Overview

This project is a Phase 2 trial testing the safety and efficacy of treatment with Durvalumab/Tremelimumab in neoadjuvant and Durvalumab in adjuvant setting in patients with BCLC A HCC treated by percutaneous irreversible electroporation (IRE) in a curative intent.

DUMELEP is a Multicentre, Phase 2 trial

Eligible patients will receive consecutively:

1. 1 Durvalumab 1500 mg/Tremelimumab 300 mg infusion in a neoadjuvant setting
2. IRE procedure in a curative attempt at Day 30
3. 11 monthly Durvalumab 1500 mg infusions.
4. Classical follow-up during an additional year (every 3 months)

Eligibility

Inclusion Criteria:

• Male or female patients ≥ 18 years of age
  • 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 IRE 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
  • At least one uni-dimensional measurable lesion by computed tomography (CT) scan or magnetic resonance imaging (MRI) according to modified RECIST for HCC
  • Liver function status Child-Pugh Class A
  • <<Eastern Cooperative Oncology Group (ECOG)>><<World Health Organisation (WHO) performance status of 0 or 1
  • 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
  • Prothrombin 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
  • Women of childbearing potential (WOCBP) need to accept one effective method of contraception until 3 months after the last infusion of durvalumab and avoid pregnancy
  • Patients affiliated to a Social Security System
  • Written informed consent signed
  • 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) >40 mL/min or Calculated creatinine clearance CL>40 mL/min by the Cockcroft-Gault formula
  • 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.
  • Patients must have a life expectancy of at least 12 weeks
  • At least 1 lesion, not previously irradiated, that qualifies as a RECIST 1.1 target lesion (TL) at baseline. Tumor assessment by computed tomography (CT) scan or magnetic resonance imaging (MRI) must be performed within 28 days prior to inclusion

Exclusion Criteria:

• Patients with contraindications to IRE (Pacemakers or patients who have a history of cardiac arrhythmias or irregular heartbeats, ascites, Coagulopathy, Ongoing infection)
• Patients with contraindication to contrast medium intravenous injection either gadolinium or iodinate
• Prior liver transplantation
• Uncontrolled HCC defined by the absence of remission > 6months following resection of percutaneous ablation at time of inclusion
• 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 uncontrolled HBV infection and viral load above 100 IU/mL.
• 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
• 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. Hepatitis B is allowed if no active replication is present (HBV replication below 100 IU/mL). Hepatitis C is allowed if no antiviral treatment is required
• 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
• Non-healing wound, ulcer or bone fracture
• Known hypersensitivity to the study drug or excipients in the formulation
• Any malabsorption condition
• Breast feeding
• Pregnancy
• 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 monotherapy or 180 days after the last dose of durvalumab and tremelimumab combination therapy.
• 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
  1. Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician.
  2. 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. <<amend as required based on any combination studies with other anticancer agents>>

• 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

  f) Patients with vitiligo or alopecia g) Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement h) Any chronic skin condition that does not require systemic therapy i) Patients without active disease in the last 5 years may be included but only after consultation with the study physician j) 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 <<and
        anti-convulsants>> for at least 14 days prior to the start of treatment. Brain metastases
        will not be recorded as RECIST Target Lesions at baseline.
          -  Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms
             calculated from 3 ECGs (within 15 minutes at 5 minutes apart)
          -  Patients with HBV infection (as characterized by positive hepatitis B virus surface
             antigen [HBsAg] and/or anti-hepatitis B core antibodies (HBcAbs) with detectable HBV
             deoxyribonucleic acid (DNA) [≥10 IU/mL or above the limit of detection per local
             laboratory]) must receive antiviral therapy at least after enrollment (sign of ICF)
             per institutional practice to ensure adequate viral suppression (HBV DNA ≤2000 IU/mL)
             prior to inclusion. Patients must remain on antiviral therapy for the study duration
             and for 6 months after the last dose of study treatment. Patients who test positive
             for anti-HBcAb with undetectable HBV DNA (<10 IU/mL or under the limit of detection
             per local laboratory) 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.
          -  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 for the study and for 6 months after the last dose of study treatment.
          -  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:
             d) Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra
             articular injection) e) Systemic corticosteroids at physiologic doses not to exceed 10
             mg/day of prednisone or its equivalent f) 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.
          -  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 monotherapy or180 days after
             the last dose of durvalumab and tremelimumab combination therapy.
          -  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:
             e) Must not have experienced a toxicity that led to permanent discontinuation of prior
             immunotherapy.
             f) All AEs while receiving prior immunotherapy must have completely resolved or
             resolved to baseline prior to screening for this study.
             g) 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.
             h) 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.
          -  Presence of any portal vein thrombosis before IRE procedure