TAC-101 in Treating Patients With Advanced Hepatocellular Carcinoma (Liver Cancer)

Phase I/II Dose Escalation, Pharmacokinetic, Safety, and Efficacy Study of Oral TAC-101 in Patients With Advanced Hepatocellular Carcinoma

RATIONALE: TAC-101 may stop the growth of cancer by stopping blood flow to the tumor.

PURPOSE: This phase I/II trial is studying the side effects and best dose of TAC-101 and to see how well it works in treating patients with advanced hepatocellular carcinoma (liver cancer).

OBJECTIVES:

Phase I

• Primary

  • Determine the maximum tolerated dose (MTD) of TAC-101 in patients with advanced hepatocellular carcinoma.
  • Determine the safety of 2 consecutive courses of this drug in these patients.
  • Determine the pharmacokinetics of this drug in these patients.
  • Determine the toxic and adverse effects profile of this drug in these patients.

Phase II

• Primary

  • Determine the objective antitumor response rate in patients treated with this drug at the MTD.

• Secondary

  • Determine the overall survival time of patients treated with this drug.
  • Determine the time to disease progression in patients treated with this drug.
  • Determine the duration of observed objective response, using WHO criteria and measurements of serum alpha-fetoprotein concentrations, in patients treated with this drug.
  • Determine the time to treatment failure in patients treated with this drug.
  • Determine the safety and tolerability of intermittent treatment with this drug in these patients.

OUTLINE: This is an open-label, dose-escalation study.

• Phase I: Patients receive oral TAC-101 once daily on days 1-14. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity.

Cohorts of 6 patients receive escalating doses of TAC-101 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity.

• Phase II: Patients receive oral TAC-101 at the MTD (determined in phase I) once daily on days 1-14. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Patients are followed at 35-60 days.

PROJECTED ACCRUAL: A total of 6-18 patients for the phase I portion and 21-41 patients for the phase II portion will be accrued for this study.

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed hepatocellular carcinoma
• At least 1 previously unirradiated, bidimensionally measurable lesion greater than 20 mm by MRI or conventional CT scan OR at least 10 mm by spiral CT scan
• Patients with CNS involvement must have completed appropriate treatment and have no progressive neurologic deficits within the past 28 days
• No carcinomatous meningitis

PATIENT CHARACTERISTICS:

Age

• 18 to 80

Performance status

• ECOG 0-2

Life expectancy

• More than 12 weeks

Hematopoietic

• Hemoglobin ≥ 10.0 g/dL
• WBC ≥ 2,000/mm^3
• Absolute neutrophil count ≥ 1,000/mm^3
• Platelet count ≥ 40,000/mm^3
• No abnormal bleeding or clotting

Hepatic

• No grade C Child-Pugh cirrhosis
• AST and ALT ≤ 2.5 times upper limit of normal (ULN)
• Albumin ≥ 2.8 g/dL
• INR ≤ 1.5 times ULN
• Bilirubin ≤ 2.0 mg/dL

Renal

• Creatinine ≤ 1.5 times ULN

Cardiovascular

• No prior deep vein thrombosis
• No prior superficial venous thrombosis
• No family history of thromboembolism in a first-degree relative
• No lower extremity thromboses by Doppler ultrasound (unless a subsequent venous angiography confirms a false positive ultrasound)

Pulmonary

• No prior pulmonary embolism

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception, except oral contraceptives containing estrogen
• Fasting triglycerides ≤ 400 mg/dL for men or ≤ 325 mg/dL for women
• No other malignancy within the past 3 years except inactive nonmelanoma skin cancer or carcinoma in situ of the cervix
• No uncontrolled metabolic disorders, other nonmalignant organ or systemic disease, or secondary effects of cancer that induce a high medical risk
• No known allergy or hypersensitivity to TAC-101 or its components

PRIOR CONCURRENT THERAPY:

Biologic therapy

• No prior thalidomide
• No prior putative antiangiogenesis therapy
• Prior interferon allowed

Chemotherapy

• No more than 2 prior chemotherapy regimens

Endocrine therapy

• No concurrent estrogen products

Radiotherapy

• See Disease Characteristics
• More than 21 days since prior radiotherapy, except small portal radiotherapy used for the palliation of isolated, symptomatic, osseous metastases
• No prior radiotherapy to evaluable lesions
• No concurrent radiotherapy unless for bone pain that is present before beginning study

Surgery

• Not specified

Other

• Prior anticancer treatment allowed provided there is clear evidence of progressive disease after the most recent treatment

• More than 21 days since prior anticancer therapy and recovered

• No more than 2 prior treatment regimens

• No concurrent therapeutic anticoagulants

  • Concurrent low-dose warfarin for prophylactic care of indwelling venous access devices allowed

• No concurrent azoles or tetracyclines

• No concurrent medications known or suspected to increase risk of venous thromboembolism

• No other concurrent retinoids