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.
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
Drug | Synonyms | Arms |
---|
Sitravatinib | MGCD516 | Cohort 1 |
Nivolumab | Opdivo | Cohort 1 |
Pembrolizumab | Keytruda | Cohort 9 |
Enfortumab vedotin | Padcev | Cohort 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
Name | Type | Description | Interventions |
---|
Cohort 1 | Experimental | 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. | |
Cohort 2 | Experimental | 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. | |
Cohort 3 | Experimental | 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. | |
Cohort 4 | Experimental | 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. | |
Cohort 5 | Experimental | 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. | |
Cohort 6 | Experimental | 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. | |
Cohort 7 | Experimental | 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. | |
Cohort 8 | Experimental | 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. | |
Cohort 9 | Experimental | 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). | - 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