Oblimersen and Doxorubicin in Treating Patients With Advanced Hepatocellular Carcinoma (Liver Cancer)

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy such as doxorubicin use different ways to stop tumor cells from dividing so they stop growing or die. Oblimersen may increase the effectiveness of doxorubicin by making tumor cells more sensitive to the drug. PURPOSE: Phase II trial to study the effectiveness of combining oblimersen with doxorubicin in treating patients who have locally advanced, recurrent, or metastatic hepatocellular carcinoma (liver cancer).

Detailed Description
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OBJECTIVES: Determine the maximum tolerated dose of oblimersen and doxorubicin in patients with advanced hepatocellular carcinoma or other incurable solid tumor (closed to accrual as of 11/7/03). (Phase I completed as of 1/16/04.) Determine the efficacy of this regimen, in terms of objective response rate, in these patients. Determine the toxicity of this regimen in these patients. Determine the time to progression, response duration, progression-free survival, median survival, and overall survival rates in patients treated with this regimen. OUTLINE: This is a dose-escalation, multicenter study. (Phase I completed as of 1/16/04.) Patients receive oblimersen IV continuously on days 1-7 and doxorubicin IV over 5 minutes on day 5. Treatment repeats every 4 weeks for up to 10 courses in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of oblimersen and doxorubicin until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Once the MTD is determined, additional patients*, including 6 patients with hepatocellular carcinoma (HCC), are treated at the recommended phase II dose. (Phase I completed as of 1/16/04.) NOTE: *Other solid tumors closed to accrual as of 11/7/03; only accruing HCC patients PROJECTED ACCRUAL: A total of 12-18 patients will be accrued for the phase I portion of this study within 6 months (phase I completed as of 1/16/04). A total of 30 patients will be accrued for the phase II portion of this study within 10-15 months.

Official Title
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A Phase II Study of G3139 in Combination With Doxorubicin in Advanced Hepatocellular Carcinoma

Conditions
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Liver Cancer

Intervention / Treatment
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* Biological: oblimersen sodium
* Drug: doxorubicin hydrochloride


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Diagnosis of 1 of the following: Histologically or cytologically confirmed hepatocellular carcinoma (HCC) Locally advanced, recurrent, or metastatic Not candidates for surgical/radical therapies Other solid tumor that is incurable (closed to accrual as of 11/7/03) At least 1 unidimensionally measurable lesion At least 20 mm by conventional techniques OR at least 10 mm by spiral CT scan Target lesion may not be in a previously irradiated field unless subsequent progression was documented No ascites No known brain metastases PATIENT CHARACTERISTICS: Age 18 and over Performance status ECOG 0-2 OR Karnofsky 60-100% Life expectancy More than 3 months Hematopoietic WBC at least 2,000/mm^3 Absolute neutrophil count at least 1,500/mm^3 Platelet count at least 100,000/mm^3 Hepatic Bilirubin no greater than 2.0 mg/dL AST no greater than 5 times upper limit of normal (ULN) Albumin greater than 3.5 g/dL No cirrhosis worse than Childs-Pugh class A Renal Creatinine no greater than 1.25 times ULN OR Creatinine clearance at least 50 mL/min Cardiovascular LVEF normal by MUGA No symptomatic congestive heart failure No unstable angina pectoris No cardiac arrhythmia Other Good nutritional status No encephalopathy No other concurrent uncontrolled illness No ongoing or active infection No psychiatric illness or social situation that would preclude study participation No prior allergic reactions to compounds of similar chemical or biological composition to oblimersen or doxorubicin Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: Biologic therapy No more than 1 prior biologic therapy regimen for patients with HCC At least 4 weeks since prior biologic therapy Chemotherapy Patients with HCC: No prior systemic chemotherapy Prior chemotherapy as part of localized chemoembolization therapy may be allowed (no more than 150 mg/m^2 for doxorubicin) if completed at least 8 weeks before study treatment All other patients (closed to accrual as of 11/7/03): At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) No prior doxorubicin, epirubicin, or other anthracycline Endocrine therapy Not specified Radiotherapy See Disease Characteristics At least 4 weeks since prior radiotherapy No more than 3,000 cGy to fields including substantial bone marrow Surgery At least 8 weeks since prior surgery Prior liver transplant for HCC allowed Other Recovered from all prior therapy At least 8 weeks since other locally ablative therapies No concurrent commercial or other investigational agents or therapies No other concurrent anticancer therapy No concurrent combination antiretroviral therapy for HIV-positive patients

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: G3139 in combination with Doxorubicin<br> | Biological: oblimersen sodium<br> <br> Drug: doxorubicin hydrochloride<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of objective response (complete and partial) | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Objective Response (OR) = CR + PR. Objective response rate of >= 30% is considered active, and <10% is considered inactive. | Up to 280 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Stable disease rate |  | Up to 280 days | 
| Duration of response |  | Up to 280 days | 
| Progression-free survival rate |  | Up to 280 days | 
| Median survival rate |  | Up to 280 days | 
| Overall survival rate |  | Up to 280 days | 
| Safety and tolerability |  | Up to 280 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adult primary hepatocellular carcinoma, advanced adult primary liver cancer, localized unresectable adult primary liver cancer, recurrent adult primary liver cancer