Phase I study of everolimus in combination with gemcitabine and split-dose cisplatin in advanced urothelial carcinoma Journal Article
| Authors: | Abida, W.; Milowsky, M. I.; Ostrovnaya, I.; Gerst, S. R.; Rosenberg, J. E.; Voss, M. H.; Apolo, A. B.; Regazzi, A. M.; McCoy, A. S.; Boyd, M. E.; Bajorin, D. F. |
| Article Title: | Phase I study of everolimus in combination with gemcitabine and split-dose cisplatin in advanced urothelial carcinoma |
| Abstract: | Background: Cisplatin-based combination chemotherapy is standard first-line treatment for patients with advanced urothelial carcinoma (UC). Molecular profiling studies reveal that the PI3K/AKT/mTOR pathway is altered in a significant percentage of UCs. Objective:We conducted a phase I trial to evaluate the feasibility of combining the mTOR inhibitor everolimus with gemcitabine and split-dose cisplatin (GC) in advanced UC in the first-line setting. Methods: Patients received gemcitabine 800 mg/m2 and cisplatin 35 mg/m2 on days 1 and 8 of 21-day cycles for a total of 6 cycles in combination with everolimus at increasing dose levels (DL1:5 mg QOD, DL2:5 mg daily, DL3:10 mg daily) following a standard 3+3 design. Responses were assessed every 2 cycles. Patients with at least stable disease (SD) continued everolimus until progression. Goals were to establish dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) for the combination. Results: 12 patients were enrolled, 3 at DL1, 3 at DL2, and an additional 6 at DL1∗(DL1 following de-escalation). 3/3 patients at DL2 had DLTs during cycle 1. 2/8 evaluable patients at DL1/DL1∗ had DLTs during cycle 1. DLTs were primarily hematologic. Further toxicities, also primarily hematologic, were observed during later treatment cycles, leading to 8 chemotherapy dose reductions overall. Partial responses were observed in 4/10 evaluable patients, and SD in 5/10. Median overall survival was 10.8 months (95% CI 6.9, not reached). Conclusions: The maximum tolerated dose was reached at the lowest dose level, 5mg QOD, for everolimus in combination with gemcitabine and split-dose cisplatin in advanced UC. The regimen was limited by hematologic toxicity. © 2016 - IOS Press and the authors. All rights reserved. |
| Keywords: | cisplatin; gemcitabine; urothelial carcinoma; everolimus; mtor inhibitor |
| Journal Title: | Bladder Cancer |
| Volume: | 2 |
| Issue: | 1 |
| ISSN: | 2352-3727 |
| Publisher: | IOS Press |
| Date Published: | 2016-01-01 |
| Start Page: | 111 |
| End Page: | 117 |
| Language: | English |
| DOI: | 10.3233/blc-150038 |
| PROVIDER: | scopus |
| PMCID: | PMC4927849 |
| PUBMED: | 27376132 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 4 September 2018 -- Source: Scopus |
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