PMID- 26091915 OWN - NLM STAT- MEDLINE DCOM- 20160627 LR - 20220311 IS - 1573-0646 (Electronic) IS - 0167-6997 (Print) IS - 0167-6997 (Linking) VI - 33 IP - 5 DP - 2015 Oct TI - Phase I study of the mTOR inhibitor ridaforolimus and the HDAC inhibitor vorinostat in advanced renal cell carcinoma and other solid tumors. PG - 1040-7 LID - 10.1007/s10637-015-0261-3 [doi] AB - 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. FAU - Zibelman, Matthew AU - Zibelman M AD - Department of Hematology/Oncology, Fox Chase Cancer Center, Temple Health, 333 Cottman Avenue, Philadelphia, PA, 19111-2497, USA. FAU - Wong, Yu-Ning AU - Wong YN AD - Department of Hematology/Oncology, Fox Chase Cancer Center, Temple Health, 333 Cottman Avenue, Philadelphia, PA, 19111-2497, USA. FAU - Devarajan, Karthik AU - Devarajan K AD - Department of Hematology/Oncology, Fox Chase Cancer Center, Temple Health, 333 Cottman Avenue, Philadelphia, PA, 19111-2497, USA. FAU - Malizzia, Lois AU - Malizzia L AD - Department of Hematology/Oncology, Fox Chase Cancer Center, Temple Health, 333 Cottman Avenue, Philadelphia, PA, 19111-2497, USA. FAU - Corrigan, Alycia AU - Corrigan A AD - Department of Hematology/Oncology, Fox Chase Cancer Center, Temple Health, 333 Cottman Avenue, Philadelphia, PA, 19111-2497, USA. FAU - Olszanski, Anthony J AU - Olszanski AJ AD - Department of Hematology/Oncology, Fox Chase Cancer Center, Temple Health, 333 Cottman Avenue, Philadelphia, PA, 19111-2497, USA. FAU - Denlinger, Crystal S AU - Denlinger CS AD - Department of Hematology/Oncology, Fox Chase Cancer Center, Temple Health, 333 Cottman Avenue, Philadelphia, PA, 19111-2497, USA. FAU - Roethke, Susan K AU - Roethke SK AD - Department of Hematology/Oncology, Fox Chase Cancer Center, Temple Health, 333 Cottman Avenue, Philadelphia, PA, 19111-2497, USA. FAU - Tetzlaff, Colleen H AU - Tetzlaff CH AD - Department of Hematology/Oncology, Fox Chase Cancer Center, Temple Health, 333 Cottman Avenue, Philadelphia, PA, 19111-2497, USA. FAU - Plimack, Elizabeth R AU - Plimack ER AD - Department of Hematology/Oncology, Fox Chase Cancer Center, Temple Health, 333 Cottman Avenue, Philadelphia, PA, 19111-2497, USA. elizabeth.plimack@fccc.edu. LA - eng SI - ClinicalTrials.gov/NCT01169532 GR - P30 CA006927/CA/NCI NIH HHS/United States PT - Clinical Trial, Phase I PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150620 PL - United States TA - Invest New Drugs JT - Investigational new drugs JID - 8309330 RN - 0 (Histone Deacetylase Inhibitors) RN - 0 (Hydroxamic Acids) RN - 48Z35KB15K (ridaforolimus) RN - 58IFB293JI (Vorinostat) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Aged MH - Aged, 80 and over MH - Antineoplastic Combined Chemotherapy Protocols/administration & dosage/adverse effects/*therapeutic use MH - Carcinoma, Renal Cell/*drug therapy/pathology MH - Dose-Response Relationship, Drug MH - Drug Administration Schedule MH - Drug Resistance, Neoplasm/*drug effects MH - Female MH - Histone Deacetylase Inhibitors/therapeutic use MH - Humans MH - Hydroxamic Acids/therapeutic use MH - Kidney Neoplasms/*drug therapy/pathology MH - Male MH - Maximum Tolerated Dose MH - Middle Aged MH - Sirolimus/analogs & derivatives/therapeutic use MH - TOR Serine-Threonine Kinases/*antagonists & inhibitors MH - Vorinostat PMC - PMC4573837 MID - NIHMS702025 OTO - NOTNLM OT - HDAC inhibition OT - Papillary OT - Renal cell carcinoma OT - mTOR inhibition OT - mTOR resistance EDAT- 2015/06/21 06:00 MHDA- 2016/06/28 06:00 PMCR- 2016/10/01 CRDT- 2015/06/21 06:00 PHST- 2015/04/30 00:00 [received] PHST- 2015/06/08 00:00 [accepted] PHST- 2015/06/21 06:00 [entrez] PHST- 2015/06/21 06:00 [pubmed] PHST- 2016/06/28 06:00 [medline] PHST- 2016/10/01 00:00 [pmc-release] AID - 10.1007/s10637-015-0261-3 [pii] AID - 10.1007/s10637-015-0261-3 [doi] PST - ppublish SO - Invest New Drugs. 2015 Oct;33(5):1040-7. doi: 10.1007/s10637-015-0261-3. Epub 2015 Jun 20.