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

Autor: Makrakis D; Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA. Electronic address: dmakrak@uw.edu., Wright JL; Department of Urology, University of Washington, Seattle, WA; VA Puget Sound Health Care System, Seattle, WA; Fred Hutchinson Cancer Research Center, Seattle, WA., Roudier MP; Department of Urology, University of Washington, Seattle, WA., Garcia J; Department of Urology, University of Washington, Seattle, WA., Vakar-Lopez F; Department of Pathology, University of Washington, Seattle, WA., Porter MP; Department of Urology, University of Washington, Seattle, WA; VA Puget Sound Health Care System, Seattle, WA., Wang Y; Department of Urology, University of Washington, Seattle, WA., Dash A; Department of Urology, University of Washington, Seattle, WA., Lin D; Department of Urology, University of Washington, Seattle, WA; Fred Hutchinson Cancer Research Center, Seattle, WA., Schade G; Department of Urology, University of Washington, Seattle, WA., Winters B; Kaiser Permanente Washington, WA., Zhang X; CellNetix Pathology and Laboratories LLC, Seattle, WA., Nelson P; Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA; Fred Hutchinson Cancer Research Center, Seattle, WA., Mostaghel E; VA Puget Sound Health Care System, Seattle, WA., Cheng HH; Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA; Fred Hutchinson Cancer Research Center, Seattle, WA., Schweizer M; Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA., Holt SK; Department of Urology, University of Washington, Seattle, WA., Gore JL; Department of Urology, University of Washington, Seattle, WA; Fred Hutchinson Cancer Research Center, Seattle, WA., Yu EY; Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA., Lam HM; Department of Urology, University of Washington, Seattle, WA., Montgomery B; Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA; VA Puget Sound Health Care System, Seattle, WA.
Jazyk: angličtina
Zdroj: Clinical genitourinary cancer [Clin Genitourin Cancer] 2023 Apr; Vol. 21 (2), pp. 265-272. Date of Electronic Publication: 2022 Dec 23.
DOI: 10.1016/j.clgc.2022.12.003
Abstrakt: Introduction: 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.
Patients & Methods: 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.
Results: 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.
Conclusion: 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.
Competing Interests: Disclosure The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper
(Copyright © 2022. Published by Elsevier Inc.)
Databáze: MEDLINE
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