Sorafenib Tosylate and Chemoembolization With Doxorubicin Hydrochloride and Mitomycin in Treating Patients With Liver Cancer That Cannot Be Removed By Surgery

Study Overview
=================
Brief Summary
-----------------
RATIONALE: Sorafenib tosylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Drugs used in chemotherapy, such as doxorubicin hydrochloride and mitomycin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Chemoembolization kills tumor cells by carrying drugs directly into the tumor and blocking the blood flow to the tumor. Giving sorafenib tosylate together with chemoembolization may kill more tumor cells. PURPOSE: This phase I trial is studying the side effects of sorafenib tosylate when given together with chemoembolization with doxorubicin hydrochloride and mitomycin in treating patients with liver cancer that cannot be removed by surgery.

Detailed Description
-----------------
OBJECTIVES: Primary To determine the safety of sorafenib tosylate when given in combination with transarterial chemoembolization (TACE) comprising doxorubicin hydrochloride and mitomycin C in patients with unresectable hepatocellular carcinoma. Secondary To estimate the time to progression (TTP) in patients treated with this regimen. To estimate the overall survival (OS) of patients treated with this regimen. To explore correlative relationships between measures of serum VEGF in the peri-procedure TACE period and changes with TACE and sorafenib tosylate as well as patient outcomes (TTP and OS). OUTLINE: This is a multicenter study. Patients receive oral sorafenib tosylate twice daily on days 1-14. Patients then undergo transarterial chemoembolization (TACE) comprising doxorubicin hydrochloride and mitomycin C on days 17-19*. Patients then receive oral sorafenib tosylate twice daily beginning after recovery from TACE and continuing in the absence of disease progression or unacceptable toxicity. NOTE: *A second course of TACE may be administered within 8 weeks after the first TACE procedure. Blood samples may be collected periodically for biomarker and pharmacokinetic analysis. After completion of study treatment, patients are followed up at 3-4 weeks and then every 3 months for up to 3 years.

Official Title
-----------------
Phase Ib Clinical Trial of Sorafenib in Combination With Transarterial Chemoembolization (TACE) in Patients With Unresectable Hepatocellular Carcinoma (HCC)

Conditions
-----------------
Liver Cancer

Intervention / Treatment
-----------------
* Drug: doxorubicin hydrochloride
* Drug: mitomycin C
* Drug: sorafenib tosylate
* Other: laboratory biomarker analysis
* Other: pharmacological study


Participation Criteria
=================
Eligibility Criteria
-----------------
DISEASE CHARACTERISTICS: Diagnosis of hepatocellular carcinoma (HCC), as defined by 1 of the following: Tissue histology Recurrence of previously resected HCC does not require tissue confirmation if there is clear radiographic recurrence, in the judgment of the investigator AFP > 400 ng/mL with compatible mass on MRI Locally advanced disease Not eligible for surgical resection or immediate liver transplantation OR have refused such procedures All disease must be amenable to embolization in one or two procedures Measurable disease, according to modified HCC RECIST criteria Must have radiographically documented measurable disease with at least one site of disease that is unidimensionally measurable as ≥ 10 mm on MRI Lesions previously treated by radiofrequency ablation should not represent the only site of measurable disease Childs-Pugh score ≤ 7 No complete thrombosis of the main portal vein If unilateral portal vein thrombosis is present, must demonstrate radiographic evidence of adequate flow to the lobe to be embolized No evidence of extrahepatic/metastatic disease, such as lymph node metastases, lung or bone metastases, or peritoneal carcinomatosis Evidence of cirrhosis is acceptable as long as the lab parameters are met No known brain metastases PATIENT CHARACTERISTICS: ECOG performance status 0-1 Life expectancy ≥ 12 weeks Hemoglobin ≥ 9.0 g/dL ANC ≥ 1,500/mm³ Platelet count ≥ 75,000/mm³ Creatinine ≤ 1.5 times upper limit of normal (ULN) OR creatinine clearance ≥ 50 mL/min Total bilirubin ≤ 3 mg/dL ALT and AST ≤ 5 times ULN INR < 1.5 Negative pregnancy test Fertile patients must use effective contraception during and for ≥ 3 months after completion of study treatment No other cancer within the past 3 years except for cervical carcinoma in situ, previously treated basal cell carcinoma, or superficial bladder tumors (Ta, Tis, or T1) No NYHA class III or IV congestive heart failure No unstable angina (anginal symptoms at rest) or new-onset angina within the past 3 months No myocardial infarction within the past 6 months No cardiac ventricular arrhythmias requiring anti-arrhythmic therapy No uncontrolled hypertension (i.e., systolic BP > 150 mm Hg or diastolic BP > 90 mm Hg, despite optimal medical management) No venous thrombotic or arterial embolic events (e.g., cerebrovascular accident, including transient ischemic attacks or venous thromboembolism) within the past 6 months No pulmonary hemorrhage/bleeding event > CTCAE grade 2 within the past 12 weeks No other hemorrhage/bleeding event > CTCAE grade 3 within the past 12 weeks No variceal bleeding within past 12 weeks No known grade 2 or 3 esophageal varices (endoscopic evaluation is not required for study entry) No evidence or history of bleeding diathesis or coagulopathy No significant traumatic injury within the past 12 weeks No serious non-healing wound, ulcer, or bone fracture No significant proteinuria (i.e., proteinuria > 1+ on urine dipstick) No HIV positivity (by patient report) No active hepatitis B or C, unless patient has been on stable medications for ≥ 2 months No active clinically serious infections (> grade 2) No active gastrointestinal malabsorption problem No condition that would impair the patient's ability to swallow whole pills No active drug or alcohol abuse No known severe hypersensitivity or suspected allergy to sorafenib tosylate, any of its excipients, or other drugs used in this study No psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule PRIOR CONCURRENT THERAPY: No prior systemic therapy, embolic therapy, or radiotherapy for HCC (e.g., chemotherapy, transarterial chemoembolization, transarterial embolization, or 90Y microspheres) At least 4 weeks since prior liver resection or ablative therapy and recovered No prior Raf/MEK/ERK-targeted therapy or VEGF-targeted therapy More than 4 weeks since prior participation in any investigational drug study More than 12 weeks since prior major surgery or open biopsy Prior core liver biopsy allowed No concurrent antiretroviral therapy for HIV No concurrent chronic anticoagulation (other than 1 mg of warfarin daily for port patency) No concurrent St. John wort or rifampin No other concurrent anticancer therapy, radiotherapy, or investigational therapy

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Single Arm<br>Single Arm Trial | Drug: doxorubicin hydrochloride<br>* TACE (day 18-20): Doxorubicin 50mg and mitomycin C 10mg mixed with lipoidal and injected in proportion to liver volume being treated, followed by embospheres. Administered until there is a pruned tree appearance on angiography. If a second TACE is to be performed it should be performed within 8 weeks of the first procedure.<br>Drug: mitomycin C<br>* TACE (day 18-20): Doxorubicin 50mg and mitomycin C 10mg mixed with lipoidal and injected in proportion to liver volume being treated, followed by embospheres. Administered until there is a pruned tree appearance on angiography. If a second TACE is to be performed it should be performed within 8 weeks of the first procedure.<br>Drug: sorafenib tosylate<br>* Sorafenib 400mg BID continuously post TACE beginning when LFTs return to entry criterion. Discontinue at time of disease progression (progression in a lobe that has already been embolized, new lesions in an untreated lobe, or evidence of extrahepatic progression).<br>Other: laboratory biomarker analysis<br>* Serum VEGF levels are required: pre TACE (day of procedure, time B), 24 hours post TACE (+/- 6 hours, time C), day 7 post first TACE (± 1 day, time D), day 28 post reinitiation of sorafenib (± 3 days, time E). These levels will not be repeated for patients receiving a second TACE procedure.<br>Other: pharmacological study<br>* Treatment with sorafenib will continue on a daily basis until disease progression (see definition protocol Section 7) or unacceptable toxicity is encountered. At the end of treatment, no further therapies are currently recommended.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and toxicity as assessed by NCI CTCAE v3.0 criteria |  | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival |  | 5 years | 
| Correlative studies |  | 3 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
adult primary hepatocellular carcinoma, localized unresectable adult primary liver cancer, recurrent adult primary liver cancer