2022TiP - Stereotactic treatment with neoadjuvant radiotherapy and enfortumab vedotin: A phase I/II study for localized, cisplatin ineligible, muscle invasive bladder cancer (STAR-EV)

Background

Up to 50% of patients with muscle invasive bladder cancer (MIBC) cannot receive cisplatin-based chemotherapy. Based on EV-103 cohort H, patients with localized, cisplatin ineligible MIBC respond well to enfortumab vedotin (EV), with 36% pathologic complete responses (pCRs) noted at radical cystectomy (RC). Radiation (XRT) is also an effective therapy for MIBC, and a retrospective patient series treated with EV and XRT showed overall safety. Therefore, we designed a trial with EV and XRT to improve pCR rates.

Trial design

This is a single center, phase 1/2 trial based at UT Southwestern Medical Center. Patients will receive EV 1.25mg/m2 IV days 1/8 every 3 weeks for 3 cycles, with either sequential or concurrent stereotactic body XRT (SBRT) in 5 fractions. The safety lead-in phase will consist of SBRT given at C3 day 21 and then escalated forward to start at C2 day 15 (level 1) or C1 day 15 (level 2). All patients will then undergo RC. Dose limiting toxicities during the safety portion include non-hematologic adverse events grade 3 or higher, non-completion of either 3 cycles of EV, delay of SBRT over 2 weeks, or delay of RC over 8 weeks. Rate of pCR is the primary endpoint for efficacy, with a goal of 60% pCR. In a Simon’s two-stage design, if ≥3pCRs are seen in the first 8 patients, 11 additional patients will be enrolled, for a total of 19. The null hypothesis will be rejected if ≥10 pCRs are seen. Main inclusion criteria include urothelial cancer of the bladder, cT2-4aN0M0, >50% urothelial histology, and cisplatin ineligible; main exclusion criteria include any small cell/neuroendocrine or plasmacytoid histology, prior systemic therapy for bladder cancer, prior pelvic XRT, baseline grade 2 or higher neuropathy, prior allergic reaction attributed to EV, or uncontrolled intercurrent illness. Secondary endpoints include safety of the EV and SBRT, rate of pathologic down-staging, and exploratory objectives include quality of life, disease free survival after RC, and delay of RC >8 weeks from end of EV/SBRT. Serum and urinary biomarkers will be explored. The study is IND-exempt and will be open and enrolling (clinicaltrials.gov: NCT06394570).

Clinical trial identification

NCT06394570.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

UT Southwestern and Astellas.

Disclosure

T. Zhang: Financial Interests, Personal and Institutional, Advisory Board, Principal Investigator: Merck, AstraZeneca, Pfizer, Eli Lilly, Exelixis; Financial Interests, Personal and Institutional, Advisory Board, Principal Investigator, SC member: Janssen; Financial Interests, Institutional, Principal Investigator: Astellas, Tempus, ALX Oncology, Janux Therapeutics, OncoC4; Financial Interests, Personal, Speaker, Consultant, Advisor: Amgen, Sanofi Aventis, BMS, Eisai, Aveo, Bayer, Gilead, Novartis, EMD Serono, MJH Associates. Q. Qin: Financial Interests, Personal, Advisory Board: Exelixis; Financial Interests, Personal, Speaker, Consultant, Advisor: MJH Associates. S. Cole: Financial Interests, Institutional, Research Funding: Merck, QED Therapeutics, FDA. W. Arafat: Financial Interests, Institutional, Research Funding: Seagen. K. Courtney: Financial Interests, Personal and Institutional, Advisory Board, Principal Investigator: Novartis; Financial Interests, Institutional, Research Funding: Astellas, Eli Lilly, Stemline Therapeutics, Clovis Oncology, Exelixis, Amgen, Harpoon Therapeutics, Pfizer, Surface Oncology, Myovant Sciences, AstraZeneca, Janssen, BMS; Financial Interests, Personal, Licencing Fees or royalty for IP: Athena Diagnostics. A.Z. Wang: Financial Interests, Personal, Stocks or ownership: Capio Biosciences, Archimmune Therapeutics, Nanobarriers, Immune-X; Financial Interests, Personal, Speaker, Consultant, Advisor: Johnson and Johnson. V. Margulis: Financial Interests, Institutional, Principal Investigator: Merck; Financial Interests, Personal, Speaker, Consultant, Advisor: Janssen, Lantheus, Veracyte. Y. Lotan: Financial Interests, Personal, Advisory Board: Seagen, Pfizer. N. Desai: Financial Interests, Personal and Institutional, Advisory Board, Research funding: Boston Scientific, Telix Pharmaceuticals; Financial Interests, Institutional, Research Funding: RefleXion, Pfizer, Bayer, Veracyte. All other authors have declared no conflicts of interest.