Y-90 Alone or With Sorafenib for Pre-Transplant Hepatocellular Carcinoma

Study Overview
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Brief Summary
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A research study to determine the safety, efficacy, and tolerability of Therasphere® (also known as Y-90, or Y-90 Therasphere) combined with or without sorafenib (Nexavar®), in patients with hepatocellular carcinoma (HCC, or liver cancer), awaiting liver transplantation.

Detailed Description
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Because Hepatocellular carcinoma (HCC) grows by forming new blood vessels liver transplant (OLT) offers the best chance for long term survival. However, with the growing number of patients who require OLT, prolonged wait list times often lead to drop out from the transplant list due to tumor progression. Some patients are granted an upgrade,within the generally accepted guidelines for transplant eligibility, in order to expedite the access of patients with early HCC to transplantation before tumor progression. The use of therapies like radioembolization also known as Yttrium-90 ([Y-90] a procedure where very small beads coated with radiation are injected directly into the tumor through an artery in your groin) while awaiting OLT has become common at most transplant centers, including Northwestern, to help patients reach transplant. Additionally, these treatments are being used to move patients to a status eligible for transplant. We are studying whether a combination approach with systemic therapy and therapy applied directly to the liver, will be more successful than a single therapy . Angiogenesis (a process involving the growth of new blood vessels from pre-existing vessels) plays an important role in the early stages of HCC. A decrease in angiogenesis both locally within the treated tumor as well as in any existing tumor cells, not yet detected, would hopefully decrease the incidence of post transplant recurrence of HCC. All subjects enrolled in this study will be treated with the use of Therasphere, Y-90, which is composed of nonbiodegradable glass microspheres coated with the radioactive compound Y-90 which are injected into the hepatic artery. The concentrated radioactive microspheres within the tumor lead to inside-out radiation. Half of the subjects will be treated with sorafenib (NEXAVAR®) in conjunction with Y-90. The determination of which subjects will receive sorafenib will be made randomly, like the flip of a coin. Sorafenib works by slowing the growth of the tumor cell , attacking the tumor from the outside. Researchers hope to determine whether the subjects treated with sorafenib have an overall improved response to liver directed therapy with Y-90 Therasphere.

Official Title
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A Single-Center Proof of Concept Pilot Study to Evaluate the Safety, Efficacy, and Tolerability of Sorafenib Combined With Therasphere in Subjects With Hepatocellular Carcinoma Awaiting Liver Transplantation.

Conditions
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Hepatocellular Carcinoma

Intervention / Treatment
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* Drug: Sorafenib
* Drug: Yttrium-90 (Y-90)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult > 18 years olf of either gender Diagnosis of HCC confirmed by biopsy, CT, or MRI Able to carry out activities of daily living, awake >50% of waking hours Meets eligibility for liver transplantation No prior treatment for HCC Ability to understand and sign the informed consent Child-bearing women and any men agree to use two forms of birth control (one of which should be a barrier method) during the course of therapy and for 8 weeks afterward. Exclusion Criteria: Less than or = 18 years old Ineligible for transplant due to comorbid disease Renal Failure requiring dialysis of any kind Severe Cardiac disease History of a stroke Evidence of metastatic disease- or tumors that have spread outside the liver Known human immunodeficiency virus (HIV) infection Uncontrolled blood pressure (systolic > 160) despite medication(s) Major surgery within 4 weeks prior to the screening visit Active clinically serious infection Serious non-healing wound, ulcer, or bone fracture. History of gastrointestinal bleeding (GIB) within 6 weeks prior to the screening visit Prior transplant of any kind Must be able to swallow oral pills, tablets or capsules of any size Use of St. John's Wort or rifampin (rifampicin). Currently being treated with Interferon and/or Ribavirin therapy due to the thrombocytopenias, lymphopenias and anemias observed with use of these two medications. Known or suspected allergy to sorafenib or any agent given in the course of this trial. Any malabsorption problem Pregnancy or lactation. Women of childbearing potential must have a negative pregnancy test 7 days prior to beginning therapy. No potential living donor transplant (LDT-donor identified and worked up by the time of randomization into this study. If a living donor is later identified- the subject will be allowed to continue in the study. Sorafenib will be stopped at a minimum of 7 days prior to transplant surgery. Active alcohol use, drug use, or a psychiatric disease that would, in the opinion of the PI or a subinvestigator (sub-I), prevent the subject from complying with the study protocol and/or endanger the subject during their participation in the study Inability of the potential subject to read, understand and sign the informed consent document

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: A: Y-90 alone<br>Patients randomized to Arm A will proceed to Y-90 treatment alone in the Northwestern standard of care procedure | Drug: Yttrium-90 (Y-90)<br>* Patients undergo radioembolization with Yttrium 90 microspheres by hepatic artery infusion<br>* Other names: Therasphere;|
| Experimental: B: Sorafenib + Y-90<br>Patients randomized to Arm B will start sorafenib at a dose of 400 mg twice daily for bilirubin ≤ 1.5 x ULN and 200 mg twice daily for bilirubin > 1.5 x ULN to ≤ 3 x ULN. After 14 days of sorafenib therapy (+/- 3 days) patients will proceed to Y-90 in the Northwestern standard of care procedure | Drug: Sorafenib<br>* Randomized to Y-90 ± Sorafenib<br>* Other names: BAY 54-9085 is the tosylate salt of BAY 43-9006; NEXAVAR®;Drug: Yttrium-90 (Y-90)<br>* Patients undergo radioembolization with Yttrium 90 microspheres by hepatic artery infusion<br>* Other names: Therasphere;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To Evaluate sorafenib as an adjunct to Y-90 for control of HCC as a bridge/downstage to transplant | Subjects randomized to receive Sorafenib take the drug for 2 weeks before treatment with Y90. They have imaging (CT/MRI) 2 weeks after starting Sorafenib then are treated. Post-treatment patients have blood drawn and adverse event evaluation at 2 weeks, 4 weeks, 6 weeks, and then every 6 weeks up to 1 year or time of transplant. Repeat imaging is done at 4 weeks, and then every 3 months post-treatment. Subjects not receiving Sorafenib are treated with Y90 and then are evaluated post-treatment the same as the subjects that receive the drug. | Up to one year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To characterize the toxicity profile of sorafenib and Y90 using NCI CTC toxicity grading scales. | Subjects randomized to receive Sorafenib take the drug for 2 weeks before treatment with Y90. They have imaging (CT/MRI) 2 weeks after starting Sorafenib then are treated. Post-treatment patients have blood drawn and adverse event evaluation at 2 weeks, 4 weeks, 6 weeks, and then every 6 weeks up to 1 year or time of transplant. Repeat imaging is done at 4 weeks, and then every 3 months post-treatment. Subjects not receiving Sorafenib are treated with Y90 and then are evaluated post-treatment the same as the subjects that receive the drug. | up to 1 year | 
| To identify predictive and prognostic markers of how the liver cancer will respond to treatment. | All subjects are evaluated with lab work and adverse event assessment at 2, 4, and 6 weeks post-treatment, and then every 6 weeks up to 1 year or when they receive transplant. | up to 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Subjects with primary hepatocellular carcinoma, intended for liver transplantation.