title: Temsirolimus combined with sorafenib in hepatocellular carcinoma: a phase I dose-finding trial with pharmacokinetic and biomarker correlates.
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).
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco. Electronic address: katie.kelley@ucsf.edu.
authors.forename: R K
authors.initials: RK
authors.lastname: Kelley
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago.
authors.forename: H S
authors.initials: HS
authors.lastname: Nimeiri
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco.
authors.forename: P N
authors.initials: PN
authors.lastname: Munster
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago.
authors.forename: M T
authors.initials: MT
authors.lastname: Vergo
authors.affiliation: Drug Studies Unit, Department of Bioengineering & Therapeutic Sciences.
authors.forename: Y
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Drug Studies Unit, Department of Bioengineering & Therapeutic Sciences.
authors.forename: C-M
authors.initials: CM
authors.lastname: Li
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco.
authors.forename: J
authors.initials: J
authors.lastname: Hwang
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago.
authors.forename: M F
authors.initials: MF
authors.lastname: Mulcahy
authors.affiliation: Department of Radiology, UCSF, San Francisco.
authors.forename: B M
authors.initials: BM
authors.lastname: Yeh
authors.affiliation: Department of Cell Biology, The Scripps Research Institute, La Jolla, USA.
authors.forename: P
authors.initials: P
authors.lastname: Kuhn
authors.affiliation: Department of Cell Biology, The Scripps Research Institute, La Jolla, USA.
authors.forename: M S
authors.initials: MS
authors.lastname: Luttgen
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco.
authors.forename: J A
authors.initials: JA
authors.lastname: Grabowsky
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago.
authors.forename: L
authors.initials: L
authors.lastname: Stucky-Marshall
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco.
authors.forename: W M
authors.initials: WM
authors.lastname: Korn
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco.
authors.forename: A H
authors.initials: AH
authors.lastname: Ko
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco.
authors.forename: E K
authors.initials: EK
authors.lastname: Bergsland
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago.
authors.forename: A B
authors.initials: AB
authors.lastname: Benson
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco.
authors.forename: A P
authors.initials: AP
authors.lastname: Venook
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D014408:Biomarkers, Tumor / Q000097:blood*; D006528:Carcinoma, Hepatocellular / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009360:Neoplastic Cells, Circulating; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives; D010671:Phenylurea Compounds / Q000008:administration & dosage; D011498:Protein Precursors / Q000097:blood; D011516:Prothrombin; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D000077157:Sorafenib; D016896:Treatment Outcome; D000509:alpha-Fetoproteins / Q000378:metabolism*
chemical_list: C097353:AFP protein, human; D015415:Biomarkers; D014408:Biomarkers, Tumor; D010671:Phenylurea Compounds; D011498:Protein Precursors; D000509:alpha-Fetoproteins; D009536:Niacinamide; C008208:acarboxyprothrombin; C401859:temsirolimus; D011516:Prothrombin; D000077157:Sorafenib; D020123:Sirolimus
keywords: hepatocellular carcinoma; mTOR; pharmacokinetics; sorafenib; temsirolimus