Checkpoint Inhibition With or Without Domatinostat in Urothelial Cancer

Summary

Participation Requirements

Description

This is a phase 1b safety, feasibility and proof-of-principle study of the addition of domatinostat to pre-operative immune checkpoint inhibition (CPI) with nivolumab and ipilimumab. Urothelial cancer patients will be included that are diagnosed with either: cT2-4aN0M0 OR cT1-4aN1-3M0 PD-L1 status w...

This is a phase 1b safety, feasibility and proof-of-principle study of the addition of domatinostat to pre-operative immune checkpoint inhibition (CPI) with nivolumab and ipilimumab. Urothelial cancer patients will be included that are diagnosed with either: cT2-4aN0M0 OR cT1-4aN1-3M0 PD-L1 status will determine the treatment cohort. Within each cohort, patients will be randomized to receive CPI + domatinostat or CPI alone Cohort A (PD-L1 CPS?10% pts): Arm A1: Domatinostat 200mg BID d1-56 + nivolumab 240 mg, q3wk, day 1, 22, 43 Arm A2: 3x nivolumab 240 mg, q3wk, day 1, 22, 43 Cohort B (PD-L1 CPS<10% pts): Arm B1: Domatinostat 200mg QD d1-56 + ipilimumab 240 mg day 1, ipilimumab 240 mg + nivolumab 80 mg day 22, nivolumab 240 mg, day 43 Arm B2: ipilimumab 240 mg day 1, ipilimumab 240 mg + nivolumab 80 mg day 22, nivolumab 240 mg, day 43 The primary endpoint is feasibility of neo-adjuvant domatinostat + nivolumab +/- ipilimumab defined by percentage of patients who are able to have surgical resection within 12 weeks from start of treatment as this is an endpoint that is clinically meaningful for this population. After surgery, patients attend study visits at day 8, day 29. Their final study visit for physical examination and laboratory testing is at day 57 (+/- 7 days), which is scheduled to anticipate late-onset adverse events. After this final visit, patients will be followed according to standard clinical guidelines. Tumor biopsies/material preservation is required at baseline and during surgery. Main secondary endpoints are: Efficacy, defined as pathological complete response (pCR) (pT0N0 or pTisN0) Provide an estimate of all grade toxicities Relapse free survival (RFS) and overall survival (OS) An important additional secondary endpoint is translational. RNA signatures associated with pathological response and RFS will be determined, as well as characterization of changes in immune infiltrates between baseline and resection.

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