Phase Ib/II umbrella trial to evaluate the safety and efficacy of multiple 2L cancer immunotherapy (CIT) combinations in advanced/metastatic urothelial carcinoma (mUC): MORPHEUS-mUC.

Abstract

TPS591 Background: Although CIT has efficacy against multiple cancers, only subsets of patients (pts) have durable responses with monotherapy. CIT combination treatment (tx) targets multiple immune-evasion mechanisms and may thus be more likely to improve outcomes. However, a large number of potential combinations need to be tested to identify effective combinations. The MORPHEUS platform comprises multiple global, open-label, randomized Phase Ib/II trials to identify early efficacy signals and safety of tx combinations in pts with different cancers. MORPHEUS-mUC is a randomized study of 6 CIT combinations compared with a single CIT control in pts with locally advanced UC/mUC who progressed during or after a platinum-containing regimen. The PD-L1 inhibitor atezolizumab will be combined with agents targeting different mechanisms (via nectin-4, PARP, CD47, CD38, DPP-4 and IL-6R) to simultaneously enhance immune cell priming and activation, tumor infiltration and/or recognition of tumor cells. To accelerate the clinical development of novel combinations, MORPHEUS has the flexibility, via amendment, to allow for the modification of eligibility criteria or the opening of new tx arms to replace arms that demonstrate no signs of clinical activity/unacceptable toxicity. Methods: MORPHEUS-mUC (NCT03869190) has 2 stages. In Stage 1, approximately 130-305 pts with histologically documented, locally advanced inoperable UC/mUC will be randomized to atezolizumab monotherapy (control) or experimental arms: atezolizumab + either enfortumab vedotin, niraparib, magrolimab (Hu5F9-G4), isatuximab, linagliptin or tocilizumab. Safety will be monitored for potential overlapping toxicities. Stage 2 arms will be atezolizumab + either enfortumab vedotin or linagliptin arms, unless these combinations show no activity in Stage 1. Eligible pts who experience unacceptable toxicity or loss of clinical benefit in Stage 1 may enroll in Stage 2 within 3 months. The primary study endpoint is investigator-assessed ORR per RECIST 1.1; secondary endpoints include PFS, OS, DOR, DCR and safety. Biomarkers will also be explored. Clinical trial information: NCT03869190.