Randomized Phase 1/2 Open-Label Trial of PR104 and Sorafenib in Patients With Advanced Hepatocellular Carcinoma (HCC)
Status:
Terminated
Trial end date:
2010-05-01
Target enrollment:
Participant gender:
Summary
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.
Primary objectives
- 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]
Secondary objectives
- 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