This is a Phase III, 3-armed randomized clinical trial that includes both cisplatin eligible and ineligible patients with first line metastatic urothelial cancer. The trial compares in a 1:1:1 randomization of single agent durvalumab to the combination of durvalumab and tremilumumab to platinum-based chemotherapy alone with gemcitabine in combination with either cisplatin or carboplatin. Patients will be treated with durvalumab or durvalumab with tremelimumab or treated with chemotherapy until progressive disease is confirmed, unacceptable toxicity occurs, withdrawal of consent, or another discontinuation criterion is met. Patients will be followed for up to 2 years.
Durvalumab is a fully human monoclonal antibody that blocks PDL-1 binding to its receptors PD-1 and CD80, resulting in enhanced T-cell responses against cancer cells. This is a randomized, open-label, controlled, multi-center, global Phase III study to determine the efficacy and safety of durvalumab (MEDI4736) monotherapy and durvalumab in combination with tremelimumab, a CTLA-4 inhibitor versus gemcitabine and cisplatin or carboplatin as first-line chemotherapy in treatment-naïve patients with histologically or cytologically documented, unresectable, Stage IV transitional cell carcinoma (transitional cell and mixed transitional/non-transitional cell histologies) of the urothelium (including renal pelvis, ureters, urinary bladder and urethra). As in the two prior studies, and to allow sufficient flexibility for Investigators and patients to select the agents that reflect their normal clinical practice and national guidelines, both cisplatin and carboplatin are permitted.
OS of the combination of durvalumab with tremelimumab compared to standard of care chemotherapy and to assess the efficacy of durvalumab monotherapy versus standard of care chemotherapy in terms of OS in patients with unresectable Stage IV PD-L1- High urothelial cancer.
An ongoing phase 1/2 open-label study of 191 adult patients with histologically or cytologically confirmed locally advanced/metastatic urothelial cancer whose disease had progressed on, were ineligible for, or refused prior chemotherapy was used to establish the clinical benefit of durvalumab as second-line therapy for locally advanced or metastatic urothelial carcinoma, resulting in its US FDA approval. As of October 24, 2016 (90-day update), the median follow-up was 5.78 months (range, 0.4-25.9 months). All patients had stage 4 disease, and 190 (99.5%) had prior anticancer therapy (182 [95.3%] post platinum). The ORR was 17.8% (34 of 191; 95% CI, 12.7%-24.0%), including 7 complete responses. Responses were seen early with a median time to response of 1.41 months, durable (median duration of response not reached), and observed irrespective of PD-L1 expression. Durvalumab, given every 2 weeks, demonstrates favorable clinical activity and an encouraging and manageable safety profile (7). The combination of durvalumab with tremelimumab have been evaluated in other tumor types.