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

A Randomized Phase I/II, Multi-Center, 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. 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

Study Overview

• Status: Terminated
• Conditions: Hepatocellular Carcinoma
• Intervention / Treatment: Drug: PR104 550 mg/m^2 + sorafenib; Drug: PR104 770 mg/m^2 + sorafenib

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.

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Hong Kong
  • New Territories
    • Shatin, New Territories, Hong Kong
      • Prince of Wales Hospital
• Singapore
  • Singapore, Singapore
    • Singapore General Hospital
• Taiwan
  • Kaohsiung, Taiwan
    • Kaohsiung Medical University Chung-Ho Memorial Hospital
  • Kaohsiung, Taiwan
    • Chang Gung Memorial Hospital
  • T'ai-nan, Taiwan
    • Chi Mei Medical Center, Liouying
  • Taichung City, Taiwan
    • China Medical University Hospital
  • Taipei, Taiwan
    • National Taiwan University Hospital
  • Taipei City, Taiwan, 10630
    • Cathay General Hospital
• United States
  • Arizona
    • Tucson, Arizona, United States, 85724
      • University of Arizona
  • California
    • La Jolla, California, United States, 92093
      • Moores UCSD Cancer Center
    • Orange, California, United States, 92868
      • University of California, Irvine
    • San Diego, California, United States, 92123
      • Sharp Clinical Oncology Research
    • San Francisco, California, United States, 94115
      • Pacific Oncology/Hematology
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Simon Cancer Center
  • Maryland
    • Baltimore, Maryland, United States, 21231
      • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

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: Nexavar; PR-104; 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: Nexavar; PR-104

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Maximum Tolerated Dose (MTD) of PR104 When Used in Combination With Standard Dose Sorafenib in the Phase I Population	4 weeks (1 cycle)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and Tolerability: Serious Adverse Events	The number of participants with at least one Serious Adverse Event was measured.	30 days following the last administration of study treatment
Pharmacokinetics [Maximum Plasma Concentration (Cmax)] of PR104 and PR104 Metabolites in Cohort 1 (770 mg/m^2 Dose Group)		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)		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)		Day 1 of Cycles 1 and 2
Pharmacokinetics (Cmax) of PR104 and PR104 Metabolites in Cohort 2 (550 mg/m^2 Dose Group)		Day 1 of Cycles 1 and 2
Pharmacokinetics (T1/2) of PR104 and PR104 Metabolites in Cohort 2 (550 mg/m^2 Dose Group)		Day 1 of Cycles 1 and 2
Pharmacokinetics (AUC) of PR104 and PR104 Metabolites in Cohort 2 (550 mg/m^2 Dose Group)		Day 1 of Cycles 1 and 2

Collaborators and Investigators

• Sponsor: Proacta, Incorporated

Study record dates

Study Major Dates

• Study Start: March 1, 2009
• Primary Completion (Actual): January 1, 2010
• Study Completion (Actual): May 1, 2010

Study Registration Dates

• First Submitted: March 12, 2009
• First Submitted That Met QC Criteria: March 13, 2009
• First Posted (Estimate): March 16, 2009

Study Record Updates

• Last Update Posted (Estimate): August 23, 2013
• Last Update Submitted That Met QC Criteria: July 19, 2013
• Last Verified: July 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Liver Diseases; Liver Neoplasms; Carcinoma; Carcinoma, Hepatocellular; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Protein Kinase Inhibitors; Sorafenib; Nitrogen Mustard Compounds
• Other Study ID Numbers: PR104-2002