Phase i study of the mTOR inhibitor ridaforolimus and the HDAC inhibitor vorinostat in advanced renal cell carcinoma and other solid tumors

Matthew Zibelman, Yu Ning Wong, Karthik Devarajan, Lois Malizzia, Alycia Corrigan, Anthony J. Olszanski, Crystal S. Denlinger, Susan Roethke, Colleen H. Tetzlaff, Elizabeth R. Plimack

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)1040-1047
Number of pages8
JournalInvestigational New Drugs
Volume33
Issue number5
DOIs
StatePublished - Oct 22 2015

Keywords

  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols/administration & dosage
  • Carcinoma, Renal Cell/drug therapy
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Drug Resistance, Neoplasm/drug effects
  • Female
  • Histone Deacetylase Inhibitors/therapeutic use
  • Humans
  • Hydroxamic Acids/therapeutic use
  • Kidney Neoplasms/drug therapy
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Sirolimus/analogs & derivatives
  • TOR Serine-Threonine Kinases/antagonists & inhibitors
  • Vorinostat

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