Study for Patients with Hepatocellular Carcinoma (HCC)

This is an open-label, prospective, multi-center, randomized, phase II trial with two treatment groups for subjects with hepatocellular carcinoma (HCC). Approximately 150 subjects will be enrolled into this study. 

The study will compare two treatment groups:

• Group A: TheraSphere™ only
• Group B: TheraSphere™ plus Durvalumab and Tremelimumab

TheraSphere™ treatment is the standard of care.

TheraSphere™ treatment in combination with Durvalumab and Tremelimumab is investigational.

The purpose of this study is to see if adding medications called Durvalumab, and Tremelimumab after TheraSphere™ treatment is safe and can improve the results usually seen with TheraSphere™ alone.

In order to participate you must meet the following criteria:

• Are aged ≥18 years at the time of screening.
• Have written informed consent and any locally required authorization (e.g., Health Insurance Portability and accountability Act in the United Sates (US), European Union (EU) data privacy regulations in the EU) obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations.
• Have a life expectancy ≥6 months.
• Have Hepatocellular Carcinoma (HCC), diagnosed by radiographic imaging or histology.
• Are not a candidate for liver resection, thermal ablation, or transplantation at the time of study entry.
• Are treatment naïve.
• Have measurable disease by modified response evaluation criteria in solid tumors (mRECIST) criteria (e.g. ≥10 mm of enhancement).
• Have tumor volume ≤25% of whole liver volume (determined by imaging).
• Have unilobar tumor.
• Have future liver remnant volume (FLRV) ≥30% of whole liver volume. FRLV is the volume of liver not planned to be treated with TheraSphere and free of HCC.
• Patients with Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) infection are to have documented virology status of hepatitis as confirmed by HBV and HCV serology test:
  • Patients with HBV infection: HBV DNA load should be ≤2000 International Units per millilitre (IU/mL) obtained within 28 days prior to initiation of study treatment, and Anti-HBV treatment (per local standard of care) for a minimum of 14 days prior to study entry and willingness to continue treatment for the length of the study.
  • Patients with chronic HCV infection are allowed in the study: For untreated patients, Aspartate aminotransferase/Alanine aminotransferase (AST/ALT) should be ≤3x Upper Limit of Normal (ULN) and for treated patients, antiviral treatment (per local standard of care) should be stopped for a minimum of 14 days prior to study entry and AST/ALT should be ≤3xULN.
• Have negative serum pregnancy test in females of child-bearing potential; patients who are breast-feeding cannot participate in this trial.
• Have adequate contraception for the patient and his/her sexual partner.
• Have adequate renal and marrow function as defined below:
  • Hemoglobin ≥9.0 g/dL
  • Absolute neutrophil count ≥1.5 x 109/L
  • Platelet count ≥75 x 109/L
  • Measured or calculated creatinine clearance ≥45 mL/min as determined by Cockcroft-Gault (using actual body weight)
• Have absolute lymphocyte count ≥1.0 X 109/L.
• Have adequate liver function, as defined by
  • Child-Pugh A
  • Serum albumin ≥30 g/L
  • Serum bilirubin <1.1 x the upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert’s syndrome, who will be permitted to enroll in the study in consultation with their physician.
  • AST and ALT <3 x ULN.
• Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 at randomization.
• Have a body weight >30 kg and BMI ≥18 kg/m2.

You will be excluded from the study if any of the following criteria apply to you:

• Have any contraindication to angiography or selective visceral catheterization.
• Have Cone Beam CT (CBCT) or Technetium-99m macroaggregated Albumin (99mTc-MAA) hepatic arterial perfusion scintigraphy shows any deposition to the gastrointestinal tract that may not be corrected by angiographic techniques.
• Have CBCT or 99mTc-MAA hepatic arterial perfusion scintigraphy shows poor tumor targeting, if lobar administration with multi-compartment dosimetry is planned.
• Have shunting of blood to the lungs that could result in delivery of >30 Gray (Gy) to the lungs in a single treatment, as seen on 99mTc-MAA hepatic arterial perfusion scintigraphy.
• Have extrahepatic metastases, including patients with hilar /mesenteric /celiac lymph nodes >1.5 cm in shorter axis, or with lung nodules (single lesion, >1 cm, or multiple smaller lesions with a total diameter >2 cm).
• Have brain metastases, leptomeningeal carcinomatosis or spinal cord compression. Patients with suspected brain metastases at screening should have an MRI (preferred) or Computed Tomography (CT) each preferably with intravenous (IV) contrast of the brain prior to study entry.
• Have evidence of any tumor vascular invasion.
• Have any prior treatment for HCC (including surgery, Trans-arterial Chemoembolization/Trans-arterial Embolization (TACE/TAE), ablation, systemic, radiation treatment).
• Have prior exposure to any immune mediated therapy, including but not limited to other anti-programmed cell death protein 1 (anti- PD-1), anti-programmed death-ligand 1 (anti-PDL-1), anti-programmed death-ligand 2 (anti-PDL-2), anti- Cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4), antibodies, Interferon (IFN).
• Have concurrent treatment for HCC or treatment in the last 4 weeks in another clinical study, unless it is an observational study (non-interventional) or during a non-interventional follow-up stage of an interventional study, or prior randomization to this study.
• Have hepatic encephalopathy present at study entry and/or episodes of encephalopathy (≥ Grade 2) within 6 months prior to randomization.
• Have presence of ascites, clinical or radiological, “trace” of ascites is acceptable.
• Have HCC with infiltrative disease presentation that is not possible to evaluate by mRECIST.
• Have a history of active primary/acquired immunodeficiency.
• Have evidence of pulmonary insufficiency (defined by an arterial oxygen pressure (Pa,O2) of <60 mmHg, or oxygen saturation (Sa,O2) of <90% (Roussos & Koutsoukou, 2003) or clinically evident chronic obstructive pulmonary disease (COPD).
• Have a history of any organ allograft, including bone marrow allo and autograft.
• Have active or prior documented autoimmune or inflammatory disorders (including but not limited to inflammatory bowel disease [e.g. ulcerative colitis or Crohn’s disease], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves’ disease, rheumatoid arthritis, hypophysitis, uveitis]). The following are exceptions to this criterion:
  • Patients with vitiligo or alopecia
  • Patients with hypothyroidism (e.g. following Hashimoto’s syndrome) stable on hormone replacement therapy
  • Any chronic skin condition that does not require systemic therapy.
  • Patients without active disease in the last 5 years may be included but only after consultation with the Sponsor Study physician.
  • Patients with celiac disease controlled by diet alone.
• Have current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. The following are exceptions to this criterion:
  • Intranasal, inhaled, topical steroids, or local steroid injections (e.g. intraarticular injection)
  • Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent.
  • Steroids as premedication for hypersensitivity reactions (e.g. CT scan premedication).
• Have a history of gastrointestinal bleeding within 28 days prior to randomization, active gastrointestinal (GI) bleeding and any bleeding diathesis or coagulopathy that is not correctable by usual therapy or hemostatic agents (e.g. closure device). Patients with known varices that have not bled can enter the study. No endoscopic exploration is required before randomization.
• Have presence of biliary stent at any time or sphincterotomy within one year prior to randomization.
• Have a history of malignancy, other than HCC, within three years, with the exception of adequately treatment carcinoma in situ of the cervix, early squamous cell carcinoma or basal cell carcinoma of the skin, localized prostate cancer, ductal carcinoma in situ, or low grade endometrial carcinoma with no myometrial invasion (negligible risk of metastases or death 5-year overall survival (OS) rate > 90%).
• Have had a major surgical procedure (as defined by the Investigator) within 28 days prior to randomization.
• Have a history of severe allergy or intolerance to contrast agents, narcotics, sedatives or atropine that cannot be managed medically.
• Have known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.
• Have active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis testing in line with local practice), or human immunodeficiency virus (positive Human Immunodeficiency Virus (HIV) 1/2 antibodies).
• Receipt of live attenuated vaccine within 30 days prior to the first dose of durvalumab and/or tremelimumab. Note: patients, if enrolled, should not receive live vaccine whilst receiving durvalumab and/or tremelimumab and up to 30 days after the last dose of durvalumab and/or tremelimumab.
• Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab and tremelimumab monotherapy.
• Have unstable chronic disease or evidence of any disease or condition that would place the patient at undue risk and preclude safe use of TheraSphere, durvalumab and tremelimumab treatment, including but not limited to, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, active interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring adverse events (AEs) or compromise the ability of the patient to give written informed consent.
• Are not able to follow the TheraSphere, durvalumab or tremelimumab treatment requirements.

This is a partial list of eligibility requirements. To inquire about your eligibility, please call the contact number provided. If you wish to inquire via email, please include the title of the study in your message.