Randomized Phase 1/2 Open-Label Trial of PR104 and Sorafenib in Patients With Advanced Hepatocellular Carcinoma (HCC)
The current understanding of PR104 justifies the evaluation of PR104 with sorafenib in patients with hepatocellular carcinoma. These include:
- Hypoxia. Hepatocellular Carcinoma (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.
- 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.
- Aldo-keto reductase 1C3 (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 maximum tolerated dose (MTD) of PR104 when used in combination with standard dose sorafenib
- Phase II: Estimate the response rate (RR) of PR104/sorafenib [Note: Phase II was never initiated]
- Evaluate survival
- Evaluate Progression Free Survival (PFS)
- Evaluate time to progression (TTP)
- Evaluate safety
- Evaluate the pharmacokinetics (PK) 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
Drug: PR104 550 mg/m^2 + sorafenib
Drug: PR104 770 mg/m^2 + sorafenib
|Study Design:||Intervention Model: Single Group Assignment
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|
- Maximum Tolerated Dose (MTD) of PR104 When Used in Combination With Standard Dose Sorafenib in the Phase I Population [ Time Frame: 4 weeks (1 cycle) ] [ Designated as safety issue: No ]
- Safety and Tolerability: Serious Adverse Events [ Time Frame: 30 days following the last administration of study treatment ] [ Designated as safety issue: Yes ]The number of participants with at least one Serious Adverse Event was measured.
- Pharmacokinetics [Maximum Plasma Concentration (Cmax)] of PR104 and PR104 Metabolites in Cohort 1 (770 mg/m^2 Dose Group) [ Time Frame: Day 1 of Cycles 1 and 2 ] [ Designated as safety issue: No ]
- Pharmacokinetics [Half Life (T1/2)] of PR104 and PR104 Metabolites in Cohort 1 (770 mg/m^2 Dose Group) [ Time Frame: Day 1 of Cycles 1 and 2 ] [ Designated as safety issue: No ]
- Pharmacokinetics [Area Under the Curve(AUC)] of PR104 and PR104 Metabolites in Cohort 1 (770 mg/m^2 Dose Group) [ Time Frame: Day 1 of Cycles 1 and 2 ] [ Designated as safety issue: No ]
- Pharmacokinetics (Cmax) of PR104 and PR104 Metabolites in Cohort 2 (550 mg/m^2 Dose Group) [ Time Frame: Day 1 of Cycles 1 and 2 ] [ Designated as safety issue: No ]
- Pharmacokinetics (T1/2) of PR104 and PR104 Metabolites in Cohort 2 (550 mg/m^2 Dose Group) [ Time Frame: Day 1 of Cycles 1 and 2 ] [ Designated as safety issue: No ]
- Pharmacokinetics (AUC) of PR104 and PR104 Metabolites in Cohort 2 (550 mg/m^2 Dose Group) [ Time Frame: Day 1 of Cycles 1 and 2 ] [ Designated as safety issue: No ]
|Study Start Date:||March 2009|
|Study Completion Date:||May 2010|
|Primary Completion Date:||January 2010 (Final data collection date for primary outcome measure)|
Experimental: PR104 + Sorafenib
PR104 will be administered IV once every four weeks, in addition to 400mg sorafenib PO twice daily
Drug: PR104 550 mg/m^2 + sorafenib
550 mg/m^2 PR104 IV on day 1 of each 28 day cycle + 400 mg sorafenib PO twice daily. Number of Cycles: until progression or unacceptable toxicity develops.
Other Names:Drug: PR104 770 mg/m^2 + sorafenib
770 mg/m^2 PR104 IV on day 1 of each 28 day cycle + 400 mg sorafenib PO twice daily. Number of Cycles: until progression or unacceptable toxicity develops.
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 PK assessment of sorafenib, PR104 and PR104 metabolites.
In the phase I portion of the study, the starting dose of PR104 will be 770 mg/mg2 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. Cohorts may be expanded up to 12 subjects to better define toxicity at a particular dose level. Following determination of the MTD of PR104, new subjects will be entered into the phase II portion of the study. [Note: the Phase II portion was never initiated]
In the phase II portion of the study, subjects will be randomized between sorafenib, 400 mg, by mouth (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|