Vactosertib With Durvalumab in Urothelial Carcinoma Failing Checkpoint Inhibition

Study Overview
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Brief Summary
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This is Phase 2, open label, non randomized single arm study to determine whether the administration of vactosertib with durvalumab will provide meaningful increases in the Overall Response Rate (ORR) in patients with urothelial cancers that fail to achieve a response with anti-PD-1/PD-L1 based regimens

Detailed Description
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This is a Phase 2, open-label, non-randomized, two-cohort multi center study with a safety run-in of 6 patients in Cohort 1. It is anticipated that a total of 48 patients will be enrolled. Durvalumab will be administered with the standard regimen of 1500 mg intravenously (IV) every four weeks. Vactosertib will be administered at a dose of 300 mg PO BID for 5 days per week All treatment will be administered up to two years and the trial is anticipated to be completed over a period of 36 months.

Official Title
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A Phase 2 Study of TGF-β Inhibition (Vactosertib) With Anti-PD-L1 (Durvalumab) in Patients With Advanced or Recurrent Urothelial Carcinoma Failing to Achieve Response With Checkpoint Inhibition

Conditions
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Urothelial Carcinoma Recurrent, Advanced Urothelial Carcinoma

Intervention / Treatment
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* Drug: Vactosertib(TEW-7197)/ Durvalumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 at enrollment Histologically or cytologically documented locally advanced/inoperable or metastatic urothelial bladder carcinoma (UBC), including renal pelvis, ureters, urinary bladder, and urethra. Prior anti-PD-(L)1 treatment. Measurable disease per RECIST 1.1 assessed by computed tomography (CT) scan or MRI. Recurrent disease after any prior platinum-based chemotherapy regimen or ineligible for platinum therapy. Adequate organ and marrow function as defined Must have a life expectancy of at least 12 weeks. Body weight > 30 kg Exclusion Criteria: History of allogeneic organ transplantation. Active or prior documented autoimmune or inflammatory disorders Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure . History of another primary malignancy History of leptomeningeal carcinomatosis. History of active primary immunodeficiency. Active infection including tuberculosis, hepatitis B (known positive HBV surface antigen [HBsAg] result), hepatitis C, or human immunodeficiency virus . Any unresolved toxicity NCI CTCAE Grade ≥ 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Phase 2, open label, non randomized single arm study with two cohorts and a safety run-in for first six patients
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vactosertib+Durvalumab<br>Vactosertib will be administered in combination with standard dose of durvalumab every four weeks. | Drug: Vactosertib(TEW-7197)/ Durvalumab<br>* Vactosertib (PO) in combination with Durvalumab (IV) every 4 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate | ORR by RECIST version 1.1 | 12months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Tumor Response | TTR by RECIST version 1.1 and iRECIST | Overall study period up to 3years | 
| Best Response | Best response (percent of tumor shrinkage) by RECIST version 1.1 and iRECIST | Overall study period up to 3years | 
| Duration of Response | DoR by RECIST version 1.1 and iRECIST | Overall study period up to 3years | 
| Progression Free Survival | PFS by RECIST version 1.1 and iRECIST | 6-month/ 12-month | 
| Overall survival | OS by RECIST version 1.1 and iRECIST | 12month | 
| Tumor-specific immune responses | tumor-specific immune responses within on-therapy biopsies measured by increased T cell infiltration and increased IFN-λ signature. and the correlation with outcome as measured by ORR, TTR, DoR, PFS and OS | Overall study period up to 3years | 
| Incidence of Treatment-Emergent Adverse Events [Safety and tolerability] | To assess safety and tolerability of vactosertib administered concurrent with Durvalumab in patients with urothelial carcinoma failing checkpoint inhibition | Overall study period up to 3years |