Summary
Introduction Drugs inhibiting the mammalian target of rapamycin (mTOR) are approved in the treatment of renal cell carcinoma (RCC), but resistance inevitably emerges. Proposed escape pathways include increased phosphorylation of Akt, which can be down regulated by histone deacetylase (HDAC) inhibitors. We hypothesized that co-treatment with the mTOR inhibitor ridaforolimus and the HDAC inhibitor vorinostat may abrogate resistance in RCC. Methods This phase 1 study evaluated the co-administration of ridaforolimus and vorinostat in patients with advanced solid tumors. The primary objective was to determine the maximum tolerated dose (MTD) in RCC patients. Although all solid tumors were allowed, prior cytotoxic chemotherapy was limited to 1 regimen. Using a modified 3 + 3 dose escalation design, various dose combinations were tested concurrently in separate cohorts. Efficacy was a secondary endpoint. Results Fifteen patients were treated at one of three dose levels, thirteen with RCC (10 clear cell, 3 papillary). Dosing was limited by thrombocytopenia. The MTD was determined to be ridaforolimus 20 mg daily days 1–5 with vorinostat 100 mg BID days 1–3 weekly, however late onset thrombocytopenia led to a lower recommended phase II dose: ridaforolimus 20 mg daily days 1–5 with vorinostat 100 mg daily days 1–3 weekly. Two patients, both with papillary RCC, maintained disease control for 54 and 80 weeks, respectively. Conclusions The combination of ridaforolimus and vorinostat was tolerable at the recommended phase II dose. Two patients with papillary RCC experienced prolonged disease stabilization, thus further study of combined HDAC and mTOR inhibition in this population is warranted.
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Acknowledgments
The authors would like to thank the patients who enrolled in this trial, as well as their families
Funding Sources
This work was supported in part by Merck Inc.
Financial Disclosures
ERP has served as a consultant for Merck Inc.
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HDAC inhibition may abrogate Akt mediated resistance to mTOR inhibition. When combined in this phase I trial, the mTOR inhibitor ridaforolimus and the HDAC inhibitor vorinostat were safe in combination and preliminary efficacy results suggest proof of concept.
Author Contributions
Conception and Design: ERP
Acquisition of data: YNW, LM, AJO, CSD, SKR, CHT, ERP.
Analysis and interpretation of data: MZ, KD, and ERP.
Writing, review and/or revision of the manuscript: All authors.
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Trial registration ID: NCT01169532
Neither the submitted manuscript nor any similar manuscript, in whole or in part, other than an abstract, is under consideration, in press, published, or reported elsewhere.
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Zibelman, M., Wong, YN., Devarajan, K. et al. Phase I study of the mTOR inhibitor ridaforolimus and the HDAC inhibitor vorinostat in advanced renal cell carcinoma and other solid tumors. Invest New Drugs 33, 1040–1047 (2015). https://doi.org/10.1007/s10637-015-0261-3
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DOI: https://doi.org/10.1007/s10637-015-0261-3