A Phase 2 Study of Sitravatinib in Combination With PD-(L)1 Checkpoint Inhibitor Regimens in Patients With Advanced or Metastatic Urothelial Carcinoma

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase 2 Study of Sitravatinib in Combination With PD-(L)1 Checkpoint Inhibitor Regimens in Patients With Advanced or Metastatic Urothelial Carcinoma

Conditions
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Urothelial Carcinoma, Urothelial Carcinoma Bladder, Urothelial Carcinoma Ureter, Urothelial Carcinoma of the Renal Pelvis and Ureter, Urothelial Carcinoma Urethra

Intervention / Treatment
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* Drug: Sitravatinib
* Drug: Nivolumab
* Drug: Pembrolizumab
* Drug: Enfortumab vedotin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of urothelial carcinoma Adequate bone marrow and organ function Exclusion Criteria: Uncontrolled tumor in the brain Unacceptable toxicity with prior checkpoint inhibitor Impaired heart function

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: There are 9 cohorts (having 9-55 maximum patients enrolled in each; based upon response rate). Patients are assigned to cohorts based upon their prior treatments for urothelial carcinoma.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>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. | Drug: Sitravatinib<br>* Sitravatinib is a small molecule inhibitor of receptor tyrosine kinases<br>* Other names: MGCD516;Drug: Nivolumab<br>* Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody<br>* Other names: Opdivo;|
| Experimental: Cohort 2<br>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. | Drug: Sitravatinib<br>* Sitravatinib is a small molecule inhibitor of receptor tyrosine kinases<br>* Other names: MGCD516;Drug: Nivolumab<br>* Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody<br>* Other names: Opdivo;|
| Experimental: Cohort 3<br>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. | Drug: Sitravatinib<br>* Sitravatinib is a small molecule inhibitor of receptor tyrosine kinases<br>* Other names: MGCD516;Drug: Nivolumab<br>* Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody<br>* Other names: Opdivo;|
| Experimental: Cohort 4<br>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. | Drug: Sitravatinib<br>* Sitravatinib is a small molecule inhibitor of receptor tyrosine kinases<br>* Other names: MGCD516;Drug: Nivolumab<br>* Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody<br>* Other names: Opdivo;|
| Experimental: Cohort 5<br>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. | Drug: Sitravatinib<br>* Sitravatinib is a small molecule inhibitor of receptor tyrosine kinases<br>* Other names: MGCD516;Drug: Nivolumab<br>* Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody<br>* Other names: Opdivo;|
| Experimental: Cohort 6<br>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. | Drug: Sitravatinib<br>* Sitravatinib is a small molecule inhibitor of receptor tyrosine kinases<br>* Other names: MGCD516;Drug: Nivolumab<br>* Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody<br>* Other names: Opdivo;|
| Experimental: Cohort 7<br>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. | Drug: Sitravatinib<br>* Sitravatinib is a small molecule inhibitor of receptor tyrosine kinases<br>* Other names: MGCD516;Drug: Nivolumab<br>* Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody<br>* Other names: Opdivo;|
| Experimental: Cohort 8<br>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. | Drug: Sitravatinib<br>* Sitravatinib is a small molecule inhibitor of receptor tyrosine kinases<br>* Other names: MGCD516;Drug: Nivolumab<br>* Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody<br>* Other names: Opdivo;|
| Experimental: Cohort 9<br>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). | Drug: Sitravatinib<br>* Sitravatinib is a small molecule inhibitor of receptor tyrosine kinases<br>* Other names: MGCD516;Drug: Pembrolizumab<br>* Pembrolizumab is a programmed death receptor-1 (PD-1) blocking antibody<br>* Other names: Keytruda;Drug: Enfortumab vedotin<br>* 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)<br>* Other names: Padcev;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | ORR was defined as the number of participants documented to have a confirmed investigator-assessed complete response (CR) or partial response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST) V1.1. CR was defined as complete disappearance of all target lesions with the exception of nodal disease. All target nodes must have decreased to normal size (short axis < 10 mm). PR was defined as a greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. | Up to approximately 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Experienced an Adverse Event (AE) | An AE was defined as any reaction, side effect or other undesirable medical event that occurred during participation in a clinical trial, regardless of treatment group or suspected causal relationship to study treatment. Any clinically significant changes from baseline in laboratory results were recorded as AEs. | Day 1 up to approximately 3 years | 
| Number of Participants Who Experienced a Serious Adverse Event (SAE) | An SAE was defined as any event that resulted in death, was life-threatening (immediate risk of death), required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/permanent damage (substantial disruption of the ability to conduct normal life functions), a congenital anomaly/birth defect, or may have jeopardized the participant and may have required medical or surgical intervention to prevent intensive treatment in an emergency room or at home (e.g. for allergic bronchospasm, blood dyscrasias or convulsions) that do not result in inpatient hospitalization, development of drug dependency or drug abuse. | Day 1 up to approximately 3 years | 
| Number of Participants Who Experienced a Treatment-related Adverse Event | A treatment-related adverse event was defined as an adverse event determined to have a possible causal relationship to the study treatment(s) by the investigator. An adverse event was defined as any reaction, side effect or other undesirable medical event that occurred during participation in a clinical trial. Any clinically significant changes from baseline in laboratory results were recorded as adverse events. | Day 1 up to approximately 3 years | 
| Duration of Response (DOR) | DOR was 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) per RECIST V1.1, or to death due to any cause in the absence of documented PD. CR was defined as complete disappearance of all target lesions with the exception of nodal disease. All target nodes must have decreased to normal size (short axis < 10 mm). PR was defined as a greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. PD was defined as 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. Per the statistical analysis plan (SAP), Cohort 9 arms are grouped as pre-specified as there was never intent to compare efficacy endpoints across Cohort 9 dose levels. | Up to approximately 3 years | 
| Clinical Benefit Rate (CBR) | Clinical Benefit Rate (CBR) was defined as the number of participants documented to have a confirmed CR, PR, or stable disease (SD), per RECIST V1.1, documented during at least 1 on-study assessment. CR was defined as complete disappearance of all target lesions with the exception of nodal disease. All target nodes must have decreased to normal size (short axis < 10 mm). PR was defined as a greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. SD was defined as target lesions increasing by less than 20% from the nadir, but enough that a previously documented 30% decrease no longer holds. | Up to approximately 3 years | 
| Progression-Free Survival (PFS) | PFS was defined as the time from date of first study treatment to first PD per RECIST V1.1, or death due to any cause in the absence of documented PD. | Up to approximately 3 years | 
| 1-Year Survival Rate | Survival was defined as the time from date of first study treatment to death due to any cause. Kaplan-Meier (product limit) estimates of the percentage of participants who died at 1-year was calculated to estimate the 1-year survival rate, defined as the percentage of participants alive at 1 year. Confidence Intervals were calculated based on Greenwood's formula. Participants who discontinued prior to 1-year were censored on the last date that they were known to be alive. For participants with no follow-up after first dose of study drug, survival rate was censored at the date of first dose (Day 1). | 1 year | 
| Overall Survival (OS) | OS was defined as the time from date of first study treatment to death due to any cause. | Up to approximately 3 years | 
| Geometric Mean Blood Plasma Concentration of Sitravatinib | Blood draws for analysis of blood plasma concentrations of sitravatinib were collected following electrocardiograms and assessment of vital signs. Concentration data below the limit of quantification were set to 0. | Cycle(C)1 Day(D)1 pre-dose, 30min, 2,4,6,7,8,24hr post-dose, C1D15 pre-dose, 30min,2,4,6,7,8,24hr post-dose, C2D1 pre-dose,7hr post-dose, C2D8,C3D1,C3D8,C5D1,C6D8 pre-dose (28 day cycles Cohorts 1-8, 21 day cycles Cohort 9) | 
| Cohort 9 Lead-in Dose Escalation Part Only: Number of Participants Who Experienced a Dose-limiting Toxicity (DLT) | A DLT was defined as any of the following events considered to be causally related to treatment with sitravatinib in combination with pembrolizumab and enfortumab in the lead-in dose escalation part of Cohort 9 (as pre-specified): hematological DLTs (Grade 4 neutropenia, thrombocytopenia, anemia unexplained by underlying disease, ≥Grade 3 febrile neutropenia or neutropenia with significant clinical sequelae, or any requirement for a platelet transfusion), non-hematological DLTs (≥Grade 4 infusion related reaction, non-hematological toxicity, Grade 3 infusion related reaction that does not resolve within 24 hours, hypertension that cannot be controlled with medical therapy), other Grade 3 non-hematologic toxicity lasting for >3 days, with exceptions, Grade 2 pneumonitis or colitis, ≥Grade 3 non-hematological laboratory abnormalities, alanine transaminase>3 x upper limit of normal (ULN) with bilirubin> 2xULN, and other related toxic effects may have been assessed as DLTs. | Cycle 1 Day 1 through pre-dose Cycle 2 Day 1 (cycle for Cohort 9 was 21 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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