Neoadjuvant and Adjuvant Durvalumab and Tremelimumab in Hepatocellular Carcinoma Patients Undergoing Curative Percutaneous Ablation
- Trial ID
- 2024-515768-30-01
- Protocol
- APHP220729
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to assess **local recurrence-free survival** at 1-year following neoadjuvant Durvalumab/Tremelimumab and adjuvant Durvalumab therapy associated with percutaneous ablation procedure in patients with Barcelona Clinic Liver Cancer A **hepatocellular carcinoma**. This is clinically relevant as it aims to evaluate the effectiveness of combining immunotherapy with a curative intent procedure, potentially improving patient outcomes by reducing the risk of cancer recurrence.
Secondary objectives include:
- Assessing changes in tumorous and non-tumorous perfusion parameters observed with MRI or CT scan after one month of neoadjuvant treatments.
- Evaluating per nodule rates of early response one month after a single procedure of percutaneous ablation (PA).
- Determining incidences of intra-segmental and extra-segmental distant recurrence.
- Assessing overall survival at 1-year following the PA procedure.
- Evaluating the adherence to the scheduled PA procedure in relation to potential serious adverse events (SAEs) during the neoadjuvant phase.
- Assessing compliance to neoadjuvant and adjuvant treatments.
- Evaluating the tolerance of Durvalumab/Tremelimumab in the context of neo- and adjuvant therapy to PA.
- For biomarker studies, assessing histopathological and molecular features of non-tumoral and tumor tissue after the neoadjuvant phase on sequential biopsies before the PA procedure.
- Assessing early effects of neoadjuvant Durvalumab/Tremelimumab on the tumor before PA, judged by histology, radiology, and sequential serum markers, including immunophenotyping of lymphocyte populations, circulating cytokine and chemokine assays, changes in inflammatory infiltrates, and expression of immunity-modulating genes.
- Studying changes in cytokine/chemokine profiling on sequential serum samples of patients before and after treatment, as well as evaluating sequential liquid biopsy on plasma samples.
Participants
The clinical trial focuses on patients diagnosed with **hepatocellular carcinoma**, specifically those classified under the Barcelona Clinic Liver Cancer A stage. The study population includes both male and female participants aged 18 years and older. Participants are required to have a general health status that allows for adequate bone marrow, liver, and renal function, as indicated by specific laboratory tests. The trial does not involve a vulnerable population. The sponsor has not provided the total number of participants. Selection criteria include lifestyle considerations such as the management of HCV according to international recommendations and antiviral therapy for HBV active infection or inactive carriage. Participants must have a life expectancy of at least three months and be willing to comply with the study protocol, including treatment and follow-up visits. Key inclusion criteria involve having at least one lesion qualifying as a RECIST 1.1 target lesion and a body weight greater than 30 kg. Women of childbearing potential are required to use effective contraception during the study and for three months after the last infusion of durvalumab. Participants must be affiliated with a Social Security System and provide written informed consent.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of **Durvalumab** and **Tremelimumab** in patients with **hepatocellular carcinoma** (HCC) undergoing a percutaneous ablation procedure. This is a Phase II, randomized, double-blind, controlled trial with a primary objective to assess local recurrence-free survival at one year. The trial is expected to commence recruitment on March 28, 2024, and conclude by September 27, 2027. Participants will be randomly assigned to receive either the investigational drugs or a control, with the study drugs administered via intravenous infusion.
The trial will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor treatment response and safety, and an end-of-study visit to assess final outcomes. The inclusion visit will involve comprehensive assessments, including imaging studies such as CT or MRI, to establish baseline disease characteristics. Follow-up visits will occur at specified intervals to evaluate changes in tumor size and perfusion parameters, as well as to monitor for any adverse events. The end-of-study visit will focus on determining the primary endpoint of local recurrence-free survival and secondary endpoints such as overall survival and treatment-related adverse events.
Participant involvement is anticipated to last up to 12 months, depending on individual treatment response and disease progression. Conditions that may lead to early termination from the study include significant adverse events, non-compliance with the study protocol, or disease progression that necessitates alternative therapeutic interventions. The trial will adhere to rigorous ethical standards, ensuring that all participants provide informed consent and meet the specified inclusion criteria, such as adequate organ function and a life expectancy of at least three months.
Treatment
The clinical trial involves the administration of **Tremelimumab**, an experimental medication formulated as a **solution for infusion**. Tremelimumab is a protein-based therapeutic agent, specifically classified under the category "Protein - Other." The medication is administered via **intravenous infusion**. The maximum daily dose is 300 mg, with a total dose not exceeding 300 mg over the treatment period. The treatment duration is limited to one cycle, and the medication is provided in batches specifically for clinical trial use, differing from commercial batches primarily in packaging. Participant compliance with the dosing schedule is monitored throughout the trial.
In addition to Tremelimumab, the trial also includes the administration of **Durvalumab**, marketed under the name **IMFINZI 50 mg/mL concentrate for solution for infusion**. Durvalumab is also a protein-based therapeutic agent, administered as a **solution for infusion** via **intravenous infusion**. The maximum daily dose for Durvalumab is 1500 mg, with a total dose not exceeding 18000 mg over a maximum treatment period of 12 cycles. This medication is authorized for use in the European Union under the marketing authorization number EU/1/18/1322/001. Compliance with the dosing regimen is closely monitored to ensure adherence to the protocol.
No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the trial documentation. The trial aims to evaluate the efficacy of these medications in the neoadjuvant and adjuvant settings for patients with hepatocellular carcinoma treated with a percutaneous ablation procedure.
Efficacy
Efficacy in the clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint is the one-year **local recurrence-free survival** following neoadjuvant and adjuvant therapy with Durvalumab and Tremelimumab in patients with hepatocellular carcinoma (HCC) treated by percutaneous ablation. This will be measured at the one-year mark post-treatment to determine the absence of local recurrence.
Secondary endpoints include several parameters: changes in tumorous and non-tumorous perfusion parameters observed with CT scan or MRI after one month of neoadjuvant treatment, changes in the size of nodules following the neoadjuvant course, and nodule rates of early response after a single procedure of percutaneous ablation. Additionally, incidences of intra-segmental and extra-segmental distant recurrence, one-year overall survival, and treatment-related adverse events will be monitored. Compliance with scheduled Durvalumab and Tremelimumab infusions, frequency of serious adverse events (SAEs), and discontinuations due to adverse events (AEs) will also be evaluated.
For biomarker studies, assessments will include tumor architecture and cytology from inclusion to the percutaneous ablation procedure, evaluated up to 30 days. This includes the absence of tumor cells and the assessment of intra- and extra-tumoral inflammatory infiltrate. Gene expression changes will be assessed through sequential whole exome sequencing. These assessments will be conducted using binary and semi-quantitative scales, with clustering analyses for gene expression changes.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Male or female patients ≥ 18 years of age. For patients aged 80 years and older, inclusion requires a systematic oncogeriatric assessment, as recommended by the Data Safety Monitoring Board (DSMB)
- Written informed consent signed (patients must be free from tutelle, curatelle or sauvegarde de justice)
- Histological or radiological diagnosis of HCC
- Patients with newly diagnosed or recurrent HCC (following a previous curative procedure performed at least 6 months before inclusion) eligible for PA prcoedure as assessed by multidisciplinary board corresponding to BCLC A stage: Uninodular HCC ≥ 2 cm and ≤ 5 cm, no macroscopic vascular invasion Multinodular maximum 3 nodules ≤ 3 cm, Body weight >30 kg Liver function status Child-Pugh Class A <><
- Adequate bone marrow, liver and renal function as assessed by the following laboratory tests: Total bilirubin ≤ 2 mg/dL Serum creatinine ≤ 1.5 x ULN Lipase ≤ 2 x ULN Prothrombine time-international normalized ratio (PT-INR) < 2.3 and PTT < 1.5 Glomerular Filtration Rate (GFR) ≥ 30 mL/min/1.73 m2
- Life expectancy ≥ 3 months
- Female of childbearing potential (WOCBP) or male or female patients of reproductive potential must to employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy or 180 days after the last dose of durvalumab and tremelimumab combination therapy
- Patients affiliated to a Social Security System
- Haemoglobin ≥9.0 g/dL
- Absolute neutrophil count (ANC ≥1.0 × 109 /L)
- Platelet count ≥75 × 109/L
- Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). (This will not apply to patients with confirmed Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician
- AST (SGOT) and ALT (SGPT) ≤5x ULN
- Measured creatinine clearance (CL) must exceed 40 mL/min. For the estimation of glomerular filtration rate (eGFR), the Cockcroft-Gault equation was applied in patients aged ≤65 years, while the MDRD equation was used for those older than 65 years
- Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
- At least 1 lesion, not previously irradiated, that qualifies as a RECIST 1.1 target lesion (TL) at preinclusion/inclusion. Tumor assessment by computed tomography (CT) scan or magnetic resonance imaging (MRI) must be performed within 28 days prior to inclusion
- Patients with HCV infection (as characterized by the presence of detectable HCV ribonucleic acid (RNA) or anti-HCV antibody) must be managed per local institutional practice
- Antiviral therapy in case of HBV active infection or inactive carriage
Exclusion Criteria
- Patients with contraindications to PA procedure (Pacemakers or patients who have a history of cardiac arrhythmias or irregular heartbeats considered as contraindication to IRE, ascites, Coagulopathy, Ongoing infection)
- Congestive heart failure New York Heart Association (NYHA) ≥ class 2
- Unstable angina or myocardial infarction within the past 6 months before enrolment
- Grade 3 (severe) hypertension ≥180 and/or ≥110 mmHG (systolic and diastolic, according to National Heart Foundation 2016)
- Patients with phaeochromocytoma
- Refractory ascites according to EASL guidelines definition (ascites that cannot be mobilized or the early recurrence of which cannot be prevented because of a lack of response to sodium restriction and diuretic treatment)
- Persistent proteinuria of NCI-CTCAE version 5.0 ≥ Grade 3
- Ongoing infection > Grade 2 according to NCI-CTCAE version 5.0
- Clinically significant bleeding NCI-CTCAE version 5.0 ≥ Grade 3 within 30 days before enrolment
- Any psychological, familial, sociological, geographical or illness or medical condition that could jeopardize the safety of the patient and/or his compliance with the study protocol and follow-up procedure
- Known history of human immunodeficiency virus (HIV) infection
- Patients with contraindication to contrast medium intravenous injection either gadolinium or iodinate
- Non-healing wound, ulcer or bone fracture
- Known hypersensitivity to the study drug or excipients in the formulation
- Any malabsorption condition
- Breast feeding
- Pregnancy
- Participation in another clinical study with an investigational product during the last 6 months
- Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study
- Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria. - Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician. - Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab or tremelimumab may be included only after consultation with the Study Physician.
- Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non–cancer-related conditions (e.g., hormone replacement therapy) is acceptable. <>
- Prior liver transplantation
- Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP. Note: Local surgery of isolated lesions for palliative intent is acceptable.
- History of allogenic organ transplantation
- Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this criterion: - Patients with vitiligo or alopecia - Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement - 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 study physician - Patients with celiac disease controlled by diet alone
- Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, 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 AEs or compromise the ability of the patient to give written informed consent
- History of another primary malignancy except for - Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of IP and of low potential risk for recurrence - Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease - Adequately treated carcinoma in situ without evidence of disease
- History of leptomeningeal carcinomatosis
- Study excludes patients with brain metastases or spinal cord compression: Patients with suspected brain metastases at screening should have an MRI (preferred) or CT each preferably with IV contrast of the brain prior to study entry. Brain metastases will not be recorded as RECIST Target Lesions at baseline if study allows patients with brain metastases.
- Has untreated central nervous system (CNS) metastases and/or carcinomatous meningitis identified either on the baseline brain imaging (RECIST)) for details on the imaging modality) obtained during the screening period or identified prior to signing the ICF. Patients whose brain metastases have been treated may participate provided they show radiographic stability (defined as 2 brain images, both of which are obtained after treatment to the brain metastases. These imaging scans should both be obtained at least four weeks apart and show no evidence of intracranial progression). In addition, any neurologic symptoms that developed either as a result of the brain metastases or their treatment must have resolved or be stable either, without the use of steroids, or are stable on a steroid dose of ≤10mg/day of prednisone or its equivalent <> for at least 14 days prior to the start of treatment. Brain metastases will not be recorded as RECIST Target Lesions at baseline.
- QT interval measurement one one ECG
- History of active primary immunodeficiency
- Known to have tested positive for human immunodeficiency virus (HIV) (positive HIV 1/2 antibodies) or active tuberculosis infection (clinical evaluation that may include clinical history, physical examination and radiographic findings, or tuberculosis testing in line with local practice).
- Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab or tremelimumab. The following are exceptions to this criterion: - Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular 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)
- Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after the last dose of IP.
- Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients
- Prior randomisation or treatment in a previous durvalumab and/or tremelimumab clinical study regardless of treatment arm assignment
- Patients who have received prior anti–PD-1, anti–PD-L1 or anti–CTLA-4: - Must not have experienced a toxicity that led to permanent discontinuation of prior immunotherapy. - All AEs while receiving prior immunotherapy must have completely resolved or resolved to baseline prior to screening for this study. - Must not have experienced a ≥Grade 3 immune related AE or an immune related neurologic or ocular AE of any grade while receiving prior immunotherapy NOTE: Patients with endocrine AE of ≤Grade 2 are permitted to enroll if they are stably maintained on appropriate replacement therapy and are asymptomatic. - Must not have required the use of additional immunosuppression other than corticosteroids for the management of an AE, not have experienced recurrence of an AE if re-challenged, and not currently require maintenance doses of > 10 mg prednisone or equivalent per day.
- Prior systemic treatment for HCC, in particular agents targeting T-cell costimulation or checkpoint pathways (including those targeting PD-1, PD-L1 or PD-L2, CD137, or cytotoxic T-lymphocyte antigen [CTLA-4]).
- Patients with large esophageal varices at risk of bleeding that are not being treated with conventional medical intervention
- Past or concurrent history of neoplasm other than HCC, except for in situ carcinoma of the cervix uteri and/or non-melanoma skin cancer and superficial bladder tumors. Any cancer curatively treated > 3 years prior to study entry is permitted
- Major surgical procedure or significant traumatic injury within 28 days before enrolment (note: local surgery for isolated lesions for palliative purposes is acceptable)
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Recruiting | 28 Mar 2024 | 30 |
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 |
|---|---|---|---|---|---|---|
IMFINZI 50 mg/mL concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENIOUS INFUSION | 1500 | 12 | PRD6651398 |
TREMELIMUMAB | Test | — | INTRAVENOUS INFUSION | 300 | 1 | SUB37101 |