Evaluation of Efficacy and Safety of TheraSphere Followed by Durvalumab and Tremelimumab in Hepatocellular Carcinoma Patients
- Trial ID
- 2023-508945-41-00
- Protocol
- S2472
- Sponsor
- Biocompatibles UK Limited
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this clinical trial is to assess the **efficacy** of treatment with TheraSphere followed by durvalumab and tremelimumab in patients with **Hepatocellular Carcinoma** (HCC). This evaluation is clinically relevant as it aims to determine the potential benefits of combining radioembolization with immunotherapy in improving patient outcomes in HCC, a common and challenging liver cancer.
Secondary objectives include:
- Exploring whether treatment with TheraSphere followed by systemic treatment with durvalumab and tremelimumab can enhance other efficacy endpoints.
- Assessing the safety and toxicity of TheraSphere followed by durvalumab and tremelimumab.
- Determining the tumor and normal tissue absorbed radioembolization dose and its relationship with response, outcomes, and liver volume changes after treatment.
- Describing the difference in quality of life before and after treatment using the FACT-Hep and EQ-5D questionnaires.
Participants
The clinical trial involves a total of **29 participants** diagnosed with **Hepatocellular Carcinoma** (HCC). The study population includes both male and female subjects, aged 18 years and older, who are not candidates for liver resection, thermal ablation, or transplantation. Participants were selected based on specific health criteria, including adequate renal, marrow, and liver function, as well as a life expectancy of at least six months. The trial includes individuals with a body weight greater than 30 kg and a BMI of at least 18 kg/m². Participants must have at least one measurable HCC lesion and meet dosimetry criteria for tumors and normal tissue. The study also considers lifestyle factors such as previous treatments, with allowances for those who have undergone transarterial chemoembolization (TACE) or liver resection, provided certain conditions are met. Individuals with controlled **Human Immunodeficiency Virus** (HIV) infection and those with **Hepatitis B Virus** (HBV) or **Hepatitis C Virus** (HCV) infections are eligible if they meet specific treatment and stabilization criteria. The trial population includes vulnerable groups, and all participants are required to provide written informed consent and adhere to adequate contraception measures. The selection process ensures that participants have no portal vein thrombosis beyond Vp2 and that any previous ascites or encephalopathy episodes are resolved without supportive treatment at study entry.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy and safety of a treatment regimen for **hepatocellular carcinoma** (HCC) involving TheraSphere followed by immunotherapy with **durvalumab** and **tremelimumab**. This is an open-label, prospective, multi-center study, categorized as a Phase IV trial. The trial will involve a series of study visits, beginning with an inclusion visit to screen participants based on specific eligibility criteria, including age, renal and marrow function, liver function, and other health parameters. Participants must provide written informed consent before any protocol-related procedures are conducted.
The trial employs a non-randomized design, as it is open-label, meaning both the researchers and participants are aware of the treatment being administered. The study is expected to last until July 2027, with recruitment starting in October 2023. Participants will be involved in the study for a maximum treatment period of 18 months, depending on their response to the treatment and any adverse events experienced. The primary endpoints include the objective response rate and the number of adverse events, while secondary endpoints focus on immune-mediated adverse events, changes in liver function tests, and overall survival, among others.
Study visits will include regular follow-up assessments to monitor the participants' health status, treatment efficacy, and any adverse effects. These visits will be scheduled at intervals deemed necessary by the study protocol to ensure comprehensive data collection and participant safety. The end-of-study visit will conclude the participant's involvement, where final assessments will be conducted to evaluate the overall outcomes of the treatment regimen.
Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with the study protocol, or if the investigator deems it in the participant's best interest. The trial aims to provide valuable insights into the treatment of HCC, contributing to the understanding of the safety and efficacy of combining TheraSphere with durvalumab and tremelimumab.
Treatment
The clinical trial involves the administration of several treatments, each with specific characteristics and administration protocols. **CellCept** 500 mg powder for concentrate for solution for infusion, containing the active substance **mycophenolate mofetil**, is a chemical-origin medication. It is provided in the form of a powder that is reconstituted into a solution for infusion. The maximum daily dose is 1 gram, with a total maximum dose of 2 grams over a treatment period of 1 day. The route of administration is via infusion.
**IMJUDO** 20 mg/ml concentrate for solution for infusion, containing the active substance **tremelimumab**, is a biological/biotechnological-origin medication. It is supplied as a sterile concentrate for infusion. The maximum daily and total dose is 300 milligrams, administered over a treatment period of 1 day. The administration is conducted through infusion.
**Remicade** 100 mg powder for concentrate for solution for infusion, containing the active substance **infliximab**, is also of biological/biotechnological origin. It is provided as a powder that is reconstituted into a solution for infusion. The dosing regimen allows for a maximum daily dose of 5 mg/kg, with a total maximum dose of 15 mg/kg over a treatment period of 6 weeks. The route of administration is infusion.
**IMFINZI** 50 mg/mL concentrate for solution for infusion, containing the active substance **durvalumab**, is a biological/biotechnological-origin medication. It is available as a concentrate for infusion. The maximum daily dose is 1500 milligrams, with a total maximum dose of 30 grams over a treatment period of 18 weeks. Administration is performed via infusion.
Throughout the trial, participant compliance with the dosing schedules is monitored to ensure adherence to the treatment protocols. Each medication is administered according to its specific pharmaceutical form and dosing regimen, with careful attention to the infusion route to maintain the integrity and efficacy of the treatment.
Efficacy
The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary effectiveness endpoint is the Objective Response Rate (ORR), which includes complete response and partial response, evaluated by the modified Response Evaluation Criteria in Solid Tumors (mRECIST) through investigator assessment. The primary safety endpoint will focus on the number of adverse events (AEs) and serious adverse events (SAEs) reported during the trial.
Secondary endpoints will include a variety of measures to further evaluate the treatment's impact. These include the number of immune-mediated AEs and SAEs, changes from baseline in liver function tests such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), and bilirubin levels, as well as changes in Child-Pugh and Albumin Bilirubin (ALBI) scores. Additionally, the trial will assess the Disease Control Rate (DCR), Duration of Disease Control (DoDC), and Progression-Free Survival (PFS) according to mRECIST and RECIST 1.1 criteria. Overall survival (OS) and disease-specific survival (DSS) will also be evaluated.
Patient-reported outcomes will be measured through changes in Quality of Life (QoL) using the Functional Assessment of Cancer Therapy – Hepatobiliary (FACT-Hep) and EuroQol-5D (EQ-5D) scales. The trial will also explore associations between absorbed doses in tumoral and normal tissues, determined by imaging techniques such as 99mTc-MAA SPECT/CT and Y-90 PET/CT, with efficacy and safety endpoints. These assessments will be conducted at various timepoints throughout the trial, including baseline and follow-up imaging assessments.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Participants must be aged ≥18 years at the time of screening.
- Dosimetry criteria for tumor(s) and normal tissue can be determined. Please refer to Supplement B for further details
- Patients with previous liver resection or ablation ≥6 months from end of previous treatment to TheraSphere administration
- Previous transarterial chemoembolization (TACE) is permitted if: a. Previous TACE performed ≥8 months before TheraSphere administration and b. Result of previous TACE was CR and c. Current tumor is not a recurrence of previously treated lesion
- Patients with no portal vein thrombosis (PVT) Vp0, OR patients with Vp1, or Vp2 are eligible Refer to Protocol Appendix F for details regarding PVT classification.
- Patients with HBV or HCV infection must have documented HBV deoxyribonucleic acid (DNA) or HCV ribonucleic acid (RNA)status and appropriate treatment must be provided as follows a. HBV DNA ≥10 IU/mL (or above the limit of detection per local laboratory): Patient must receive antiviral therapy per institutional practice. Patients must show evidence of HBV stabilization or signs of viral response (e.g., reduction HBV DNA levels) prior to enrollment. Patients must remain on antiviral therapy for the study duration and for 6 months after the last dose of study treatment. b. HBV DNA <10 IU/mL (or under the limit of detection per local laboratory): Patients do not require antiviral therapy. These patients will be tested at every cycle to monitor HBV DNA levels and initiate antiviral therapy if HBV DNA is detected (≥10 IU/mL or above the limit of detection per local laboratory). Patients with detectable HBV DNA during the study must initiate and remain on antiviral therapy for the study duration and for 6 months after the last dose of study treatment. c. Detectable HCV RNA: Patients with active HCV infection must be managed per local institutional practice for the study duration.
- Patients with Human Immunodeficiency Virus (HIV) infection are eligible, provided the HIV infection is well controlled with no current or previous AIDS-related complications and CD4+ T-cell (CD4+) counts ≥ 350 cells/μL
- Negative urine/serum pregnancy test in females of childbearing potential
- Adequate contraception for the patient and his/her sexual partner.
- Adequate renal and marrow function as defined below: a. Hemoglobin (Hgb) ≥9.0 g/dL b. Absolute neutrophil count (ANC) ≥1.0 x 109/L c. Platelet count ≥50 x 109/L d. Measured or calculated creatinine clearance ≥40 mL/min as determined by Cockcroft-Gault (using actual body weight)
- Absolute lymphocyte count ≥0.5 X 109/L
- Written informed consent and any locally required authorization (e.g., Health Insurance Portability and Accountability Act in the 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.
- Adequate liver function, as defined by a. Child-Pugh A b. Albumin-bilirubin (ALBI) score ≤ -2 with upper limit for(i.e., ALBI score ≤ -grade 1 and subset of ALBI grade 2.). Patients with confirmed Gilbert’s syndrome may not have an evaluable bilirubin value; therefore, ALBI score should not be considered for such patients. Patients with Gilbert’s syndrome will be eligible with any bilirubin value, as long as Albumin level is ≥ 34 g/L. . c. AST and ALT <3 x ULN
- Body weight >30 kg and BMI ≥18 kg/m2.
- Life expectancy ≥6 months
- HCC, diagnosed by radiographic imaging or histology
- Patient not a candidate for liver resection, thermal ablation, or transplantation at the time of study entry.
- ECOG 0 or 1
- At least one HCC lesion measurable by mRECIST criteria (e.g. ≥10 mm of enhancement).
- Tumor volume ≤35% of whole liver volume (determined by imaging).
- Future remnant liver volume (FRLV) ≥30% of whole liver volume. FRLV is the volume of liver not planned to be treated with TheraSphere and free of HCC.
- Patients that have had previous ascites/encephalopathy episodes should be free of symptoms and of supportive treatment (lactulose or equivalent, diuretics) at study entry.
Exclusion Criteria
- Any contraindication to angiography or selective visceral catheterization.
- 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.
- 99mTc-MAA hepatic arterial perfusion scintigraphy shows poor tumor and/or portal vein thrombosis (PVT) targeting that would lead to a dose that does not meet the liver dosing criteria. Please refer to Supplement B for further details
- Shunting of blood to the lungs that could result in delivery of >30 Gy to the lungs in a single treatment, or >50 Gy cumulative dose to the lungs in case of multiple TheraSphere treatments, as seen on 99mTc-MAA hepatic arterial perfusion scintigraphy.
- Vp3, Vp4, hepatic vein invasion, or inferior vena cava (IVC) invasion
- Extrahepatic metastases (patients with extrahepatic spread [EHS]): a. EHS is any extrahepatic lesion that, according to clinical symptoms, histology, or radiological imaging data, is highly suspicious of being metastases. b. For patients with bone pain/neurological symptoms (deficit, seizure or else) at baseline and suspected of metastases at screening, a bone scan/brain MRI is recommended prior to study entry. c. Extrahepatic nontarget non-measurable lesions (<1 cm per RECIST 1.1) are acceptable if considered not suspicious by the investigator.
- Any previous systemic HCC treatment
- Prior exposure to immune mediated therapy for other disease, such as other anti-PD-1, anti-PDL-1, anti-PDL-2, anti-CTLA-4, antibodies, etc
- Previous liver radiation (external beam radiation therapy (EBRT) or peptide receptor radionuclide therapy (PRRT) or selective internal radiation therapy (SIRT).
- 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 to inclusion in this study.
- HCC with infiltrative disease that is not evaluable by mRECIST.
- Pulmonary insufficiency (defined by an arterial oxygen pressure (PaO2) of <60 mmHg, or oxygen saturation (SaO2) of <90% or clinically evident chronic obstructive pulmonary disease (COPD).
- Medical history of radiation pneumonitis or recent pneumonitis, regardless of causality
- History of any organ allograft, including bone marrow allo and autograft.
- History of active primary/acquired immunodeficiency, that makes patients unsuitable for additional immunotherapy in this study (per investigator and as detailed in exclusion criterion #17).
- Active or prior documented autoimmune or inflammatory disorders (including but not limited to auto immune hepatitis, 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 a. Patients with vitiligo or alopecia b. Patients with hypothyroidism (e.g. following Hashimoto’s syndrome) stable on hormone replacement therapy c. Any chronic skin condition that does not require systemic therapy. d. Patients without active disease in the last 5 years may be included but only after consultation with the Sponsor Study physician. e. Patients with celiac disease controlled by diet alone
- Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. The following are exceptions to this criterion: a. Intranasal, inhaled, topical steroids, or local steroid injections (e.g. intra-articular injection) b. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent. c. Steroids as premedication for hypersensitivity reactions (e.g. CT scan premedication).
- History of gastrointestinal bleeding (GI) within 42 days prior to study inclusion, active GI bleeding and any bleeding diathesis or coagulopathy that is not correctable by usual therapy or hemostatic agents (e.g. closure device). Patients with gastrointestinal bleeding related to portal hypertension that cannot be controlled with a non-selective betablocker. Patients with known varices that have not bled or which have been clinically addressed can enter the study. No endoscopic exploration is required before study inclusion.
- Presence of biliary stent or sphincterotomy within one year prior to study inclusion
- History of malignancy, other than HCC, within three years, except the condition is one of the following: a. Adequately treated carcinoma in situ of the cervix, early squamous cell carcinoma or basal cell carcinoma of the skin, localized prostate cancer, breast ductal carcinoma in situ, or low-grade endometrial carcinoma with no myometrial invasion b. Localized prostate cancer under active surveillance. c. Other cancer when there is a negligible risk of recurrence or progression or death (5-year OS rate > 90%).
- Major surgical procedure (as defined by the Investigator) within 42 days prior to study inclusion
- A history of severe allergy or intolerance to contrast agents, narcotics, sedatives, or atropine that cannot be managed medically
- Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients that cannot be managed medically
- Active infection, including: a. Tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis testing in line with local practice), b. HBV and HCV co-infection, c. HBV and Hep D co-infection, d. Human immunodeficiency virus (HIV 1/2 antibodies) plus HCV or HBV coinfection.
- 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 and who do not want to stop breastfeeding. Male or female patients of reproductive potential who are not willing to employ any effective birth control method from screening and for at least 90 days after TheraSphere administration, 90 days after the last dose of durvalumab, and 6 months after the last dose of tremelimumab.
- 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 as deemed by the site principal investigator. Patients who have stable respiratory disease adequately treated with medication are not excluded, for example COPD.
- Patients who are not able to follow the TheraSphere, durvalumab or tremelimumab treatment requirements.
- Patients that have had previous ascites/encephalopathy episode should be free of symptoms and of supportive treatment (lactulose or equivalent, diuretics) at study entry.
- For France Patients Only Persons deprived of their liberty by a judicial or administrative decision, persons subject to psychiatric care under articles L. 3212-1 and L. 3213-1 who are not covered by the provisions of Article L. 1121-8 and persons admitted to a health or social establishment for purposes other than research, including: a. Pregnant, parturient, breast-feeding women (see also inclusion criterion 16 and exclusion criterion 27) b. Minors (see also inclusion criterion 1) c. Persons receiving psychiatric treatment (see also exclusion criteria 28) d. Persons admitted to a health or social establishment for purposes other than research e. Person of full age under curatorship f. Adult subject to a mandate for future protection, a family authorization, or a guardianship measure g. Person not affiliated or not beneficiary of a social security scheme
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 31 Oct 2023 | 39 |
 Italy | Not Recruiting | 31 Oct 2023 | 3 |
 Spain | Not Recruiting | 31 Oct 2023 | 39 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Remicade 100 mg powder for concentrate for solution for infusion. | Other | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION. | INFUSION | 5 | 6 | PRD708230 |
IMFINZI 50 mg/mL concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INFUSION | 1500 | 18 | PRD6651398 |
IMJUDO 20 mg/ml concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION (STERILE CONCENTRATE). | INFUSION | 300 | 1 | PRD10239823 |
CellCept 500 mg powder for concentrate for solution for infusion | Other | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | INFUSION | 1 | 1 | PRD364728 |