Sorafenib Therapy Prior to Radiofrequency Ablation for Intermediate Sized Hepatocellular Cancer
Phase: Phase 2
Diagnosis: Liver Cancer, Gastrointestinal Malignancies
NCT ID: NCT00813293
(View complete trial on ClinicalTrials.gov)
DFCI Protocol ID: 08-256
The purpose of this research study is to determine if sorafenib improves the effectiveness of a procedure called radiofrequency ablation for the treatment of hepatocellular cancer. During radiofrequency ablation (RF ablation) a needle is inserted into the tumor tissue and heat is used to kill the tumor cells. Sorafenib has been approved by the FDA for the treatment of hepatocellular cancer that cannot be treated with surgery. Radiofrequency ablation has been used to treat many types of tumors, including hepatocellular cancers. Pre-clinical data suggests that sorafenib may improve the efficacy of RFA. The use of sorafenib prior to RF ablation in this study is "investigational" and has not been approved by the FDA. "Investigational" means that this combination is still being studied and that research doctors are trying to find out more about it. In this study, the study doctors hope to better understand the extent to which the combination of sorafenib and RFA may be done practically and successfully. Correlative imaging and tumor studies will evaluate mechanisms of action as well as novel predictors of RFA efficacy.
Dana-Farber Cancer Institute, Beth-Israel Deaconess Medical Center, Brigham and Women's Hospital
Thomas Abrams, MD,
Dana-Farber Cancer Institute
Rebecca Miksad, MD,
Beth Israel Deaconess Medical Center
Beth-Israel Deaconess Medical Center:
Cancer Trials Call Center, 617-667-3060
Dana-Farber Cancer Institute:
Gastrointestinal Research Line, 617-632-5960
- Participants must have hepatocellular cancer (HCC) as confirmed by: histopathologic
findings or by the finding of a liver tumor with arterial hypervascularization on
contrast-enhanced computed tomography (CT) or magnetic resonance imaging and a serum
alpha-fetoprotein (AFP) value exceeding 400ng/mL (European Association for the Study
of Liver criteria for the diagnosis of hepatocellular carcinoma)
- All stages of HCC are allowed, including patients with distant metastases. Patients
may have multiple liver lesions as long as one lesion meets criteria
- Patients may be liver transplant candidates.
- Participants must have at least one tumor (index tumor) which can be accurately
measured as 3.5-7cm in diameter (longest diameter to be recorded) on baseline imaging
multi-phasic CT performed within 2 weeks of trial entry. See section 11 for the
evaluation of measurable disease.
- No prior therapy for the index hepatic tumor(s) being considered for radiofrequency
- No prior systemic treatment for HCC within 4 weeks prior to study entry. In addition,
no prior anti-VEGF therapy allowed within 8 weeks prior to study entry.
- Age 18 years or older. Because no dosing or adverse event data are currently available
on the use of sorafenib in participants <18 years of age, children are excluded from
this study but will be eligible for future pediatric Phase II trials.
- Life expectancy > 8 weeks.
- Eastern Cooperative Oncology Group performance status 0 or 1. (See appendix for
- RFA treatment must be clinically indicated for index tumor. Specifically, patients
must not be candidates for surgical resection of the index tumor and clinical benefit
must be anticipated by the primary physician from liver-direct treatment of the index
- Participants must have acceptable overall RFA procedure risk: adequate cardiovascular,
and functional status as specifically detailed in eligibility and exclusion criterion,
acceptable intravenous sedation or general anesthesia risk and be able to lie flat for
- Participants must have acceptable RFA procedure technique risk: the tumor must have
adequate distance from adjacent vasculature and other organs to permit safe
application of RFA (generally, less than a less than a 2.5cm clearance of the RF
electrode from any vital structure such as the bowel, inferior vena cava, or aorta).
The safety of the electrode placement will be made an attending radiologist
experienced in RFA based on imaging studies.
- Adequate bone marrow, liver and renal function as assessed by the following:
Hemoglobin ≥ 9.0 g/dl Absolute neutrophil count (ANC) ≥ 1,500/mm3 Platelet count
correctable to ≥ 50,000/mm3 Total bilirubin ≤ 1.5 times upper limit of normal (ULN) ALT and
AST ≤ 5 x ULN Creatinine ≤1.5 times ULN or estimated glomerular filtration rate GFR ≥ 45
mL/min/m2 INR correctable to ≤ 1.5 or a PT/PTT correctable to 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 at least weekly, or as defined by the local standard
of care, until INR is stable. However, heparin or warfarin must be held prior to RFA as per
standard of care such that the above criteria are met.
- Ability to take oral medication and no evidence of impaired absorption.
- The effects of sorafenib on the developing human fetus are unknown. For this reason
and because anti-cancer agents are known to be teratogenic, women of child-bearing
potential and men must agree to use adequate contraception (hormonal or barrier method
of birth control; abstinence) prior to study entry and for the duration of study
participation and 2 weeks after the end of sorafenib treatment. Should a woman become
pregnant or suspect she is pregnant while participating in this study, she should
inform her treating physician immediately. In addition, women may not be breast
feeding during the time period of the study.
- Women of childbearing potential must have a negative serum pregnancy test performed
within 7 days prior to the start of treatment.
- Ability to understand and the willingness to sign a written informed consent. A signed
informed consent must be obtained prior to any study specific procedures.
- Participants who are anticipated to require treatment of the index treatment sooner
than permitted by the nine day neoadjuvant course of sorafenib.
- Participants who have had chemotherapy or radiotherapy within 4 weeks prior to
entering the study or those who have not recovered from adverse events due to agents
administered more than 4 weeks earlier. Participants currently receiving any other
- Participants with known brain metastases should be excluded from this clinical trial
because of their poor prognosis and because they often develop progressive neurologic
dysfunction that would confound the evaluation of neurologic and other adverse
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to sorafenib.
- Participants receiving any medications or substances that are inducers of CYP3A4 are
ineligible because systemic sorafenib exposure may be decreased: rifampicin, St.
John's wort, phenytoin, carbamazepine, Phenobarbital and dexamethasone. In addition,
participants should not be receiving compounds that are metabolized/eliminated by
predominantly UGT1A1 pathway (irinotecan) or CYP2B6 and CYP2C8 as systemic exposure
may be increased.
- Participants who exhibit any of the following conditions at screening will not be
eligible for admission into the study.
- Advanced liver disease (Child-Pugh C). (See appendix for definition of Child-Pugh
- Uncontrolled hypertension defined as systolic blood pressure > 150 mmHg or
diastolic pressure > 90 mmHg, despite optimal medical management.
- Thrombolic or embolic events such as a cerebrovascular accident including
transient ischemic attacks within the past 6 months.
- Pulmonary hemorrhage/bleeding event ≥ CTCAE Grade 2 within 4 weeks of first dose
of study drug. (CTAE=Common Terminology Criteria for Adverse Events (CTCAE v3.0)
which is available at http://ctep.cancer.gov/reporting//ctc.html).
- Any other hemorrhage/bleeding event ≥ CTCAE Grade 3 within 4 weeks of first dose
of study drug.
- Serious non-healing wound, ulcer, or bone fracture.
- Evidence of severe or uncorrectable bleeding diathesis or coagulopathy
- Major surgery, open biopsy or significant traumatic injury within 4 weeks of
first study drug.
- Use of St. John's Wort or rifampin (rifampicin).
- Any condition that impairs ability to swallow whole pills.
- Any malabsorption problem.
- The index tumor was treated with RFA or other treatment in the past.
- Contraindication to or inability to undergo the RFA procedure, including adequate
sedation and analgesia during the procedure. Contraindication to intravenous sedation
or general anesthesia will be determined by Pre-Admission evaluation by the Department
of Anesthesiology as per institutional standard of care.
- Contraindication to or inability to undergo imaging with MRI (Pacemaker, MRI
incompatible metal implant, Recently implanted vascular clip, history of
claustrophobia not controlled with mild anxiolytic, metal fragment within the eye)
- Uncontrolled intercurrent illness including, but not limited to ongoing or serious
active infection (> CTCAE Grade 2), symptomatic congestive heart failure (> class II
NYHA), unstable or new (<3 months) angina pectoris, recent myocardial infarction
(within the past 6 months), cardiac arrhythmia (uncontrolled), or psychiatric
illness/social situations that would limit compliance with study requirements.
- Pregnant women are ineligible for this study because sorafenib is an anti-cancer agent
with the potential for teratogenic or abortifacient effects.
Because there is an unknown but potential risk of adverse events in nursing infants
secondary to treatment of the mother with sorafenib, breastfeeding should be discontinued
if the mother is treated with sorafenib.
- Individuals with a history of a different malignancy are ineligible except for the
following circumstances. Individuals with a history of other malignancies are eligible
if they have been disease-free for at least 5 years and are deemed by the investigator
to be at low risk for recurrence of that malignancy. Individuals with the following
cancers are eligible if diagnosed and treated within the past 5 years: cervical cancer
in situ, and basal cell or squamous cell carcinoma of the skin.
- HIV-positive individuals on combination antiretroviral therapy are ineligible because
of the potential for pharmacokinetic interactions with sorafenib. In addition, these
individuals are at increased risk of lethal infections when treated with
marrow-suppressive therapy. Appropriate studies will be undertaken in participants
receiving combination antiretroviral therapy when indicated.