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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
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.

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
Urothelial Carcinoma Urothelial Carcinoma Bladder Urothelial Carcinoma Ureter Urothelial Carcinoma of the Renal Pelvis and Ureter Urothelial Carcinoma Urethra Drug: Sitravatinib Drug: Nivolumab Drug: Pembrolizumab Drug: Enfortumab vedotin 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.

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Study Type : Interventional  (Clinical Trial)
Estimated 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.
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 : September 11, 2018
Estimated Primary Completion Date : January 31, 2022
Estimated Study Completion Date : September 30, 2022

Resource links provided by the National Library of Medicine

Drug Information available for: Nivolumab

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 Name: MGCD516

Drug: Nivolumab
Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody
Other Name: 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 Name: MGCD516

Drug: Nivolumab
Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody
Other Name: 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 Name: MGCD516

Drug: Nivolumab
Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody
Other Name: 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 Name: MGCD516

Drug: Nivolumab
Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody
Other Name: 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 Name: MGCD516

Drug: Nivolumab
Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody
Other Name: 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 Name: MGCD516

Drug: Nivolumab
Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody
Other Name: 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 Name: MGCD516

Drug: Nivolumab
Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody
Other Name: 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 Name: MGCD516

Drug: Nivolumab
Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody
Other Name: 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 Name: MGCD516

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




Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. Adverse Events [ Time Frame: 36 months ]
    Frequency of subjects experiencing treatment-related AEs

  2. Pharmacokinetics of Sitravatinib [ Time Frame: 36 months ]
    Blood plasma concentration of sitravatinib

  3. 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

  4. 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

  5. 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

  6. 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. 7. Recommended Phase 2 combinatorial doses of sitravatinib, pembrolizumab, and enfortumab [ Time Frame: 12 months ]
    Number of participants with dose limiting toxicity (DLT)



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03606174


Contacts
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Contact: Mirati Therapeutics Study Locator Services 1-844-893-5530 (toll free) miratistudylocator@emergingmed.com

Locations
Show Show 26 study locations
Sponsors and Collaborators
Mirati Therapeutics Inc.
Investigators
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Study Director: Hirak Der-Torossian, MD Mirati Therapeutics Inc.
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Responsible Party: Mirati Therapeutics Inc.
ClinicalTrials.gov Identifier: NCT03606174    
Other Study ID Numbers: 516-003
First Posted: July 30, 2018    Key Record Dates
Last Update Posted: September 28, 2020
Last Verified: September 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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:
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Carcinoma
Carcinoma, Transitional Cell
Urinary Bladder Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Urologic Diseases
Urinary Bladder Diseases
Pembrolizumab
Nivolumab
Antineoplastic Agents, Immunological
Antineoplastic Agents