Temsirolimus combined with sorafenib in hepatocellular carcinoma: A phase I dose-finding trial with pharmacokinetic and biomarker correlates

R. K. Kelley Dr., H. S. Nimeiri, P. N. Munster, M. T. Vergo, Y. Huang, C. M. Li, J. Hwang, M. F. Mulcahy, B. M. Yeh, P. Kuhn, M. S. Luttgen, J. A. Grabowsky, L. Stucky-Marshall, W. M. Korn, A. H. Ko, E. K. Bergsland, A. B. Benson, A. P. Venook

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50 Scopus citations

Abstract

Background: Based upon preclinical evidence for improved antitumor activity in combination, this phase I study investigated the maximum-tolerated dose (MTD), safety, activity, pharmacokinetics (PK), and biomarkers of the mammalian target of rapamycin inhibitor, temsirolimus, combined with sorafenib in hepatocellular carcinoma (HCC). Patients and methods: Patients with incurable HCC and Child Pugh score <B7 were treated with sorafenib plus temsirolimus by 3 + 3 design. The dose-limiting toxicity (DLT) interval was 28 days. The response was assessed every two cycles. PK of temsirolimus was measured in a cohort at MTD. Results: Twenty-five patients were enrolled. The MTD was temsirolimus 10 mg weekly plus sorafenib 200 mg twice daily. Among 18 patients at MTD, DLT included grade 3 hand-foot skin reaction (HFSR) and grade 3 thrombocytopenia. Grade 3 or 4 related adverse events at MTD included hypophosphatemia (33%), infection (22%), thrombocytopenia (17%), HFSR (11%), and fatigue (11%). With sorafenib, temsirolimus clearance was more rapid (P < 0.05). Two patients (8%) had a confirmed partial response (PR); 15 (60%) had stable disease (SD). Alphafetoprotein (AFP) declined >50% in 60% assessable patients. Conclusion: The MTD of sorafenib plus temsirolimus in HCC was lower than in other tumor types. HCC-specific phase I studies are necessary. The observed efficacy warrants further study.

Original languageEnglish (US)
Pages (from-to)1900-1907
Number of pages8
JournalAnnals of Oncology
Volume24
Issue number7
DOIs
StatePublished - Jul 2013

Funding

This work was supported by the National Comprehensive Cancer Network (NCCN) with general research support provided by Pfizer, Inc. Temsirolimus was provided by Pfizer, Inc. RKK’s effort was supported by a Young Investigator Award (YIA) from the American Society of Clinical Oncology (ASCO) in 2011. A support for specimen banking was provided by the Bili Project Foundation. A support for circulating tumor cell testing was provided by National Institutes of Health U54CA143906 to PK. Research funding is reported by: PNM, Bayer/Onyx and Pfizer Oncology; PK, Epic Sciences; ABB and APV, Bayer/Onyx.

Keywords

  • Hepatocellular carcinoma
  • MTOR
  • Pharmacokinetics
  • Sorafenib
  • Temsirolimus

ASJC Scopus subject areas

  • Hematology
  • Oncology

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