TAC-101 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