title: Phase I/II study of temsirolimus for patients with unresectable Hepatocellular Carcinoma (HCC)- a correlative study to explore potential biomarkers for response.
abstract: BACKGROUND
  The oncogenic PI3K/Akt/mTOR pathway is frequently activated in HCC. Data on the mTOR inhibitor, temsirolimus, is limited in HCC patients with concomitant chronic liver disease. The objectives of this study were: (1) In phase I, to determine DLTs and MTD of temsirolimus in HCC patients with chronic liver disease; (2) In phase II, to assess activity of temsirolimus in HCC, and (3) to explore potential biomarkers for response.
  
  
  METHODS
  Major eligibility criteria included histologically confirmed advanced HCC and adequate organ function. In Phase I part of the study, temsirolimus was given weekly in 3-weekly cycle; dose levels were 20 mg (level 1), 25 mg (level 2) and 30 mg (level 3). The MTD was used in the subsequent phase II part; the primary endpoint was PFS and secondary endpoints were response and OS. In addition, exploratory analysis was conducted on pre-treatment tumour tissues to determine stathmin, pS6, pMTOR or p-AKT expressions as potential biomarkers for response. Overall survival and PFS were calculated using the Kaplan-Meier method. Reassessment CT scans were done every 6 weeks. All adverse events were reported using CTCAE v3.
  
  
  RESULTS
  The Phase I part consisted of 19 patients, 2 of 6 patients at level 3 experienced DLT; dose level 2 was determined to be the MTD. The phase II part consisted of 36 patients. Amongst 35 assessable patients, there were 1 PR, 20 SD and 14 PD. Overall, the median PFS was 2.83 months (95% C.I. 1.63-5.24). The median OS was 8.89 months (95% C.I. 5.89-13.30). Grade ≥ 3 that occurred in > 10% of patients included thrombocytopenia (4) and hyponatraemia (4). Exploratory analysis revealed that disease stabilization (defined as CR + PR + SD > 12 weeks) in tumours having high and low pMTOR H-scores to be 70% and 29% respectively (OR 5.667, 95% CI 1.129-28.454, p = 0.035).
  
  
  CONCLUSIONS
  In HCC patients with chronic liver disease, the MTD of temsirolimus was 25 mg weekly in a 3-week cycle. The targeted PFS endpoint was not reached. However, further studies to identify appropriate patient subgroup are warranted.
  
  
  BACKGROUND
  This study has been registered in ClinicalTrials.gov (Id: NCT00321594) on 1 December 2010.
authors.affiliation: Comprehensive Cancer Trials Unit, Department of Clinical Oncology, State Key Lab in Oncology in South China, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong. winnie@clo.cuhk.edu.hk.
authors.forename: Winnie
authors.initials: W
authors.lastname: Yeo
authors.affiliation: Comprehensive Cancer Trials Unit, Department of Clinical Oncology, State Key Lab in Oncology in South China, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong. l_chan@clo.cuhk.edu.hk.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Chan
authors.affiliation: Comprehensive Cancer Trials Unit, Department of Clinical Oncology, State Key Lab in Oncology in South China, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong. frankie@clo.cuhk.edu.hk.
authors.forename: Frankie K F
authors.initials: FK
authors.lastname: Mo
authors.affiliation: Department of Diagnostic and Interventional Radiology, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong. ccm715@ha.org.
authors.forename: Cheuk M
authors.initials: CM
authors.lastname: Chu
authors.affiliation: Department of Diagnostic and Interventional Radiology, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong. joyce.water@gmail.com.
authors.forename: Joyce W Y
authors.initials: JW
authors.lastname: Hui
authors.affiliation: Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong. jtong@cuhk.edu.hk.
authors.forename: Joanne H M
authors.initials: JH
authors.lastname: Tong
authors.affiliation: Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong. awh_chan@yahoo.com.hk.
authors.forename: Anthony W H
authors.initials: AW
authors.lastname: Chan
authors.affiliation: Comprehensive Cancer Trials Unit, Department of Clinical Oncology, State Key Lab in Oncology in South China, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong. jane@clo.cuhk.edu.hk.
authors.forename: Jane
authors.initials: J
authors.lastname: Koh
authors.affiliation: Comprehensive Cancer Trials Unit, Department of Clinical Oncology, State Key Lab in Oncology in South China, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong. p_hui@clo.cuhk.edu.hk.
authors.forename: Edwin P
authors.initials: EP
authors.lastname: Hui
authors.affiliation: Comprehensive Cancer Trials Unit, Department of Clinical Oncology, State Key Lab in Oncology in South China, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong. h_loong@clo.cuhk.edu.hk.
authors.forename: Herbert
authors.initials: H
authors.lastname: Loong
authors.affiliation: Comprehensive Cancer Trials Unit, Department of Clinical Oncology, State Key Lab in Oncology in South China, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong. kirsty.lee@gmail.com.
authors.forename: Kirsty
authors.initials: K
authors.lastname: Lee
authors.affiliation: Comprehensive Cancer Trials Unit, Department of Clinical Oncology, State Key Lab in Oncology in South China, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong. lileungvil@gmail.com.
authors.forename: Leung
authors.initials: L
authors.lastname: Li
authors.affiliation: Comprehensive Cancer Trials Unit, Department of Clinical Oncology, State Key Lab in Oncology in South China, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong. brigette@clo.cuhk.edu.hk.
authors.forename: Brigette
authors.initials: B
authors.lastname: Ma
authors.affiliation: Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong. kfto@cuhk.edu.hk.
authors.forename: Ka F
authors.initials: KF
authors.lastname: To
authors.affiliation: Department of Diagnostic and Interventional Radiology, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong. simonyu@cuhk.edu.hk.
authors.forename: Simon C H
authors.initials: SC
authors.lastname: Yu
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use* / Q000633:toxicity; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000401:mortality; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use / Q000633:toxicity; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; C401859:temsirolimus; D020123:Sirolimus