Clincosm LogoSign in Get a demo

Study of Sitravatinib + PD-(L)1 Checkpoint Inhibitor Regimens in Urothelial Carcinoma

Sponsor
Mirati Therapeutics Inc. (Industry)
Overall Status
Recruiting
CT.gov ID
NCT03606174
Collaborator
(none)
425
Enrollment
34
Locations
9
Arms
48.6
Anticipated Duration (Months)
12.5
Patients Per Site
0.3
Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
Phase 2

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.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
425 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
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.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)
Primary Purpose:
Treatment
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
Actual Study Start Date :
Sep 11, 2018
Anticipated Primary Completion Date :
Jan 31, 2022
Anticipated Study Completion Date :
Sep 30, 2022

Arms and Interventions

Arm Intervention/Treatment
Experimental: Cohort 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.

Drug: Sitravatinib
Sitravatinib is a small molecule inhibitor of receptor tyrosine kinases
Other Names:
  • MGCD516

    • Drug: Nivolumab
    Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody
    Other Names:
  • Opdivo

    		•
    Experimental: Cohort 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.

    Drug: Sitravatinib
    Sitravatinib is a small molecule inhibitor of receptor tyrosine kinases
    Other Names:
  • MGCD516

    • Drug: Nivolumab
    Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody
    Other Names:
  • Opdivo

    		•
    Experimental: Cohort 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.

    Drug: Sitravatinib
    Sitravatinib is a small molecule inhibitor of receptor tyrosine kinases
    Other Names:
  • MGCD516

    • Drug: Nivolumab
    Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody
    Other Names:
  • Opdivo

    		•
    Experimental: Cohort 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.

    Drug: Sitravatinib
    Sitravatinib is a small molecule inhibitor of receptor tyrosine kinases
    Other Names:
  • MGCD516

    • Drug: Nivolumab
    Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody
    Other Names:
  • Opdivo

    		•
    Experimental: Cohort 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.

    Drug: Sitravatinib
    Sitravatinib is a small molecule inhibitor of receptor tyrosine kinases
    Other Names:
  • MGCD516

    • Drug: Nivolumab
    Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody
    Other Names:
  • Opdivo

    		•
    Experimental: Cohort 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.

    Drug: Sitravatinib
    Sitravatinib is a small molecule inhibitor of receptor tyrosine kinases
    Other Names:
  • MGCD516

    • Drug: Nivolumab
    Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody
    Other Names:
  • Opdivo

    		•
    Experimental: Cohort 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.

    Drug: Sitravatinib
    Sitravatinib is a small molecule inhibitor of receptor tyrosine kinases
    Other Names:
  • MGCD516

    • Drug: Nivolumab
    Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody
    Other Names:
  • Opdivo

    		•
    Experimental: Cohort 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.

    Drug: Sitravatinib
    Sitravatinib is a small molecule inhibitor of receptor tyrosine kinases
    Other Names:
  • MGCD516

    • Drug: Nivolumab
    Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody
    Other Names:
  • Opdivo

    		•
    Experimental: Cohort 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).

    Drug: Sitravatinib
    Sitravatinib is a small molecule inhibitor of receptor tyrosine kinases
    Other Names:
  • MGCD516

    • Drug: Pembrolizumab
    Pembrolizumab is a programmed death receptor-1 (PD-1) blocking antibody
    Other Names:
  • Keytruda

    • Drug: 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)
    Other Names:
  • Padcev

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Objective Response Rate (ORR) [36 months]

      Objective Response Rate (ORR) is defined as the percent of subjects documented to have a confirmed complete response (CR) or partial response (PR) per RECIST version 1.1 recorded until disease progression or start of new anti-cancer therapy

    Secondary Outcome Measures

    1. Adverse Events [36 months]

      Frequency of subjects experiencing treatment-related AEs

    2. Pharmacokinetics of Sitravatinib [36 months]

      Blood plasma concentration of sitravatinib

    3. Duration of Response (DOR) [36 months]

      DOR is defined as the time from date of the first documentation of objective tumor response [complete response (CR) or partial response (PR)] to the first documentation of objective disease progression (PD) or to death due to any cause in the absence of documented PD

    4. Clinical Benefit Rate (CBR) [36 months]

      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 assessment

    5. Progression-free survival (PFS) [36 months]

      PFS is defined as the time from first study treatment to first documentation of objective disease progression or death due to any cause

    6. Overall Survival (OS) [36 months]

      OS is defined as time from first study treatment to date of death due to any cause

    7. 7. Recommended Phase 2 combinatorial doses of sitravatinib, pembrolizumab, and enfortumab [12 months]

      Number of participants with dose limiting toxicity (DLT)

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 The University of Arizona Cancer Center Tucson Arizona United States 85724
    2 University of California Irvine Irvine California United States 92868
    3 Rocky Mountain Cancer Centers Aurora Colorado United States 80012
    4 Yale School of Medicine New Haven Connecticut United States 06510
    5 SCRI - Florida Cancer Specialists- North Region Saint Petersburg Florida United States 33705
    6 Moffitt Cancer Center Tampa Florida United States 33612
    7 SCRI - Florida Cancer Specialists - West Palm Beach West Palm Beach Florida United States 33401
    8 The University of Chicago Chicago Illinois United States 60637
    9 Indiana University - Melvin & Bren Simon Cancer Center Indianapolis Indiana United States 46202
    10 Norton Cancer Institute - Broadway Louisville Kentucky United States 40202
    11 Ochsner Cancer Institute New Orleans Louisiana United States 70121
    12 Maryland Oncology Hematology, P.A. Lanham Maryland United States 20706
    13 Dana Farber Cancer Institute Boston Massachusetts United States 02215
    14 Barbara Ann Karmanos Cancer Institute Detroit Michigan United States 48201
    15 Washington University School of Medicine - Siteman Cancer Center Saint Louis Missouri United States 63110
    16 GU Research Network/Urology Cancer Center Omaha Nebraska United States 68130
    17 Comprehensive Cancer Centers of Nevada - Southwest Las Vegas Nevada United States 89169
    18 New York Oncology Hematology - Albany Medical Center Albany New York United States 12206
    19 Roswell Park Cancer Institute Buffalo New York United States 14263
    20 Northwell Health Monter Cancer Center Lake Success New York United States 11042
    21 NYU Langone Laura & Isaac Perlmutter Cancer Center New York New York United States 10016
    22 Memorial Sloan-Kettering Cancer Center New York New York United States 10065
    23 University of North Carolina - Lineberger Comprehensive Cancer Center Chapel Hill North Carolina United States 27599
    24 Duke University Hospital Durham North Carolina United States 27710
    25 The Ohio State University College of Medicine Columbus Ohio United States 43202
    26 Allegheny General Hospital Pittsburgh Pennsylvania United States 15212
    27 Vanderbilt University - Ingram Cancer Center Nashville Tennessee United States 37232
    28 Texas Oncology-Austin Central Austin Texas United States 78731
    29 Texas Oncology- Memorial City Houston Texas United States 77024
    30 University of Texas - MD Anderson Cancer Center Houston Texas United States 77030
    31 Texas Oncology - Tyler Tyler Texas United States 75702
    32 Virginia Cancer Specialists- Fairfax Fairfax Virginia United States 22031
    33 Virginia Oncology Associates Norfolk Virginia United States 23502
    34 Seattle Cancer Center Alliance Seattle Washington United States 98109

    Sponsors and Collaborators

    • Mirati Therapeutics Inc.

    Investigators

    • Study Director: Hirak Der-Torossian, MD, Mirati Therapeutics Inc.

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Mirati Therapeutics Inc.
    ClinicalTrials.gov Identifier:
    NCT03606174
    Other Study ID Numbers:
    • 516-003
    First Posted:
    Jul 30, 2018
    Last Update Posted:
    May 24, 2021
    Last Verified:
    May 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Mirati Therapeutics Inc.
    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
    Additional relevant MeSH terms:
    Carcinoma
    Carcinoma, Transitional Cell
    Urinary Bladder Neoplasms
    Pembrolizumab
    Nivolumab

    Study Results

    No Results Posted as of May 24, 2021