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Randomized Phase 1/2 Open-Label Trial of PR104 and Sorafenib in Patients With Advanced Hepatocellular Carcinoma (HCC)

This study has been terminated.
(PR104 plus sorafenib was poorly tolerated in patients with advanced HCC)
Information provided by (Responsible Party):
Proacta, Incorporated Identifier:
First received: March 12, 2009
Last updated: July 19, 2013
Last verified: July 2013

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

Condition Intervention Phase
Hepatocellular Carcinoma
Drug: PR104 550 mg/m^2 + sorafenib
Drug: PR104 770 mg/m^2 + sorafenib
Phase 1
Phase 2

Study Type: Interventional
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

Resource links provided by NLM:

Further study details as provided by Proacta, Incorporated:

Primary Outcome Measures:
  • 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) ]

Secondary Outcome Measures:
  • Safety and Tolerability: Serious Adverse Events [ Time Frame: 30 days following the last administration of study treatment ]
    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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]

Enrollment: 14
Study Start Date: March 2009
Study Completion Date: May 2010
Primary Completion Date: January 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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:
  • PR-104
  • Nexavar
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.
Other Names:
  • PR-104
  • Nexavar

Detailed Description:

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.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT00862082

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
Pacific Oncology/Hematology
San Francisco, California, United States, 94115
United States, Illinois
Northwestern University
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
Hong Kong
Prince of Wales Hospital
Shatin, New Territories, Hong Kong
Singapore General Hospital
Singapore, Singapore
Chang Gung Memorial Hospital
Kaohsiung, Taiwan
Kaohsiung Medical University Chung-Ho Memorial Hospital
Kaohsiung, Taiwan
Chi Mei Medical Center, Liouying
T'ai-nan, Taiwan
China Medical University Hospital
Taichung City, Taiwan
Cathay General Hospital
Taipei City, Taiwan, 10630
National Taiwan University Hospital
Taipei, Taiwan
Sponsors and Collaborators
Proacta, Incorporated
  More Information

Responsible Party: Proacta, Incorporated Identifier: NCT00862082     History of Changes
Obsolete Identifiers: NCT00838604
Other Study ID Numbers: PR104-2002
Study First Received: March 12, 2009
Results First Received: May 31, 2011
Last Updated: July 19, 2013

Additional relevant MeSH terms:
Carcinoma, Hepatocellular
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Liver Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases
Nitrogen Mustard Compounds
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Vitamin B Complex
Growth Substances
Physiological Effects of Drugs
Antineoplastic Agents, Alkylating
Alkylating Agents processed this record on May 25, 2017