Study of Sitravatinib + PD-(L)1 Checkpoint Inhibitor Regimens in Urothelial Carcinoma
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| ClinicalTrials.gov Identifier: NCT03606174 |
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Recruitment Status :
Recruiting
First Posted : July 30, 2018
Last Update Posted : May 24, 2021
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| 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 |
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 : | 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 |
| Arm | Intervention/treatment |
|---|---|
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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.
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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 |
- 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
- 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)
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| 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
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
| Contact: Mirati Therapeutics Study Locator Services | 1-844-893-5530 (toll free) | miratistudylocator@emergingmed.com |
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| Study Director: | Hirak Der-Torossian, MD | Mirati Therapeutics Inc. |
| 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: | May 24, 2021 |
| Last Verified: | May 2021 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | No |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
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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 |
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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 |
Urinary Bladder Diseases Urologic Diseases Pembrolizumab Nivolumab Antineoplastic Agents, Immunological Antineoplastic Agents Immune Checkpoint Inhibitors Molecular Mechanisms of Pharmacological Action |