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: 0
• Participant gender: All

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

• Phase: Phase 1/Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Proacta, Incorporated
• Treatments: Niacinamide; Nitrogen Mustard Compounds; Sorafenib

Criteria

Inclusion Criteria:

• Advanced-stage hepatocellular carcinoma considered non-operable that is suitable for treatment with sorafenib. Subjects who have demonstrated progression following initial surgical or locoregional therapy are eligible

• Confirmed hepatocellular carcinoma by pathological analysis (tissue aspirate or biopsy)

• No previous systemic therapy for hepatocellular carcinoma

• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1

• Child-Pugh liver function class A

• Life expectancy of 12 weeks or more

• Adequate hematologic function [Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L; platelet count ≥100×10^9 per liter; hemoglobin ≥8.5 g per deciliter maintained in the absence of red blood cell transfusions; and prothrombin time international normalized ratio ≤1.7; or prothrombin time ≤2 seconds above control]

• Adequate hepatic function (albumin ≥2.8 g per deciliter; total bilirubin ≤2 mg per deciliter [51.3 μmol per liter]; and alanine aminotransferase and aspartate aminotransferase ≤5 times the upper limit of the normal range)

• Adequate renal function (serum creatinine ≤1.5 times the upper limit of the normal range or creatinine clearance ≥60 mL/min).

• At least one untreated target lesion that could be measured in one dimension, according to the Response Evaluation Criteria in Solid Tumors (RECIST)

• Concomitant systemic antiviral therapy allowed

Exclusion Criteria:

• Previous molecularly targeted therapies or any other systemic treatment for hepatocellular carcinoma

• Active concomitant malignancy likely to effect any of the primary or secondary outcome measures in the current study

• Women who are pregnant, breast-feeding or planning to become pregnant during the study

• Men or women of reproductive-potential who are unwilling to use an effective method of contraception during the study and for 30 days following the last dose of study medication

• Evidence of a significant medical disorder or laboratory finding that, in the opinion of the Investigator, compromises the subject's safety during study participation such as: uncontrolled infection or infection requiring a concomitant parenteral antibiotic; uncontrolled diabetes; congestive heart failure; myocardial infarction within 6 months of study; chronic renal disease; or coagulopathy (excluding prophylactic anticoagulation)

• Active central nervous system metastatic disease requiring intervention

• Less than four weeks since major surgery

• Known Human Immunodeficiency Virus (HIV) positivity