 Multigated Acquisition Scan or Echocardiogram  
Echocardiogram (ECHO) or Multigated Acquisition Scan (MUGA) will be performed at screening, and 
thereafter at Cycle 3 Day 1, and as clinically indicated and also at the 7-Day post-treatment visit as in 
Schedule of Assessments Tables 1-3 of the protocol. Additional assessments of left ventricular ejection 
fraction (LVEF) may be performed as clinically indicated at the investigator’s discretion if there are signs or 
symptoms of cardiotoxicity.   
 
MUGA or ECHO parameters, including LVEF, will be summarized. Observed values and changes from 
baseline will be presented for each planned visit. Additionally, patients who have at least one on-treatment 
decrease in value will be summarized using the following four categories: 10-<20% decrease from baseline 
and value ≥40%, 10-<20% decrease from baseline and value <40%, ≥20% drop from baseline and value 
≥40%, and ≥20% drop from baseline and value <40%. More specifically, the summary table for LVEF (%) 
would reflect the following 4 categories with the number and percentage: 
1. Decrease from Baseline of ≥10% and Absolute on-treatment Value ≥40% 
2. Decrease from Baseline of ≥10% and Absolute on-treatment Value <40% 
3. Decrease from Baseline of ≥20% and Absolute on-treatment Value ≥40% 
4. Decrease from Baseline of ≥20% and Absolute on-treatment Value <40% 
A separate listing of the MUGA or ECHO results will be presented. 
11.7.6.5 Pregnancy Test 
Pregnancy testing data will be listed for the Safety population.  
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11.7.6.6 Long Term Follow-up 
Long term follow-up/survival data will be listed for the safety population. Additionally, all follow-up anti-
cancer therapy will be listed. 
11.7.6.7 Death Report 
Death report data will be summarized by cohort and listed for the Enrolled Population. 
11.8 Other Endpoints 
• 
Pharmacokinetic evaluations of sitravatinib. 
• 
Pharmacodynamic evaluation in tumor tissue. 
• 
Pharmacodynamic evaluation in the blood. 
• 
Circulating tumor DNA. 
12.0 References 
Brookmeyer, R and Crowley, J. A confidence interval for mean survival time. Biometrics, 1982, 38, 29-41. 
 
Guo W, Wang SJ, Yang S, Lynn H, Ji Y. A Bayesian interval dose-finding design addressingOckham's 
razor: mTPI-2. Contemp Clin Trials. 2017;58:23-33. 
 
Ji Y, Wang S-J. Modified Toxicity Probability Interval Design: A Safer and More Reliable Method than the 
3 + 3 Design for Practical Phase I Trials. J Clin Oncol. 2013;31(14):1785-1791. 
doi:10.1200/JCO.2012.45.7903. 
 
Kalbfleisch, JD and Prentice, RL. The statistical analysis of time failure data. 1980, New York: John Wiley 
 
Lee J-J, Liu D-D. A predictive probability design for phase II cancer clinical trials. Clin Trials 2008;5(2):93-
106. doi: 10.1177/17/1740774508089279. 
 
Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 1989;10(1):1-10. 
 
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Appendix 1 Glossary of Abbreviations 
Glossary of Abbreviations: 
ADC 
Antibody-Drug Conjugate 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
ATC 
Anatomic Therapeutic Class 
BOR 
Best Overall Response 
BUN 
Blood Urea Nitrogen 
C 
Celsius 
CBR 
Clinical Benefit Rate 
CI 
Confidence Interval 
CIT 
Checkpoint Inhibitor Therapy 
CO2 
Carbon Dioxide 
CR 
Complete Response 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
CT 
Computed Tomography Scan 
CTCAE 
Common Toxicity Criteria for Adverse Events 
ctDNA 
Circulating Tumor Deoxyribonucleic Acid 
DBP 
Diastolic Blood Pressure 
DLT 
Dose-Limiting Toxicity 
DR 
Duration of Response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EV 
Enfortumab 
FDA 
Food and Drug Administration 
INR 
Internal Normalization Ratio 
irAE 
Immune-related Adverse Event 
LVEF 
Left Ventricular Ejection Fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
NCI 
National Cancer Institute 
NE 
Not Evaluable 
NPCB 
No Prior clinical benefit 
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Glossary of Abbreviations: 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PCB 
Prior clinical benefit 
PD 
Progressive Disease 
PD-1 
Programmed Cell Death 1 
PD-L1 
Programmed Cell Death Ligand 1 
PET 
Positron Emission Tomography Scan 
PFS 
Progression-free Survival 
PK 
Pharmacokinetic 
PPD 
Predictive Probability Design 
PR 
Partial Response 
PT 
Preferred Term 
PTT 
Partial Thromboplastin Time 
Q1 
First Quartile 
Q2W 
Every 2 Weeks 
Q3 
Third Quartile 
QD 
Once Daily 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SD 
Stable Disease 
SI 
International System 
SOC 
System Organ Class 
STD 
Standard Deviation 
TEAE 
Treatment-emergent Adverse Event 
TFL 
Tables, Figures, and Listings  
TSH 
Thyroid-stimulating Hormone 
WBC 
White Blood Cell 
WHO 
World Health Organization 
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Appendix 2 Dose De-Escalation Decision Table Using the mTPI Method 
The table below will be used for decision making with regards to potential starting dose escalations in 
subsequent patients.  The assessment is based on the number of patients with toxicity at a given dose 
regimen of sitravatinib in combination with pembrolizumab and enfortumab in the lead-in dose escalation 
evaluation (Cohort 9) as defined in Error! Reference source not found. and assumes a maximum 
toxicity level of no more than 30% at the tolerated dose.  The letters in different colors are computed 
based on the decision rules under the mTPI-2 method (Guo-2017) and represent different dose-finding 
actions which include: E = Escalate to next higher dose; S = Stay at the current dose; D = De-escalate to 
the next lower dose; and U = The current dose in unacceptably toxic. 
 
 
Number of Patients Treated at Current Dose 
 
 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 
Number of Toxicities 
0 E E E E E E E E E E E E E E E E E E E E E E E E E E E E E E 
1 D D D S E E E E E E E E E E E E E E E E E E E E E E E E E E 
2  D
U D D D D S S E E E E E E E E E E E E E E E E E E E E E E 
3  
 
D
U 
D
U D D D D D S S S E E E E E E E E E E E E E E E E E E 
4  
 
 
D
U 
D
U 
D
U D D D D D D S S S S E E E E E E E E E E E E E E 
5  
 
 
 
D
U 
D
U 
D
U 
D
U 
D
U D D D D D D S S S S S E E E E E E E E E E 
6  
 
 
 
 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U D D D D D D D S S S S S S E E E E E E 
7  
 
 
 
 
 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U D D D D D D D D S S S S S S S E E 
8  
 
 
 
 
 
 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U D D D D D D D D S S S S S S 
9  
 
 
 
 
 
 
 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U D D D D D D D D S S S 
1
0  
 
 
 
 
 
 
 
 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U D D D D D D D D D 
1
1  
 
 
 
 
 
 
 
 
 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U D D D D D D 
1
2  
 
 
 
 
 
 
 
 
 
 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U D D D 
1
3  
 
 
 
 
 
 
 
 
 
 
 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U D 
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Page 47 of 51 
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1
4  
 
 
 
 
 
 
 
 
 
 
 
 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
1
5  
 
 
 
 
 
 
 
 
 
 
 
 
 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
1
6  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
1
7  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
1
8  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
1
9  
 E = Escalate to the next higher dose 
 S = Stay at the current dose 
 D = De-escalate to the next lower dose 
 U = The current dose is unacceptable toxic 
 MTD = 0.30 
 Sample size = 30 
 Epsilon1 (ɛ1) = 0.05 
 Epsilon1 (ɛ2) = 0.03 
 
 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
2
0  
 
 
 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
2
1  
 
 
 
 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
2
2  
 
 
 
 
 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
2
3  
 
 
 
 
 
 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
2
4  
 
 
 
 
 
 
 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
2
5  
 
 
 
 
 
 
 
 
D
U 
D
U 
D
U 
D
U 
D
U 
D
U 
2
6  
 
 
 
 
 
 
 
 
 
D
U 
D
U 
D
U 
D
U 
D
U 
2
7  
 
 
 
 
 
 
 
 
 
 
D
U 
D
U 
D
U 
D
U 
2
8  
 
 
 
 
 
 
 
 
 
 
 
D
U 
D
U 
D
U 
2
9  
 
 
 
 
 
 
 
 
 
 
 
 
D
U 
D
U 
3
0  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
D
U 
 
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Appendix 3 Abbreviated Presentation of RECIST Version 1.1 Guidelines 
 
A modification to RECIST 1.1 has been made to account for the possibility of temporary changes 
resulting from the potentially beneficial treatment responses of tumor necrosis, cavitation or flare 
response.   
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 treatment.  If the baseline assessment is inadequate, subsequent 
statuses generally should be indeterminate.   
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. 
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Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ, 5 lesions in total, representative of all 
involved organs, should be identified as target lesions at baseline.  Target lesions should be selected on 
the basis of size (longest lesions) and suitability for accurate repeated measurements.  Record the 
longest diameter for each lesion, except in the case of pathological lymph nodes for which the short axis 
should be recorded.  The sum of the diameters (longest for non-nodal lesions, short axis for nodal 
lesions) for all target lesions at baseline will be the basis for comparison to look for partial response at 
later assessments.   
• 
If 2 target lesions coalesce the longest diameter measurement of the coalesced mass is used.  If 
a large target lesion splits, the sum of the parts is used. 
• 
Measurements for target lesions that become small should continue to be recorded.  If a target 
lesion becomes too small to measure, 0 mm should be recorded if the lesion is considered to 
have disappeared; otherwise a default value of 5 mm should be recorded. 
• 
When nodal lesions decrease to <10 mm (normal), the actual measurement should still be 
recorded. 
Non-Target Lesions 
All non-measurable disease is non-target.  All measurable lesions not identified as target lesions are also 
included as non-target disease.  Measurements are not required but rather qualitative evaluations of 
status will be recorded.  Multiple non-target lesions in one organ may be recorded as a single item on the 
CRF (e.g., ‘multiple liver metastases’). 
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 indeterminate.   
Target Disease 
• 
Complete Response (CR): Complete disappearance of all target lesions with the exception of 
nodal disease.  All target nodes must decrease to normal size (short axis < 10 mm).  All target 
lesions must be assessed. 
• 
Partial Response (PR): Greater than or equal to 30% decrease under baseline of the sum of 
diameters of all target measurable lesions.  The short diameter is used in the sum for target 
nodes, while the longest diameter is used in the sum for all other target lesions.  All target lesions 
must be assessed.   
• 
Stable Disease (SD): Does not qualify for CR, PR or Progression.  All target lesions must be 
assessed.  Stable can follow PR only in the rare case that the sum increases by less than 20% 
from the nadir, but enough that a previously documented 30% decrease no longer holds.   
• 
Progressive Disease (PD): 20% increase in the sum of diameters of target measurable lesions 
above the smallest sum observed (over baseline if no decrease in the sum is observed during 
therapy) with a minimum absolute increase of 5 mm.   
• 
Indeterminate: Progression has not been documented, and  
o 
one or more target lesions have not been assessed,  
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o 
or assessment methods used were inconsistent with those used at baseline and impaired 
assessment, 
o 
or one or more target lesions cannot be measured accurately (eg, poorly visible unless due to 
being too small to measure), 
o 
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.   
• 
Indeterminate: Progression has not been determined and 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. 
Lesion Changes That May Be Transient 
Potential exists for individual tumor lesions to develop necrosis, to cavitate, have a flare response to 
treatment or become otherwise difficult to evaluate for a period of time as the result of beneficial study 
treatment impact.  For example, tumor necrosis, cavitation or flare may result in increase in overall size of 
individual lesions or unclear tumor margins prior to recovery to smaller lesions, development of scar 
tissue, or complete resolution.  The true tumor measurements of lesions should be recorded but the 
conclusion of progressive disease may be suspended until continued assessment clarifies the nature of 
the tumor change.  If repeat assessments indicate progression of disease, then PD should be recorded 
on the date of the first assessment giving the impression of progression.  If repeat assessments indicate 
that the change was a process of transition, then NE (not evaluable) should be recorded during the period 
of transition, and PR or CR may be recorded for subsequent evaluations.  The CRF will collect 
information on the observations during the period of transition to support the assessment conclusions.   
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. 
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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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