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

Published:December 22, 2022DOI:https://doi.org/10.1016/j.clgc.2022.12.003

      Abstract

      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.

      Keywords

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      References

        • Saginala K
        • Barsouk A
        • Aluru JS
        • Rawla P
        • Padala SA
        • Barsouk A
        Epidemiology of bladder cancer.
        Med Sci Basel Switz. 2020; 8: 15https://doi.org/10.3390/medsci8010015
        • Mari A
        • Campi R
        • Tellini R
        • Gandaglia G
        Patterns and predictors of recurrence after open radical cystectomy for bladder cancer: a comprehensive review of the literature.
        World J Urol. 2018; 36: 157-170https://doi.org/10.1007/s00345-017-2115-4
        • Yin M
        • Joshi M
        • Meijer RP
        • et al.
        Neoadjuvant chemotherapy for muscle-invasive bladder cancer: a systematic review and two-step meta-analysis.
        Oncologist. 2016; 21: 708-715https://doi.org/10.1634/theoncologist.2015-0440
        • Vale CL
        Neoadjuvant chemotherapy in invasive bladder cancer: update of a systematic review and meta-analysis of individual patient data: advanced bladder cancer (ABC) meta-analysis collaboration.
        Eur Urol. 2005; 48: 202-206https://doi.org/10.1016/j.eururo.2005.04.006
        • Grossman HB
        • Natale RB
        • Tangen CM
        • et al.
        Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer.
        New Engl J Med. 2003; 349: 859-866
        • von der Maase H
        • Hansen SW
        • Roberts JT
        • et al.
        Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study.
        J Clin Oncol. 2000; 18: 3068-3077https://doi.org/10.1200/JCO.2000.18.17.3068
        • International Collaboration of Trialists
        • Medical research council advanced bladder cancer working party (now the National Cancer Research Institute Bladder Cancer Clinical Studies Group)
        • European Organisation for Research and Treatment of Cancer Genito-Urinary Tract Cancer Group
        International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long-term results of the BA06 30894 trial.
        J Clin Oncol. 2011; 29: 2171-2177https://doi.org/10.1200/JCO.2010.32.3139
        • Advanced Bladder Cancer Overview C
        Neoadjuvant chemotherapy for invasive bladder cancer.
        Cochrane Database System Rev (Online). 2005; CD005246
        • Meeks JJ
        • Bellmunt J
        • Bochner BH
        • et al.
        A systematic review of neoadjuvant and adjuvant chemotherapy for muscle-invasive bladder cancer.
        Eur Urol. 2012; 62: 523-533
        • Sonpavde G
        • Sternberg CN
        Neoadjuvant chemotherapy for invasive bladder cancer.
        Curr Urol Rep. 2012; 13: 136-146
        • Waingankar N
        • Jia R
        • Marqueen KE
        • et al.
        The impact of pathologic response to neoadjuvant chemotherapy on conditional survival among patients with muscle-invasive bladder cancer.
        Urol Oncol. 2019; 37: 572.e21-572.e28https://doi.org/10.1016/j.urolonc.2019.04.027
        • Rosenblatt R
        • Sherif A
        • Rintala E
        • et al.
        Pathologic downstaging is a surrogate marker for efficacy and increased survival following neoadjuvant chemotherapy and radical cystectomy for muscle-invasive urothelial bladder cancer.
        Eur Urol. 2012; 61: 1229-1238https://doi.org/10.1016/j.eururo.2011.12.010
        • Petrelli F
        • Coinu A
        • Cabiddu M
        • Ghilardi M
        • Vavassori I
        • Barni S
        Correlation of pathologic complete response with survival after neoadjuvant chemotherapy in bladder cancer treated with cystectomy: a meta-analysis.
        Eur Urol. 2014; 65: 350-357https://doi.org/10.1016/j.eururo.2013.06.049
        • Gomez-Sarosi L
        • Sun Y
        • Coleman I
        • Bianchi-Frias D
        • Nelson PS
        DNA damage induces a secretory program in the quiescent TME that fosters adverse cancer phenotypes.
        Mol Cancer Res. 2017; 15: 842-851https://doi.org/10.1158/1541-7786.MCR-16-0387
        • Nguyen DH
        • Oketch-Rabah HA
        • Illa-Bochaca I
        • et al.
        Radiation acts on the microenvironment to affect breast carcinogenesis by distinct mechanisms that decrease cancer latency and affect tumor type.
        Cancer Cell. 2011; 19: 640-651https://doi.org/10.1016/j.ccr.2011.03.011
        • Zhang B
        • Fu D
        • Xu Q
        • et al.
        The senescence-associated secretory phenotype is potentiated by feedforward regulatory mechanisms involving Zscan4 and TAK1.
        Nat Commun. 2018; 9: 1723https://doi.org/10.1038/s41467-018-04010-4
        • Laberge RM
        • Sun Y
        • Orjalo AV
        • et al.
        MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation.
        Nat Cell Biol. 2015; 17: 1049-1061https://doi.org/10.1038/ncb3195
        • Mansure JJ
        • Nassim R
        • Chevalier S
        • Rocha J
        • Scarlata E
        • Kassouf W
        Inhibition of mammalian target of rapamycin as a therapeutic strategy in the management of bladder cancer.
        Cancer Biol Ther. 2009; 8: 2339-2347https://doi.org/10.4161/cbt.8.24.9987
        • Cohen EE
        • Wu K
        • Hartford C
        • et al.
        Phase I studies of sirolimus alone or in combination with pharmacokinetic modulators in advanced cancer patients.
        Clin Cancer Res. 2012; 18: 4785-4793
        • Winters BR
        • Vakar-Lopez F
        • Brown L
        • et al.
        Mechanistic target of rapamycin (MTOR) protein expression in the tumor and its microenvironment correlates with more aggressive pathology at cystectomy.
        Urol Oncol. 2018; 36 (e7-342.e14): 342https://doi.org/10.1016/j.urolonc.2018.03.016
        • Lam HM
        • McMullin R
        • Nguyen HM
        • et al.
        Characterization of an abiraterone ultraresponsive phenotype in castration-resistant prostate cancer patient-derived xenografts.
        Clin Cancer Res. 2017; 23: 2301-2312https://doi.org/10.1158/1078-0432.CCR-16-2054
        • Seiler R
        • Gibb EA
        • Wang NQ
        • et al.
        Divergent biological response to neoadjuvant chemotherapy in muscle-invasive bladder cancer.
        Clin Cancer Res. 2019; 25: 5082-5093https://doi.org/10.1158/1078-0432.CCR-18-1106
        • Renner A
        • Burotto M
        • Valdes JM
        • Roman JC
        • Walton-Diaz A
        Neoadjuvant immunotherapy for muscle invasive urothelial bladder carcinoma: will it change current standards?.
        Ther Adv Urol. 2021; 13 (17562872211029780-17562872211029780)https://doi.org/10.1177/17562872211029779
        • Sun Y
        • Nelson PS
        Molecular pathways: involving microenvironment damage responses in cancer therapy resistance.
        Clin Cancer Res. 2012; 18: 4019-4025https://doi.org/10.1158/1078-0432.CCR-11-0768
        • Krtolica A
        • Parrinello S
        • Lockett S
        • Desprez PY
        • Campisi J
        Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging.
        Proc Natl Acad Sci U S A. 2001; 98: 12072-12077https://doi.org/10.1073/pnas.211053698
        • Sun Y
        • Campisi J
        • Higano C
        • et al.
        Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B.
        Nat Med. 2012; 18: 1359-1368https://doi.org/10.1038/nm.2890
        • Bavik C
        • Coleman I
        • Dean JP
        • Knudsen B
        • Plymate S
        • Nelson PS
        The gene expression program of prostate fibroblast senescence modulates neoplastic epithelial cell proliferation through paracrine mechanisms.
        Cancer Res. 2006; 66: 794-802https://doi.org/10.1158/0008-5472.CAN-05-1716
        • Gilbert LA
        • Hemann MT
        DNA damage-mediated induction of a chemoresistant niche.
        Cell. 2010; 143: 355-366https://doi.org/10.1016/j.cell.2010.09.043
        • Sun Y
        • Zhu D
        • Chen F
        • et al.
        SFRP2 augments WNT16B signaling to promote therapeutic resistance in the damaged tumor microenvironment.
        Oncogene. 2016; 35: 4321-4334https://doi.org/10.1038/onc.2015.494
        • Wang T
        • Notta F
        • Navab R
        • et al.
        Senescent carcinoma-associated fibroblasts upregulate IL8 to enhance prometastatic phenotypes.
        Mol Cancer Res. 2017; 15: 3-14https://doi.org/10.1158/1541-7786.MCR-16-0192
        • Coppé JP
        • Patil CK
        • Rodier F
        • et al.
        Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor.
        PLoS Biol. 2008; 6: 2853-2868https://doi.org/10.1371/journal.pbio.0060301
        • Herranz N
        • Gallage S
        • Mellone M
        • et al.
        mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype.
        Nat Cell Biol. 2015; 17: 1205-1217https://doi.org/10.1038/ncb3225
        • Choo AY
        • Yoon SO
        • Kim SG
        • Roux PP
        • Blenis J
        Rapamycin differentially inhibits S6Ks and 4E-BP1 to mediate cell-type-specific repression of mRNA translation.
        Proc Natl Acad Sci. 2008; 105: 17414https://doi.org/10.1073/pnas.0809136105
        • Adib E
        • Klonowska K
        • Giannikou K
        • et al.
        Phase II clinical trial of everolimus in a pan-cancer cohort of patients with mTOR pathway alterations.
        Clin Cancer Res. 2021; 27: 3845-3853https://doi.org/10.1158/1078-0432.CCR-20-4548
        • Li J
        • Kim SG
        • Blenis J
        Rapamycin: one drug, many effects.
        Cell Metab. 2014; 19: 373-379https://doi.org/10.1016/j.cmet.2014.01.001
        • Goel S
        • Sinha RJ
        • Bhaskar V
        • Aeron R
        • Sharma A
        • Singh V
        Role of gemcitabine and cisplatin as neoadjuvant chemotherapy in muscle invasive bladder cancer: experience over the last decade.
        Asian J Urol. 2019; 6: 222-229https://doi.org/10.1016/j.ajur.2018.06.006
        • Nguyen LS
        • Vautier M
        • Allenbach Y
        • et al.
        Sirolimus and mTOR inhibitors: a review of side effects and specific management in solid organ transplantation.
        Drug Saf. 2019; 42: 813-825https://doi.org/10.1007/s40264-019-00810-9
        • Weiner SM
        • Sellin L
        • Vonend O
        • et al.
        Pneumonitis associated with sirolimus: clinical characteristics, risk factors and outcome—a single-centre experience and review of the literature.
        Nephrol Dial Transplant. 2007; 22: 3631-3637https://doi.org/10.1093/ndt/gfm420
        • Marti HP
        • Frey FJ
        Nephrotoxicity of rapamycin: an emerging problem in clinical medicine.
        Nephrol Dial Transplant. 2005; 20: 13-15https://doi.org/10.1093/ndt/gfh639
        • Peyrottes A
        • Ouzaid I
        • Califano G
        • Hermieu JF
        • Xylinas E
        Neoadjuvant immunotherapy for muscle-invasive bladder cancer.
        Medicina (Kaunas). 2021; 57 (Published 2021 Jul 29): 769https://doi.org/10.3390/medicina57080769