Clinical trial NCT01011010: Sorafenib Tosylate and Chemoembolization With Doxorubicin Hydrochloride and Mitomycin in Treating Patients With Liver Cancer That Cannot Be Removed By Surgery
Official title: Phase Ib Clinical Trial of Sorafenib in Combination With Transarterial Chemoembolization (TACE) in Patients With Unresectable Hepatocellular Carcinoma (HCC)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Liver Cancer
Keywords: adult primary hepatocellular carcinoma
localized unresectable adult primary liver cancer
recurrent adult primary liver cancer
Lead sponsor: UNC Lineberger Comprehensive Cancer Center
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2009-11-11
Enrollment: 11
Sex: ALL
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Safety and toxicity as assessed by NCI CTCAE v3.0 criteria
timeFrame: 3 years
Secondary outcomes:
measure: Overall survival
timeFrame: 5 years
measure: Correlative studies
timeFrame: 3 years
Other outcomes:
Locations:
city: Chapel Hill
country: United States
facility: Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University Comprehensive Cancer Center
state: North Carolina
Study officials:
affiliation: UNC Lineberger Comprehensive Cancer Center
name: Hanna H. Sanoff, MD
role: PRINCIPAL_INVESTIGATOR
References: