Randomized Phase Open-Label Trial of PR104 and Sorafenib in Patients With Advanced Hepatocellular Carcinoma
The current understanding of PR104 justifies the evaluation of PR104 with sorafenib in patients with hepatocellular carcinoma. These include:
- Hypoxia. HCC is likely to demonstrate a level of hypoxia sufficient to activate PR104 to its active metabolites PR104H and PR104M. In addition, in preclinical models, sorafenib has been demonstrated to increase the degree of hypoxia in tumors following treatment (21;22).
- Non-overlapping toxicity. PR104 and sorafenib do not share major toxicities. It is anticipated that both drugs can be administered at their full single agent dose when used in combination.
- AKR1C3. HCC has been shown to express high levels of AKR1C3 which should lead to selective activation of PR104 within both hypoxic and oxic HCC cells.
- Preclinical data. The use of sorafenib and PR104 alone and in combination in a hepatocellular carcinoma model demonstrates activity of PR104 as a single agent and increased activity when PR104 and sorafenib are used in combination.
The current study will provide an estimate of the activity of PR104 in subjects with HCC. This information will prove valuable in defining the future clinical development of PR104, and in determining if PR104 has sufficient activity in HCC to warrant a larger phase III registration study in this indication.
- Phase I: Determine the MTD of PR104 when used in combination with standard dose sorafenib
- Phase II: Estimate the response rate (RR) of PR104/sorafenib
- Evaluate survival
- Evaluate Progression Free Survival (PFS)
- Evaluate time to progression (TTP)
- Evaluate safety
- Evaluate the pharmacokinetics of sorafenib, PR104 and PR104 metabolites
- Collect diagnostic biopsy samples for the determination of aldo-keto reductase 1C3
- Collect plasma samples for assessment of potential biomarkers of tumor hypoxia
|Study Design:||Allocation: Randomized
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Randomized Phase I/II, Multi-Center, Open-Label Trial of PR104 and Sorafenib in Patients With Advanced Hepatocellular Carcinoma|
|Study Start Date:||March 2009|
|Study Completion Date:||May 2010|
|Primary Completion Date:||January 2010 (Final data collection date for primary outcome measure)|
|Experimental: Arm I||Drug: sorafenib|
|Experimental: Arm II||Drug: PR104 Drug: sorafenib|
A randomized phase I/II, multi-center, open-label, study with a single arm phase I portion to determine the appropriate dose of PR104 combined with sorafenib, followed by a phase II portion with randomization between sorafenib and sorafenib/PR104.
Following informed consent, subjects will undergo baseline evaluation with history, physical exams, blood work and disease assessment. Selected subjects will undergo pharmacokinetic assessment of sorafenib, PR104 and PR104 metabolites.
In the phase I portion of the study, subjects will be assigned to the current dose cohort for PR104 in combination with standard dose sorafenib. PR104 will be administered on an every 4 week schedule with the dose of PR104 escalated in a standard phase I fashion (3 subjects per cohort, dose escalation between cohorts) in order to determine the MTD of PR104. Following determination of the MTD of PR104, new subjects will be entered into the phase II portion of the study.
In the phase II portion of the study, subjects will be randomized between sorafenib, 400 mg, PO, twice a day (the approved dose and schedule) versus sorafenib with PR104 at the dose determined in the phase I portion of the study. PR104 will be administered every 4 weeks (one cycle). Subjects will be evaluated each week during cycle 1 and every two weeks thereafter. A disease assessment will be performed after every two cycles. Subjects with progression will be removed from study. Subjects with a response or stable disease may continue on study if this is considered beneficial by their physician.
|United States, Arizona|
|University of Arizona|
|Tucson, Arizona, United States, 85724|
|United States, California|
|Moores UCSD Cancer Center|
|La Jolla, California, United States, 92093|
|University of California, Irvine|
|Orange, California, United States, 92868|
|Sharp Clinical Oncology Research|
|San Diego, California, United States, 92123|
|San Francisco, California, United States, 94115|
|United States, Illinois|
|Chicago, Illinois, United States, 60611|
|United States, Indiana|
|Indiana University Simon Cancer Center|
|Indianapolis, Indiana, United States, 46202|
|United States, Maryland|
|Sidney Kimmel Comprehensive Cancer Center At Johns Hopkins|
|Baltimore, Maryland, United States, 21231|
|United States, New York|
|Columbia University Medical Center|
|New York, New York, United States, 10032|
|Prince of Wales Hospital|
|Shatin, New Territories, Hong Kong|
|Singapore General Hospital|
|Chang Gung Memorial Hospital|
|Kaohsiung Medical University Chung-Ho Memorial Hospital|
|Chi Mei Medical Center, Liouying|
|China Medical University Hospital|
|Taichung City, Taiwan|
|National Taiwan University Hospital|
|Cathay General Hospital|
|Taipei City, Taiwan, 10630|