Back to resultsRandomized Phase 1/2 Open-Label Trial of PR104 and Sorafenib in Patients With Advanced Hepatocellular Carcinoma (HCC)
Primary Purpose
Hepatocellular Carcinoma
Status
Terminated
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
PR104 550 mg/m^2 + sorafenib
PR104 770 mg/m^2 + sorafenib
Sponsored by
About this trial
This is an interventional treatment trial for Hepatocellular Carcinoma
Eligibility 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
Sites / Locations
- University of Arizona
- Moores UCSD Cancer Center
- University of California, Irvine
- Sharp Clinical Oncology Research
- Pacific Oncology/Hematology
- Northwestern University
- Indiana University Simon Cancer Center
- Sidney Kimmel Comprehensive Cancer Center At Johns Hopkins
- Columbia University Medical Center
- Prince of Wales Hospital
- Singapore General Hospital
- Chang Gung Memorial Hospital
- Kaohsiung Medical University Chung-Ho Memorial Hospital
- Chi Mei Medical Center, Liouying
- China Medical University Hospital
- Cathay General Hospital
- National Taiwan University Hospital
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
PR104 + Sorafenib
Arm Description
PR104 will be administered IV once every four weeks, in addition to 400mg sorafenib PO twice daily
Outcomes
Primary Outcome Measures
Maximum Tolerated Dose (MTD) of PR104 When Used in Combination With Standard Dose Sorafenib in the Phase I Population
Secondary Outcome Measures
Safety and Tolerability: Serious Adverse Events
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)
Pharmacokinetics [Half Life (T1/2)] of PR104 and PR104 Metabolites in Cohort 1 (770 mg/m^2 Dose Group)
Pharmacokinetics [Area Under the Curve(AUC)] of PR104 and PR104 Metabolites in Cohort 1 (770 mg/m^2 Dose Group)
Pharmacokinetics (Cmax) of PR104 and PR104 Metabolites in Cohort 2 (550 mg/m^2 Dose Group)
Pharmacokinetics (T1/2) of PR104 and PR104 Metabolites in Cohort 2 (550 mg/m^2 Dose Group)
Pharmacokinetics (AUC) of PR104 and PR104 Metabolites in Cohort 2 (550 mg/m^2 Dose Group)
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT00862082
Brief Title
Randomized Phase 1/2 Open-Label Trial of PR104 and Sorafenib in Patients With Advanced Hepatocellular Carcinoma (HCC)
Official Title
A Randomized Phase I/II, Multi-Center, Open-Label Trial of PR104 and Sorafenib in Patients With Advanced Hepatocellular Carcinoma
Study Type
Interventional
2. Study Status
Record Verification Date
July 2013
Overall Recruitment Status
Terminated
Why Stopped
PR104 plus sorafenib was poorly tolerated in patients with advanced HCC
Study Start Date
March 2009 (undefined)
Primary Completion Date
January 2010 (Actual)
Study Completion Date
May 2010 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Proacta, Incorporated
4. Oversight
5. Study Description
Brief 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
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hepatocellular Carcinoma
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
14 (Actual)
8. Arms, Groups, and Interventions
Arm Title
PR104 + Sorafenib
Arm Type
Experimental
Arm Description
PR104 will be administered IV once every four weeks, in addition to 400mg sorafenib PO twice daily
Intervention Type
Drug
Intervention Name(s)
PR104 550 mg/m^2 + sorafenib
Other Intervention Name(s)
PR-104, Nexavar
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
PR104 770 mg/m^2 + sorafenib
Other Intervention Name(s)
PR-104, Nexavar
Intervention Description
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.
Primary Outcome Measure Information:
Title
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 Measure Information:
Title
Safety and Tolerability: Serious Adverse Events
Description
The number of participants with at least one Serious Adverse Event was measured.
Time Frame
30 days following the last administration of study treatment
Title
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
Title
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
Title
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
Title
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
Title
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
Title
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
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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
Facility Information:
Facility Name
University of Arizona
City
Tucson
State/Province
Arizona
ZIP/Postal Code
85724
Country
United States
Facility Name
Moores UCSD Cancer Center
City
La Jolla
State/Province
California
ZIP/Postal Code
92093
Country
United States
Facility Name
University of California, Irvine
City
Orange
State/Province
California
ZIP/Postal Code
92868
Country
United States
Facility Name
Sharp Clinical Oncology Research
City
San Diego
State/Province
California
ZIP/Postal Code
92123
Country
United States
Facility Name
Pacific Oncology/Hematology
City
San Francisco
State/Province
California
ZIP/Postal Code
94115
Country
United States
Facility Name
Northwestern University
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
Indiana University Simon Cancer Center
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46202
Country
United States
Facility Name
Sidney Kimmel Comprehensive Cancer Center At Johns Hopkins
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21231
Country
United States
Facility Name
Columbia University Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Facility Name
Prince of Wales Hospital
City
Shatin
State/Province
New Territories
Country
Hong Kong
Facility Name
Singapore General Hospital
City
Singapore
Country
Singapore
Facility Name
Chang Gung Memorial Hospital
City
Kaohsiung
Country
Taiwan
Facility Name
Kaohsiung Medical University Chung-Ho Memorial Hospital
City
Kaohsiung
Country
Taiwan
Facility Name
Chi Mei Medical Center, Liouying
City
T'ai-nan
Country
Taiwan
Facility Name
China Medical University Hospital
City
Taichung City
Country
Taiwan
Facility Name
Cathay General Hospital
City
Taipei City
ZIP/Postal Code
10630
Country
Taiwan
Facility Name
National Taiwan University Hospital
City
Taipei
Country
Taiwan
12. IPD Sharing Statement
Learn more about this trial
Randomized Phase 1/2 Open-Label Trial of PR104 and Sorafenib in Patients With Advanced Hepatocellular Carcinoma (HCC)
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