Clinical trial NCT03606174: A Phase 2 Study of Sitravatinib in Combination With PD-(L)1 Checkpoint Inhibitor Regimens in Patients With Advanced or Metastatic Urothelial Carcinoma
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
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
Lead sponsor: Mirati Therapeutics Inc.
Sponsor class: INDUSTRY
First posted: 2018-07-30
Enrollment: 260
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Objective Response Rate (ORR)
timeFrame: Up to approximately 3 years
Secondary outcomes:
measure: Number of Participants Who Experienced an Adverse Event (AE)
timeFrame: Day 1 up to approximately 3 years
measure: Number of Participants Who Experienced a Serious Adverse Event (SAE)
timeFrame: Day 1 up to approximately 3 years
measure: Number of Participants Who Experienced a Treatment-related Adverse Event
timeFrame: Day 1 up to approximately 3 years
measure: Duration of Response (DOR)
timeFrame: Up to approximately 3 years
measure: Clinical Benefit Rate (CBR)
timeFrame: Up to approximately 3 years
measure: Progression-Free Survival (PFS)
timeFrame: Up to approximately 3 years
measure: 1-Year Survival Rate
timeFrame: 1 year
measure: Overall Survival (OS)
timeFrame: Up to approximately 3 years
measure: Geometric Mean Blood Plasma Concentration of Sitravatinib
timeFrame: 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)
measure: Cohort 9 Lead-in Dose Escalation Part Only: Number of Participants Who Experienced a Dose-limiting Toxicity (DLT)
timeFrame: Cycle 1 Day 1 through pre-dose Cycle 2 Day 1 (cycle for Cohort 9 was 21 days)
Other outcomes:
Locations:
city: Tucson
country: United States
facility: The University of Arizona Cancer Center
state: Arizona
city: Irvine
country: United States
facility: University of California Irvine
state: California
city: Aurora
country: United States
facility: Rocky Mountain Cancer Centers
state: Colorado
city: New Haven
country: United States
facility: Yale School of Medicine
state: Connecticut
city: Saint Petersburg
country: United States
facility: SCRI - Florida Cancer Specialists- North Region
state: Florida
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: West Palm Beach
country: United States
facility: SCRI - Florida Cancer Specialists - West Palm Beach
state: Florida
city: Chicago
country: United States
facility: The University of Chicago
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University - Melvin & Bren Simon Cancer Center
state: Indiana
city: Louisville
country: United States
facility: Norton Cancer Institute - Broadway
state: Kentucky
city: New Orleans
country: United States
facility: Ochsner Cancer Institute
state: Louisiana
city: Lanham
country: United States
facility: Maryland Oncology Hematology, P.A.
state: Maryland
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Detroit
country: United States
facility: Barbara Ann Karmanos Cancer Institute
state: Michigan
city: Saint Louis
country: United States
facility: Washington University School of Medicine - Siteman Cancer Center
state: Missouri
city: Omaha
country: United States
facility: GU Research Network/Urology Cancer Center
state: Nebraska
city: Las Vegas
country: United States
facility: Comprehensive Cancer Centers of Nevada - Southwest
state: Nevada
city: Albany
country: United States
facility: New York Oncology Hematology - Albany Medical Center
state: New York
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: Lake Success
country: United States
facility: Northwell Health Monter Cancer Center
state: New York
city: New York
country: United States
facility: NYU Langone Laura & Isaac Perlmutter Cancer Center
state: New York
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: New York
country: United States
facility: New York-Presbyterian - Weill Cornell Medical Center
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina - Lineberger Comprehensive Cancer Center
state: North Carolina
city: Durham
country: United States
facility: Duke University Hospital
state: North Carolina
city: Columbus
country: United States
facility: The Ohio State University College of Medicine
state: Ohio
city: Pittsburgh
country: United States
facility: Allegheny General Hospital
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University - Ingram Cancer Center
state: Tennessee
city: Austin
country: United States
facility: Texas Oncology-Austin Central
state: Texas
city: Houston
country: United States
facility: Texas Oncology- Memorial City
state: Texas
city: Houston
country: United States
facility: University of Texas - MD Anderson Cancer Center
state: Texas
city: San Antonio
country: United States
facility: University of Texas Health Science Center
state: Texas
city: Tyler
country: United States
facility: Texas Oncology - Tyler
state: Texas
city: Fairfax
country: United States
facility: Virginia Cancer Specialists- Fairfax
state: Virginia
city: Norfolk
country: United States
facility: Virginia Oncology Associates
state: Virginia
city: Seattle
country: United States
facility: Seattle Cancer Center Alliance
state: Washington
Study officials:
affiliation: Mirati Therapeutics Inc.
name: Hirak Der-Torossian, MD
role: STUDY_DIRECTOR
References: