A Phase 1/2 Study of Rapamycin and Cisplatin/Gemcitabine for Treatment of Patients With Muscle-Invasive Bladder Cancer

• Published in: Clinical genitourinary cancer 2023-04, Vol.21 (2), p.265-272
• Main Authors: Makrakis, Dimitrios, Wright, Jonathan L., Roudier, Martine P., Garcia, Jose, Vakar-Lopez, Funda, Porter, Michael P., Wang, Yan, Dash, Atreya, Lin, Daniel, Schade, George, Winters, Brian, Zhang, Xiotun, Nelson, Peter, Mostaghel, Elahe, Cheng, Heather H., Schweizer, Michael, Holt, Sarah K., Gore, John L., Yu, Evan Y., Lam, Hung Ming, Montgomery, Bruce
• Format: Article
• Language: English
• Subjects: Antineoplastic Combined Chemotherapy Protocols - adverse effects; Cisplatin - therapeutic use; Cystectomy; Damage response; Deoxycytidine; Gemcitabine; Humans; MIBC; Muscles - pathology; Neoadjuvant chemotherapy; Neoadjuvant Therapy - adverse effects; Neoplasm Invasiveness; Rapamycin; Sirolimus - adverse effects; TOR Serine-Threonine Kinases; Tumor Microenvironment; Urinary Bladder Neoplasms - pathology
• ISSN: 1558-7673; 1938-0682
• DOI: 10.1016/j.clgc.2022.12.003

Cisplatin-based neoadjuvant chemotherapy (NAC) followed by cystectomy is the standard for muscle-invasive bladder cancer (MIBC), however, NAC confers only a small survival benefit and new strategies are needed to increase its efficacy. Pre-clinical data suggest that in response to DNA damage the tumor microenvironment (TME) adopts a paracrine secretory phenotype dependent on mTOR signaling which may provide an escape mechanism for tumor resistance, thus offering an opportunity to increase NAC effectiveness with mTOR blockade. We conducted a phase I/II clinical trial to assess the safety and efficacy of gemcitabine-cisplatin-rapamycin combination. Grapefruit juice was administered to enhance rapamycin pharmacokinetics by inhibiting intestinal enzymatic degradation. Phase I was a dose determination/safety study followed by a single arm Phase II study of NAC prior to radical cystectomy evaluating pathologic response with a 26% pCR rate target. In phase I, 6 patients enrolled, and the phase 2 dose of 35 mg rapamycin established. Fifteen patients enrolled in phase II; 13 were evaluable. Rapamycin was tolerated without serious adverse events. At the preplanned analysis, the complete response rate (23%) did not meet the prespecified level for continuing and the study was stopped due to futility. With immunohistochemistry, successful suppression of the mTOR signaling pathway in the tumor was achieved while limited mTOR activity was seen in the TME. Adding rapamycin to gemcitabine-cisplatin therapy for patients with MIBC was well tolerated but failed to improve therapeutic efficacy despite evidence of mTOR blockade in tumor cells. Further efforts to understand the role of the tumor microenvironment in chemotherapy resistance is needed. Platinum-based NAC followed by cystectomy is standard of care for MIBC, however improvement of response rates is needed. In this phase I/II trial, neoadjuvant gemcitabine-cisplatin-rapamycin combination was used to suppress response to platinum-derived DNA damage by the tumor microenvironment. Although rapamycin successfully suppressed damage response, treatment efficacy did not improve, suggesting the existence of alternative platinum resistance pathways.