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Phase I Open-Label, Dose-Finding Study of BAY 43-9006 (Sorafenib) in High-risk Hepatocellular Cancer Patients After Liver Transplantation

Phase 1
18 Years
Open (Enrolling)
Hepatocellular Cancer

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Trial Information

Phase I Open-Label, Dose-Finding Study of BAY 43-9006 (Sorafenib) in High-risk Hepatocellular Cancer Patients After Liver Transplantation

Sorafenib (BAY 43-9006) is an oral multi-kinase inhibitor with effects on tumor
proliferation and angiogenesis. Sorafenib is approved for the treatment of patients with
advanced renal cancer and unresectable hepatocellular carcinoma (HCC). The recommended
daily dose of Sorafenib is 400 mg (2 x 200 mg tablets) taken twice daily without food (at
least 1 hour before or 2 hours after a meal). Studies of single-agent sorafenib showed
treatment was well-tolerated with manageable side effects. The results seen with sorafenib
in the Phase III (SHARP) trial suggest that VEGF and RAF kinase inhibition prolong survival
in patients with advanced HCC. It is not known whether a drug which is considered primarily
cytostatic will be effective in preventing cancer recurrences in the setting of minimal
residual disease.

This is a phase I, single center, open-label, dose-escalation study to determine the maximum
tolerated dose (MTD) and overall safety profile of daily sorafenib as therapy to prevent HCC
recurrence in liver transplant subjects with high-risk HCC. For each subject, the study will
consist of two phases: a treatment phase and an extension phase.

Inclusion Criteria:

- Age ≥18 years old

- ECOG Performance Status 0-2 (See Appendix I)

- All patients will be post liver transplant and have explants with histologically
confirmed hepatocellular carcinoma.

- Patient should have no evidence of HCC disease at study entry by imaging

- Patients will be eligible to start 4 weeks post transplant (29 days post transplant)
as long as they are on stable doses of immunosuppressants. Patient must start
treatment within 16 weeks (112 days) after transplant.

- Patients must be deemed "high risk" for recurrence after transplantation, by either
being outside Milan criteria before transplant or on explant, having tumors with
micro or macrovascular invasion, and/or poorly differentiated tumor histology.

- Patients may have received prior surgical resection, chemoembolization or other local
therapy prior to transplant. They may not have received prior anti-angiogenic
therapy, systemic targeted agents or systemic chemotherapy. They also may not have
received M-Tor inhibitors.

- Patients must have Child-Pugh Class A or compensated Child-Pugh Class B liver
dysfunction at the start of therapy (See Appendix II).

- Patients must have adequate bone marrow, liver and renal function as assessed by the

- Hemoglobin ≥ 8.0 g/dl

- Absolute neutrophil count (ANC) ≥ 1,500/mm3

- Platelet count ≥ 75,000/mm3

- Total bilirubin ≤ 1.5 times ULN

- ALT and AST ≤ 5 x ULN

- Creatinine ≤ 1.5 times ULN

- Albumin ≥ 2.5 mg/dl

- Women of childbearing potential must have a negative serum pregnancy test performed
within 14 days prior to the start of treatment

- Women of childbearing potential and men must agree to use adequate contraception
(barrier method of birth control) prior to study entry and for the duration of study
participation. Men should use adequate birth control for at least three months after
the last administration of sorafenib.

- Subjects must exhibit the ability to understand and willingness to sign a written
informed consent regarding the study and alternative treatments.

- INR < 1.5 or a PT/PTT within normal limits. Patients receiving anti-coagulation
treatment with an agent such as warfarin or heparin may be allowed to participate.
For patients on warfarin, the INR should be measured prior to initiation of sorafenib
and monitored carefully. Patients must be warned of possible increased risk of
bleeding on the combination.

Exclusion Criteria:

- Cardiac disease: Congestive heart failure > class II NYHA. Patients must not have
unstable angina (anginal symptoms at rest), new onset angina (began within the last 3
months) or myocardial infarction within the past 6 months.

- Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy.

- Uncontrolled hypertension, defined as systolic blood pressure > 150 mmHg or diastolic
pressure > 90 mmHg, despite optimal medical management.

- Active clinically serious infection > CTCAE Grade 2.

- Thromboembolic events such as a cerebrovascular accident (including transient
ischemic attacks) within the past 6 months.

- Any hemorrhage/bleeding event ≥ CTCAE Grade 3 within 4 weeks of first dose of study

- Serious non-healing wound, ulcer, or bone fracture within 4 weeks of first dose of
study drug.

- Evidence or history of bleeding diathesis or coagulopathy within 4 weeks of first
dose of study drug.

- Major surgery, open biopsy or significant traumatic injury within 4 weeks of first
study drug.

- Use of St. John's Wort or rifampin within 4 weeks of first dose of study drug.

- Known or suspected allergy to sorafenib or any agent given in the course of this

- Any condition that impairs patient's ability to swallow whole pills.

- Patients who are pregnant or breastfeeding. Breastfeeding should be discontinued if
the patient is to be treated.

- Prior malignancy treated during the prior 5-years (other than localized non-melanoma
carcinoma of the skin).

- Any condition or social situation that may limit patient's compliance with the study

- Known brain metastasis. Patients with neurological symptoms must undergo a CT
scan/MRI of the brain to exclude brain metastasis prior to enrollment.

- Known human immunodeficiency virus (HIV) infection (hepatitis B and hepatitis C
infection will not be exclusion criteria.

- Pulmonary hemorrhage/bleeding event ≥ CTCAE Grade 2 within 4 weeks of first dose of
study drug.

- Any malabsorption problem which in the investigator's opinion would prevent adequate
absorption of the sorafenib.

- Patients may not be on M-Tor inhibitors

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum tolerated dose of daily sorafenib

Outcome Time Frame:

Every two weeks throughout six cycles

Safety Issue:


Principal Investigator

Abby Siegel, MD, MS

Investigator Role:

Principal Investigator

Investigator Affiliation:

Columbia University


United States: Institutional Review Board

Study ID:




Start Date:

January 2009

Completion Date:

January 2016

Related Keywords:

  • Hepatocellular Cancer
  • HCC
  • High-risk Hepatocellular Cancer
  • Liver Neoplasms



University of California, Los AngelesLos Angeles, California  
University of Southern CaliforniaLos Angeles, California  90033
Columbia University Medical CenterNew York, New York  10032