Clinical trial NCT00862082: 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
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Hepatocellular Carcinoma
Lead sponsor: Proacta, Incorporated
Sponsor class: INDUSTRY
First posted: 2009-03-16
Enrollment: 14
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Maximum Tolerated Dose (MTD) of PR104 When Used in Combination With Standard Dose Sorafenib in the Phase I Population
timeFrame: 4 weeks (1 cycle)
Secondary outcomes:
measure: Safety and Tolerability: Serious Adverse Events
timeFrame: 30 days following the last administration of study treatment
measure: Pharmacokinetics [Maximum Plasma Concentration (Cmax)] of PR104 and PR104 Metabolites in Cohort 1 (770 mg/m^2 Dose Group)
timeFrame: Day 1 of Cycles 1 and 2
measure: Pharmacokinetics [Half Life (T1/2)] of PR104 and PR104 Metabolites in Cohort 1 (770 mg/m^2 Dose Group)
timeFrame: Day 1 of Cycles 1 and 2
measure: Pharmacokinetics [Area Under the Curve(AUC)] of PR104 and PR104 Metabolites in Cohort 1 (770 mg/m^2 Dose Group)
timeFrame: Day 1 of Cycles 1 and 2
measure: Pharmacokinetics (Cmax) of PR104 and PR104 Metabolites in Cohort 2 (550 mg/m^2 Dose Group)
timeFrame: Day 1 of Cycles 1 and 2
measure: Pharmacokinetics (T1/2) of PR104 and PR104 Metabolites in Cohort 2 (550 mg/m^2 Dose Group)
timeFrame: Day 1 of Cycles 1 and 2
measure: Pharmacokinetics (AUC) of PR104 and PR104 Metabolites in Cohort 2 (550 mg/m^2 Dose Group)
timeFrame: Day 1 of Cycles 1 and 2
Other outcomes:
Locations:
city: Tucson
country: United States
facility: University of Arizona
state: Arizona
city: La Jolla
country: United States
facility: Moores UCSD Cancer Center
state: California
city: Orange
country: United States
facility: University of California, Irvine
state: California
city: San Diego
country: United States
facility: Sharp Clinical Oncology Research
state: California
city: San Francisco
country: United States
facility: Pacific Oncology/Hematology
state: California
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University Simon Cancer Center
state: Indiana
city: Baltimore
country: United States
facility: Sidney Kimmel Comprehensive Cancer Center At Johns Hopkins
state: Maryland
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Shatin
country: Hong Kong
facility: Prince of Wales Hospital
state: New Territories
city: Singapore
country: Singapore
facility: Singapore General Hospital
city: Kaohsiung
country: Taiwan
facility: Chang Gung Memorial Hospital
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Medical University Chung-Ho Memorial Hospital
city: T'ai-nan
country: Taiwan
facility: Chi Mei Medical Center, Liouying
city: Taichung City
country: Taiwan
facility: China Medical University Hospital
city: Taipei City
country: Taiwan
facility: Cathay General Hospital
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
Study officials:
References: