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Ann Oncol. 2013 Jul;24(7):1900-7. doi: 10.1093/annonc/mdt109. Epub 2013 Mar 21.

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

Author information

1
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA 94143, USA. katie.kelley@ucsf.edu

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). Alpha-fetoprotein (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.

KEYWORDS:

hepatocellular carcinoma; mTOR; pharmacokinetics; sorafenib; temsirolimus

PMID:
23519998
PMCID:
PMC3690907
DOI:
10.1093/annonc/mdt109
[Indexed for MEDLINE]
Free PMC Article

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