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

Urothelial Carcinoma Clinical Trial

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03606174
• Other study ID #: 516-003
• Status: Terminated
• Phase: Phase 2
• Start date: September 11, 2018
• Est. completion date: August 22, 2022

Study information

• Verified date: August 2023
• Source: Mirati Therapeutics Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 260
• Est. completion date: August 22, 2022
• Est. primary completion date: August 3, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Transitional Cell
• Urinary Bladder Neoplasms
• Urothelial Carcinoma
• Urothelial Carcinoma Bladder
• Urothelial Carcinoma of the Renal Pelvis and Ureter
• Urothelial Carcinoma Ureter
• Urothelial Carcinoma Urethra

Intervention

Drug:
• Sitravatinib
Sitravatinib is a small molecule inhibitor of receptor tyrosine kinases
• Nivolumab
Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody
• Pembrolizumab
Pembrolizumab is a programmed death receptor-1 (PD-1) blocking antibody
• Enfortumab vedotin
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)

Locations

Country	Name	City	State
United States	New York Oncology Hematology - Albany Medical Center	Albany	New York
United States	Rocky Mountain Cancer Centers	Aurora	Colorado
United States	Texas Oncology-Austin Central	Austin	Texas
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	University of North Carolina - Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina
United States	The University of Chicago	Chicago	Illinois
United States	The Ohio State University College of Medicine	Columbus	Ohio
United States	Barbara Ann Karmanos Cancer Institute	Detroit	Michigan
United States	Duke University Hospital	Durham	North Carolina
United States	Virginia Cancer Specialists- Fairfax	Fairfax	Virginia
United States	Texas Oncology- Memorial City	Houston	Texas
United States	University of Texas - MD Anderson Cancer Center	Houston	Texas
United States	Indiana University - Melvin & Bren Simon Cancer Center	Indianapolis	Indiana
United States	University of California Irvine	Irvine	California
United States	Northwell Health Monter Cancer Center	Lake Success	New York
United States	Maryland Oncology Hematology, P.A.	Lanham	Maryland
United States	Comprehensive Cancer Centers of Nevada - Southwest	Las Vegas	Nevada
United States	Norton Cancer Institute - Broadway	Louisville	Kentucky
United States	Vanderbilt University - Ingram Cancer Center	Nashville	Tennessee
United States	Yale School of Medicine	New Haven	Connecticut
United States	Ochsner Cancer Institute	New Orleans	Louisiana
United States	Memorial Sloan-Kettering Cancer Center	New York	New York
United States	New York-Presbyterian - Weill Cornell Medical Center	New York	New York
United States	NYU Langone Laura & Isaac Perlmutter Cancer Center	New York	New York
United States	Virginia Oncology Associates	Norfolk	Virginia
United States	GU Research Network/Urology Cancer Center	Omaha	Nebraska
United States	Allegheny General Hospital	Pittsburgh	Pennsylvania
United States	Washington University School of Medicine - Siteman Cancer Center	Saint Louis	Missouri
United States	SCRI - Florida Cancer Specialists- North Region	Saint Petersburg	Florida
United States	University of Texas Health Science Center	San Antonio	Texas
United States	Seattle Cancer Center Alliance	Seattle	Washington
United States	Moffitt Cancer Center	Tampa	Florida
United States	The University of Arizona Cancer Center	Tucson	Arizona
United States	Texas Oncology - Tyler	Tyler	Texas
United States	SCRI - Florida Cancer Specialists - West Palm Beach	West Palm Beach	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Mirati Therapeutics Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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)
Secondary	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)