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

Phase 1

Terminated

Conditions: Hepatocellular Carcinoma

Interventions: Drug: PR104 550 mg/m^2 + sorafenib
Drug: PR104 770 mg/m^2 + sorafenib

Registration Number: NCT00862082

Lead Sponsor: Proacta, Incorporated

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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 14

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 & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
PR104 + Sorafenib	PR104 550 mg/m^2 + sorafenib	PR104 will be administered IV once every four weeks, in addition to 400mg sorafenib PO twice daily
PR104 + Sorafenib	PR104 770 mg/m^2 + sorafenib	PR104 will be administered IV once every four weeks, in addition to 400mg sorafenib PO twice daily

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
Safety and Tolerability: Serious Adverse Events	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)	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

Trial Locations

Locations (17): Pacific Oncology/Hematology
🇺🇸
San Francisco, California, United States
Chi Mei Medical Center, Liouying
🇨🇳
T'ai-nan, Taiwan
Moores UCSD Cancer Center
🇺🇸
La Jolla, California, United States
Columbia University Medical Center
🇺🇸
New York, New York, United States
Sharp Clinical Oncology Research
🇺🇸
San Diego, California, United States
China Medical University Hospital
🇨🇳
Taichung City, Taiwan
Northwestern University
🇺🇸
Chicago, Illinois, United States
Sidney Kimmel Comprehensive Cancer Center At Johns Hopkins
🇺🇸
Baltimore, Maryland, United States
Singapore General Hospital
🇸🇬
Singapore, Singapore
Indiana University Simon Cancer Center
🇺🇸
Indianapolis, Indiana, United States
Chang Gung Memorial Hospital
🇨🇳
Kaohsiung, Taiwan
Cathay General Hospital
🇨🇳
Taipei City, Taiwan
University of Arizona
🇺🇸
Tucson, Arizona, United States
University of California, Irvine
🇺🇸
Orange, California, United States
Kaohsiung Medical University Chung-Ho Memorial Hospital
🇨🇳
Kaohsiung, Taiwan
National Taiwan University Hospital
🇨🇳
Taipei, Taiwan
Prince of Wales Hospital
🇭🇰
Shatin, New Territories, Hong Kong