A Phase I/II Open Label Study of T138067-sodium in Patients with Advanced, Surgically Unresectable Hepatocellular Carcinoma

SPONSOR: Genentech, Inc.

PRINCIPAL INVESTIGATOR: James Posey, M.D.

OBJECTIVES

The primary study objectives are as follows:

Phase I

1. To further characterize the quantitative and qualitative toxicities and pharmacokinetics of T138067-sodium administered by intravenous infusion over three hours every week at a dose of 220 mg/m2 in patients who have advanced, surgically unresectable hepatocellular carcinoma. Treatment once a week for three weeks defines a cycle of therapy. In the event that 220 mg/m2 is not tolerated, subsequent patients will be treated at 165 mg/m2.

Phase II

1. To obtain the objective response rate to T138067-sodium when administered at a dose level determined from the ongoing Phase I study and the Phase I experience in the current study. This dose level will not be higher than 220 mg/m2 weekly. T138067-sodium will be given by intravenous infusion over three hours in patients with advanced, surgically unresectable hepatocellular carcinoma. Two groups of patients will be studied: those who have not received any prior chemotherapy and those that have received on prior chemotherapy regimen.
2. To characterize the quantitative and qualitative toxicities of intravenous T138067-sodium administered over three hours every week in these patient populations.
3. To measure the time to event efficacy variables including:
   • Duration of response for responding patients
   • Time to disease progression
   • Median survival time

Secondary objectives include:

1. To determine the number of patients who have disease progression on therapy.
2. To correlate toxicities with plasma levels during the first cycle of therapy.

Eligible patients will receive T138067-sodium by intravenous infusion over three hours every seven days on Day 1, Day 8, and Day 15. Three weeks of treatment defines one cycle of therapy. The study enrollment period is nine months. Up to 20 clinical centers will participate in this study. Patients wil be monitored closely throughout the study for safety and efficacy parameters by physical, radiologic, and laboratory examinations.

PATIENT SELECTION CRITERIA

Inclusion Criteria

1. All patients must have a pathologic (histological or cytological) confirmation of hepatocellular carcinoma.
2. Patients may have had either no prior chemotherapy or one prior chotherapeutic regimen.
3. Patients must be at least 18 years of age.
4. Patients in the Phase II portion of the trial must have bidimensionally measurable disease amenable to radiologic imaging techniques. Ulatrasound will not be allowed as a method of tumor measurement.
5. Karnofsky Performance status (KPS) of 70 or above.
6. Patients must have an estimated life expectancy of at least 12 weeks.
7. Patients capable of reproduction must agree to use effective methods of contraception during the study and for three months afterwards. Female patients of childbearing potential must have a negative pregancy test no more than 7 days before study enrollment.
8. Patients are able to comply with study procedures and follow-up examinations.
9. Patient must sign a written informed consent form.
10. For patients not receiving anticoagulants INR < 1.5/
11. Plasma creatinine < 2 x ULN.
12. Child-Pugh liver classification of A or B.
13. Patients must have adequate organ function as indicated by the following laboratory values, obtained < three days prior to the first day of study drug:
    • Serum bilirubin < 1.5 x ULN
    • Albumin > g/dL (U.S.) {25 g/L (U.K>)}
    • Aspartate transaminases (AST/SGOT) and alanine transaminases (ALT/SGPT) < 3 x ULN
    • In the absence of growth factor:
      • Absolute neutrophil count (ANC) > 1500 mm3 {1.5 x 109/L}
      • Platelets > 75,000 mm3 {75 x 109/L}
      • Hemoglobin (Hgb) > 8.5 g/dL

Exclusion Criteria

Patients who meet any of the following criteria will be excluded from the study:

1. Patients with any severe, concurrent disease, infection or co-morbidity that in the judgment of the investigator would make the patient inappropriate for study entry.
2. Patients who have received prior radiotherapy, immunotherapy, or cryotherapy. Prior intratumoral ethanol or radiocarbon is permitted ONLY if 6 weeks have elapsed since therapy AND the indicator lesion is outside the area of prior treatment AND the edges of the indicator lesion are clearly distinct on CT scanning. Patients who have received prior chemoembolization are permitted, but will be entered into the group of patients who have had one prior chemotherapeutic regimen.
3. Patients who have used any investigational agent within four weeks of study entry.
4. Patients who are pregnant or breast-feeding.
5. History of prior malignancy other than hepatocellular carcinoma within the last 5 years, except for an adequately treated basal cell or squamous cell skin cancer, or carcinomatous meningitis.
6. Patients who are receiving concomitant chemotherapy, radiotherapy, or immunotherapy.
7. Major surgery within four weeks of the study.
8. Patients requiring concomitant anticonvulsant medication.
9. Any know defect of GSH metabolism or the need for large doses of acetaminophen (paracetamol)(i.e. > 4g/day)
10. A known clinical diagnosis of or a history pertinent to Gilbert's syndrome (i.e., does the patient become jaundiced when fasting or with exposure to estrogen). Values of conjugated and unconjugated bilirubin should be obtained. A diagnosis of Gilbert's syndrome should be excluded before patients are entered into the study.
11. Patients with organ allografts.

ADDITIONAL INFORMATION

For further information, contact Karen Akins, RN, BSN at (205) 934-8614 or page through the UAB Paging Operator at (205) 934-3411, Pager #5816.