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

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ClinicalTrials.gov Identifier: NCT03606174
Recruitment Status : Recruiting
First Posted : July 30, 2018
Last Update Posted : September 28, 2020
Sponsor:
Information provided by (Responsible Party):
Mirati Therapeutics Inc.

Tracking Information
First Submitted Date  ICMJE July 20, 2018
First Posted Date  ICMJE July 30, 2018
Last Update Posted Date September 28, 2020
Actual Study Start Date  ICMJE September 11, 2018
Estimated Primary Completion Date January 31, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 23, 2020)
Objective Response Rate (ORR) [ Time Frame: 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
Original Primary Outcome Measures  ICMJE
 (submitted: July 20, 2018)
Number of patients experiencing tumor size reduction [ Time Frame: up to 3 months ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 23, 2020)
  • Adverse Events [ Time Frame: 36 months ]
    Frequency of subjects experiencing treatment-related AEs
  • Pharmacokinetics of Sitravatinib [ Time Frame: 36 months ]
    Blood plasma concentration of sitravatinib
  • Duration of Response (DOR) [ Time Frame: 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
  • Clinical Benefit Rate (CBR) [ Time Frame: 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
  • Progression-free survival (PFS) [ Time Frame: 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
  • Overall Survival (OS) [ Time Frame: 36 months ]
    OS is defined as time from first study treatment to date of death due to any cause
  • 7. Recommended Phase 2 combinatorial doses of sitravatinib, pembrolizumab, and enfortumab [ Time Frame: 12 months ]
    Number of participants with dose limiting toxicity (DLT)
Original Secondary Outcome Measures  ICMJE
 (submitted: July 20, 2018)
  • Number of patients experiencing adverse events [ Time Frame: up to 12 months ]
  • Blood plasma concentration of the investigational agent [ Time Frame: up to 20 weeks ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of Sitravatinib + PD-(L)1 Checkpoint Inhibitor Regimens in Urothelial Carcinoma
Official Title  ICMJE A Phase 2 Study of Sitravatinib in Combination With PD-(L)1 Checkpoint Inhibitor Regimens in Patients With Advanced or Metastatic Urothelial Carcinoma
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE 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.
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Urothelial Carcinoma
  • Urothelial Carcinoma Bladder
  • Urothelial Carcinoma Ureter
  • Urothelial Carcinoma of the Renal Pelvis and Ureter
  • Urothelial Carcinoma Urethra
Intervention  ICMJE
  • Drug: Sitravatinib
    Sitravatinib is a small molecule inhibitor of receptor tyrosine kinases
    Other Name: MGCD516
  • Drug: Nivolumab
    Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody
    Other Name: Opdivo
  • Drug: Pembrolizumab
    Pembrolizumab is a programmed death receptor-1 (PD-1) blocking antibody
    Other Name: 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 Name: Padcev
Study Arms  ICMJE
  • 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.
    Interventions:
    • Drug: Sitravatinib
    • Drug: Nivolumab
  • 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.
    Interventions:
    • Drug: Sitravatinib
    • Drug: Nivolumab
  • 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.
    Interventions:
    • Drug: Sitravatinib
    • Drug: Nivolumab
  • 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.
    Interventions:
    • Drug: Sitravatinib
    • Drug: Nivolumab
  • 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.
    Interventions:
    • Drug: Sitravatinib
    • Drug: Nivolumab
  • 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.
    Interventions:
    • Drug: Sitravatinib
    • Drug: Nivolumab
  • 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.
    Interventions:
    • Drug: Sitravatinib
    • Drug: Nivolumab
  • 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.
    Interventions:
    • Drug: Sitravatinib
    • Drug: Nivolumab
  • 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).
    Interventions:
    • Drug: Sitravatinib
    • Drug: Pembrolizumab
    • Drug: Enfortumab vedotin
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: September 23, 2020)
425
Original Estimated Enrollment  ICMJE
 (submitted: July 20, 2018)
80
Estimated Study Completion Date  ICMJE September 30, 2022
Estimated Primary Completion Date January 31, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Mirati Therapeutics Study Locator Services 1-844-893-5530 (toll free) miratistudylocator@emergingmed.com
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03606174
Other Study ID Numbers  ICMJE 516-003
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Mirati Therapeutics Inc.
Study Sponsor  ICMJE Mirati Therapeutics Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Hirak Der-Torossian, MD Mirati Therapeutics Inc.
PRS Account Mirati Therapeutics Inc.
Verification Date September 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP