Phase I/II study of temsirolimus for patients with unresectable Hepatocellular Carcinoma (HCC)- a correlative study to explore potential biomarkers for response

Winnie Yeo, Stephen L Chan, Frankie K F Mo, Cheuk M Chu, Joyce W Y Hui, Joanne H M Tong, Anthony W H Chan, Jane Koh, Edwin P Hui, Herbert Loong, Kirsty Lee, Leung Li, Brigette Ma, Ka F To, Simon C H Yu, Winnie Yeo, Stephen L Chan, Frankie K F Mo, Cheuk M Chu, Joyce W Y Hui, Joanne H M Tong, Anthony W H Chan, Jane Koh, Edwin P Hui, Herbert Loong, Kirsty Lee, Leung Li, Brigette Ma, Ka F To, Simon C H Yu

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.

Trial registration: This study has been registered in ClinicalTrials.gov (Id: NCT00321594) on 1 December 2010.

Figures

Figure 1
Figure 1
(a) Progression-free survival; (b) Overall survival of patients in the phase II study.
Figure 2
Figure 2
Immunohistochemical staining of pretreatment tumour tissues. A. high stathmin H-score (2/300). B. low stathmin H-score (210/300). C. high pS6 H-score (0/300). D. low pS6 H-score (270/300). E. high pMTOR H-score (3/300). F. low pMTOR H-score (105/300). G. high p-AKT H-score (5/300). H. low p-AKT H-score (240/300).

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