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

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.

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