Vactosertib with Durvalumab in Urothelial Carcinoma Failing Checkpoint Inhibition

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

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

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.

Inclusion Criteria:

1. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 at enrollment
2. Histologically or cytologically documented locally advanced/inoperable or metastatic urothelial bladder carcinoma (UBC), including renal pelvis, ureters, urinary bladder, and urethra.
3. Prior anti-PD-(L)1 treatment.
4. Measurable disease per RECIST 1.1 assessed by computed tomography (CT) scan or MRI.
5. Recurrent disease after any prior platinum-based chemotherapy regimen or ineligible for platinum therapy.
6. Adequate organ and marrow function as defined
7. Must have a life expectancy of at least 12 weeks.
8. Body weight > 30 kg

Exclusion Criteria:

1. History of allogeneic organ transplantation.
2. Active or prior documented autoimmune or inflammatory disorders
3. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure .
4. History of another primary malignancy
5. History of leptomeningeal carcinomatosis.
6. History of active primary immunodeficiency.
7. Active infection including tuberculosis, hepatitis B (known positive HBV surface antigen [HBsAg] result), hepatitis C, or human immunodeficiency virus .
8. 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