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

UNC Lineberger Comprehensive Cancer Center

Status and phase

Completed

Phase 1

Conditions

Liver Cancer

Treatments

Drug: mitomycin C

Other: laboratory biomarker analysis

Drug: doxorubicin hydrochloride

Drug: sorafenib tosylate

Other: pharmacological study

Study type

Interventional

Funder types

Other

NIH

Identifiers

NCT01011010

LCCC 0902

CDR0000648296 (Other Identifier)

P30CA016086 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

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.

Full 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.

Enrollment

11 patients

Sex

All

Ages

18 to 120 years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion 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