This trial will include metastatic urothelial carcinoma patients who progressed during or after treatment with anti-PD(L)1 therapy and have been treated by a platinum-containing regimen, or are cisplatin-ineligible.~A run-in safety phase will be followed by a non-comparative 3-arm randomized study with a Simon's 2-stage optimal design.~Screening:~Before enrollment, patients will need to complete the following screening procedures (among other assessments):~Baseline evaluation by CT chest/abdomen/pelvis (<4 weeks)~Laboratory assessment~Tissue biopsy (in at least 6 patients per arm)~Run-in phase-1 (R1): n=3 patients will be treated with:~paclitaxel 70 mg/m2 on day 1, 8, 15 of cycles 1-6~tremelimumab 75 mg on day 1 of cycles 2-6 and then every 12 weeks until week 45~Run-in phase-2 (R2): n=3 patients will be treated with:~paclitaxel 70 mg/m2 on day 1, 8, 15 of cycles 1-6~tremelimumab 225 mg on day 1 of cycles 2-6 and then every 12 weeks until week 45~Run-in phase-3 (R3): n=2 x 3 patients will be randomized over 2 arms:~paclitaxel 70 mg/m2 on day 1, 8, 15 of cycles 1-6~tremelimumab 750 mg on day 1 of cycles 2-6 and then every 12 weeks until week 45 OR~paclitaxel 70 mg/m2 on day 1, 8, 15 of cycles 1-6~tremelimumab 75 mg on day 1 of cycles 2-5~durvalumab 1500 mg on day 1 of cycles 2-12, every four weeks (until week 49)~Run-in phase-4 (R4): n=3 patients will be treated with:~paclitaxel 70 mg/m2 on day 1, 8, 15 of cycles 1-6~tremelimumab 300 mg once on day 1 of cycle 2~durvalumab 1500 mg on day 1 of cycles 2-12, every four weeks (until week 49)~Enrollment will start with the first run-in cohort (R1) and will be halted after inclusion of the 3rd patient, until 60 days after start of treatment of this patient. Stopping rules are defined in the section 6.3 of the protocol. In case unexpected toxicity occurs (either as defined by the stopping rules or otherwise unexpected severe toxicity), the study team will discuss with the IDMC whether expansion to include 3 additional subjects is warranted. If no unexpected toxicity has occurred within 60 days after initiation of treatment of the 3rd patient of R1, enrollment for R2 will begin in a similar fashion. If 2 or more nonhematological toxicities as described in section 6.3 Definition of DLT occur in R1 or R2, enrollment will be suspended until the IDMC has formulated an advice. After this advice, the sponsor will decide on continuation.~If no unexpected toxicity has occurred within 60 days after initiation of treatment of the 3rd patient of R2, the study will continue with a third run-in cohort (R3) where patients will be randomized over 2 arms (R3A and R3B), n=3 per arm. If no unexpected toxicity has occurred within 60 days after initiation of treatment of the 3rd patient in arm R3A, this arm will be continued into the main study phase (as Arm A). If unacceptable toxicity is observed at either 225 mg or 750 mg of tremelimumab during one of the run-in cohorts, a lower dose level can be used in the main study. In addition, after completion of R3A and continuation in the main study phase, a control arm (Arm C) will be initiated where patients will be treated with tremelimumab monotherapy (without paclitaxel).~If no unexpected toxicity has occurred within 60 days after initiation of treatment of the 3rd patient of R3B, enrollment for run-in cohort R4 will begin in a similar fashion as described for the earlier run-in cohorts. Expansion arms A and C will be paused while this cohort is enrolling. If no unexpected toxicity has occurred within 60 days after initiation of treatment of the 3rd patient of R4, enrollment for arm R4 will be continued into the main study phase (as Arm B). If unacceptable toxicity is observed at 300 mg of tremelimumab in combination with 1500mg durvalumab, arm B, combining paclitaxel, tremelimumab and durvalumab, will be discontinued.~Main study:~Arm A:~paclitaxel 70 mg/m2 on day 1, 8, 15 of cycles 1-6~tremelimumab 750 mg on day 1 of cycles 2-6 and then every 12 weeks until week 45~Arm B:~paclitaxel 70 mg/m2 on day 1, 8, 15 of cycles 1-6~tremelimumab 300 mg once on day 1 of cycle 2~durvalumab 1500 mg on day 1 of cycles 2-12, every four weeks (until week 49)~Arm C (control arm):~• tremelimumab 750 mg on day 1 of cycles 1-5 and then every 12 weeks until week 41~Enrollment will be halted when 12 patients are enrolled in each arm; this will include patients treated in R3 and R4 at the dose level used in the main study. These patients will be included in the efficacy analysis.~After the last patient has had the second evaluation scan, the Objective Response Rate (ORR) of each treatment arm will be evaluated. If one or more of the experimental arms has ≥2 responses, the study team will discuss continuation of one of the experimental arms to n=20 with the IDMC. In case 2 responses are seen in one of the arms prior to the second evaluation scan of the last patient, a decision on expansion of that arm may be recommended earlier.
This trial will include metastatic urothelial carcinoma patients who progressed during or after treatment with anti-PD(L)1 therapy and have been treated by a platinum-containing regimen, or are cisplatin-ineligible. Patients will receive either paclitaxel in combination with durvalumab (anti-PDL-1) and a single dose (300 mg) of tremelimumab (anti-CTLA4), or paclitaxel with only a high dose of tremelimumab (750 mg). Tremelimumab (750 mg), without paclitaxel will be used as a comparison arm.~A run-in safety phase will be followed by a non-comparative 3-arm randomized study with a Simon's 2-stage optimal design.