Clinical Trials /

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

NCT03606174

Description:

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.

Related Conditions:
  • Urothelial Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

URL:

https://clinicaltrials.gov/show/NCT03606174

Trial Eligibility

Document

Title

  • Brief Title: Study of Sitravatinib + PD-(L)1 Checkpoint Inhibitor Regimens in 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

Clinical Trial IDs

  • ORG STUDY ID: 516-003
  • NCT ID: NCT03606174

Conditions

  • Urothelial Carcinoma
  • Urothelial Carcinoma Bladder
  • Urothelial Carcinoma Ureter
  • Urothelial Carcinoma of the Renal Pelvis and Ureter
  • Urothelial Carcinoma Urethra

Interventions

DrugSynonymsArms
SitravatinibMGCD516Cohort 1
NivolumabOpdivoCohort 1
PembrolizumabKeytrudaCohort 9
Enfortumab vedotinPadcevCohort 9

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Cohort 1ExperimentalPatients 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.
  • Sitravatinib
  • Nivolumab
Cohort 2ExperimentalPatients 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.
  • Sitravatinib
  • Nivolumab
Cohort 3ExperimentalPatients 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.
  • Sitravatinib
  • Nivolumab
Cohort 4ExperimentalPatients 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.
  • Sitravatinib
  • Nivolumab
Cohort 5ExperimentalPatients 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.
  • Sitravatinib
  • Nivolumab
Cohort 6ExperimentalPatients 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.
  • Sitravatinib
  • Nivolumab
Cohort 7ExperimentalPatients 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.
  • Sitravatinib
  • Nivolumab
Cohort 8ExperimentalPatients 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.
  • Sitravatinib
  • Nivolumab
Cohort 9ExperimentalPatients 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).
  • Sitravatinib
  • Pembrolizumab
  • Enfortumab vedotin

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
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective Response Rate (ORR)
Time Frame:36 months
Safety Issue:
Description: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

Measure:Adverse Events
Time Frame:36 months
Safety Issue:
Description:Frequency of subjects experiencing treatment-related AEs
Measure:Pharmacokinetics of Sitravatinib
Time Frame:36 months
Safety Issue:
Description:Blood plasma concentration of sitravatinib
Measure:Duration of Response (DOR)
Time Frame:36 months
Safety Issue:
Description: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
Measure:Clinical Benefit Rate (CBR)
Time Frame:36 months
Safety Issue:
Description: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
Measure:Progression-free survival (PFS)
Time Frame:36 months
Safety Issue:
Description:PFS is defined as the time from first study treatment to first documentation of objective disease progression or death due to any cause
Measure:Overall Survival (OS)
Time Frame:36 months
Safety Issue:
Description:OS is defined as time from first study treatment to date of death due to any cause
Measure:7. Recommended Phase 2 combinatorial doses of sitravatinib, pembrolizumab, and enfortumab
Time Frame:12 months
Safety Issue:
Description:Number of participants with dose limiting toxicity (DLT)

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Mirati Therapeutics Inc.

Trial 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

Last Updated

May 24, 2021