Neoadjuvant and Adjuvant Nivolumab in HCC Patients Treated by Electroporation (NIVOLEP)

• ClinicalTrials.gov Identifier: NCT03630640
• Recruitment Status: Active, not recruiting
• First Posted: August 15, 2018
• Last Update Posted: August 10, 2022
• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborator: Bristol-Myers Squibb
• Information provided by (Responsible Party): Assistance Publique - Hôpitaux de Paris

Study Description

Brief Summary:

Percutaneous ablation (PA) is the only non-surgical curative treatment of hepatocellular carcinoma (HCC). Due to its excellent tolerance, particularly in patients with portal hypertension or bearing comorbidities, it now represents in France nearly 70% of the first-line curative treatment of "in Milan" tumours. For HCC less than 3 cm, ideal indication for percutaneous ablations, results of monopolar radiofrequency ablation (mRFA), are excellent with only 5% of reported non-tumoral control after a first procedure .

In addition to mRFA the arsenal of ablations has grown considerably with the emergence of new techniques. They allow the expansion of indications for PA, especially in patients with poor prognostic tumors or relatively advanced beyond the Milan criteria . In this setting, multibipolar mode using no touch technique (mbpRFAnt) increases the tumour volume that can be ablated, allowing the removal of large tumors> 5 cm . Furthermore, electroporation (EP) is a new PA technique that does not promote thermoablation but induce tumoral cells apoptosis and is particularly interesting for difficult-to-treat lesions located near vascular or biliary trunks . Inadequate tumour control is then de facto greater in these situations, around 20% at one year.

The idea of optimizing HCC curative treatments using neoadjuvant or adjuvant biotherapy, particularly in patients with advanced tumors in curative intent, is particularly attractive. One trial in adjuvant setting was conducted, the STORM trial, that tested the benefit of sorafenib in curative intent of in Milan HCC. This negative trial included patients with in Milan HCC, with an expected low rate of recurrence with only few patients treated by PA.

In parallel, the development of new molecules for HCC treatment, especially immunotherapy, seems to give promising results in palliative setting . Furthermore, PA procedures and most likely electroporation induce T-cell recruitement that may foster immunomodulation .

Neoadjuvant and adjuvant trials using these new molecules must now be cautiously designed based on the rigorous selection of special populations and therapeutic indications.

This project proposes a Phase 2 trial testing the safety and efficacy of treatment with Nivolumab in neoadjuvant and adjuvant setting in patients with advanced HCC treated by electroporation in curative intent.

Condition or disease	Intervention/treatment	Phase
Hepatocellular Carcinoma	Drug: Nivolumab Injection [Opdivo]	Phase 2

Detailed Description:

Multicenter (6 centers), Phase 2 trial.

-Inclusion visit The inclusion visit takes place between 15 days and no later than 3 days before the patient's hospitalization for Neoadjuvant therapy

Eligible patients will receive :

• 2 nivolumab infusions in a neoadjuvant setting (every 15 days) The treatment will be carried out every 2 weeks s, for 2 cycles before EP procedure The patient is hospitalized one day for treatment
• EP procedure performed in a curative attempt EP procedure will be performed according to previously described procedure in the setting of routine management of HCC as decided in multidisciplinary boards in each centre.
• 12 nivolumab infusions in an adjuvant setting (every 30 days) during one year. The patient is hospitalized one day for infusion
• Classical follow-up during an additional year (every 3 months) Follow up after adjuvant therapy (M12-M24) The usual evaluation will be performed every 3 months

Constitution of a biobank with :

• paraffin and frozen tumoral and non tumoral biopsy sampled at before and after one month of neoadjuvant Nivolumab (second biopsies at the time of the electroporation procedure)
• Serum samples and Peripheral blood mononuclear cells (PBMC) before and after one month of neoadjuvant Nivolumab then after EP at 1, 3, 6, 9 and 12 months after procedure.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 43 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: Clinical study phase II
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Immunotherapy by Nivolumab in Neoadjuvant and Adjuvant Setting in Patients With Advanced HCC Treated by Electroporation in Curative Intent: French Multicenter Phase 2 Therapeutic Trial.
• Actual Study Start Date: October 11, 2018
• Estimated Primary Completion Date: November 11, 2023
• Estimated Study Completion Date: November 30, 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Nivolumab Injection [Opdivo]; Intravenous Nivolumab 240 Q2W neoadjuvant Intravenous Nivolumab 480 mg Q4W- adjuvant for 12 months	Drug: Nivolumab Injection [Opdivo]; Intravenous Nivolumab 240 Q2W neoadjuvant Intravenous Nivolumab 480 mg Q4W- adjuvant up to 12 months after EP; Other Name: Irreversible electroporation

Outcome Measures

Primary Outcome Measures :

1. Local recurrence-free survival during a 1-year follow-up after Nivolumab neoadjuvant/adjuvant therapy and EP procedure [ Time Frame: At 1 year ]
   Recurrence rates (whether local or distant) will be assessed using imaging techniques as recommended by international guidelines (3-months US and MRI during two years). Patients who will meet primary endpoint will be alive 1 year after EP procedure without evidence of local recurrence on 3-months US/MRI evaluations.

Secondary Outcome Measures :

1. Changes of tumorous and non-tumorous perfusion parameters observed with CUS and MRI after one months of neoadjuvant treatments [ Time Frame: after one month of neoadjuvant treatment ]
   Evaluation performed by CUS and MRI
2. Per nodule rates of early response [ Time Frame: At one month after a single procedure of EP ]
   Evaluation performed by MRI
3. Incidences of intra segmental/ extra segmental distant recurrence [ Time Frame: During follow-up (2 yrs) ]
   Evaluation performed by MRI
4. Assessment of overall survival [ Time Frame: At 2-yrs following EP procedure ]
   patients will meet this endpoint if they are alive with or without HCC recurrence 2 years after EP. procedures. Causes and date of death will be specified when applicable during this timeframe.
5. Assessment of tolerance of the immunotherapy treatment: [ Time Frame: During follow-up (2 yrs) ]
   Adverse events related to Nivolumab infusions will be monitored according to manufacturer guidelines and recommendation.
6. Compliance to neoadjuvant treatments [ Time Frame: During follow-up (13 months) ]
   Respect of scheduled Nivolumab infusions
7. Compliance to adjuvant treatments [ Time Frame: During follow-up (13 months) ]
   Respect of scheduled Nivolumab infusions
8. Frequency of SAEs [ Time Frame: During follow-up (2 yrs) ]
   adverse events related to Nivolumab infusions will be monitored according to manufacturer guidelines and recommendation.
9. Frequency of discontinuations treatment due to AEs [ Time Frame: During follow-up (2 yrs) ]
   adverse events related to Nivolumab infusions will be monitored according to manufacturer guidelines and recommendation.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 99 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Male or female patients ≥ 18 years of age
• Histological diagnosis of HCC, whether new or recurrent following a prior curative therapeutic management > 6 months.
• Barcelona Clinical Liver Cancer(BCLC) stage Category A

• Patients with HCC eligible for EP as assessed by multidisciplinary board corresponding to the following extension:

  • Uninodular HCC≥ 2 cm and ≤ 5 cm, no macroscopic vascular invasion
  • Multinodular HCC maximum 3 nodules ≤ 3 cm, no macroscopic vascular invasion
• 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) Performance Status ≤ 2
• Adequate bone marrow, liver and renal function
• Life expectancy ≥ 3 months
• Women of childbearing potential and men must agree to use adequate contraception
• Patients affiliated to a Social Security System
• Written informed consent signed

Exclusion Criteria:

• Patients with contraindications to EP (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 or candidates for liver transplantation
• 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
• Known history or symptomatic metastatic brain or meningeal tumors
• 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 4.0 ≥ Grade 3
• Ongoing infection > Grade 2 according to NCI-CTCAE version 4.0. 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 4.0 ≥ Grade 3 within 30 days before enrolment
• Arterial or venous thrombotic or embolic events such as cerebrovascular accident, deep vein thrombosis or pulmonary embolism within 6 months 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
• Seizure disorder requiring medication
• Non-healing wound, ulcer or bone fracture
• Known hypersensitivity to the study drug or excipients in the formulation
• Any malabsorption condition
• Breast feeding
• Pregnancy

Contacts and Locations

Locations

France

Hôpital Jean Verdier

Bondy, France, 93140

Sponsors and Collaborators

Assistance Publique - Hôpitaux de Paris

Bristol-Myers Squibb

Investigators

• Principal Investigator: Pierre NAHON, MD,PhD; APHP-Hôpital Jean Verdier

More Information

Publications:

Sutter O, Calvo J, N'Kontchou G, Nault JC, Ourabia R, Nahon P, Ganne-Carrie N, Bourcier V, Zentar N, Bouhafs F, Sellier N, Diallo A, Seror O. Safety and Efficacy of Irreversible Electroporation for the Treatment of Hepatocellular Carcinoma Not Amenable to Thermal Ablation Techniques: A Retrospective Single-Center Case Series. Radiology. 2017 Sep;284(3):877-886. doi: 10.1148/radiol.2017161413. Epub 2017 Apr 28.

Bruix J, Takayama T, Mazzaferro V, Chau GY, Yang J, Kudo M, Cai J, Poon RT, Han KH, Tak WY, Lee HC, Song T, Roayaie S, Bolondi L, Lee KS, Makuuchi M, Souza F, Berre MA, Meinhardt G, Llovet JM; STORM investigators. Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2015 Oct;16(13):1344-54. doi: 10.1016/S1470-2045(15)00198-9. Epub 2015 Sep 8.

El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, Kim TY, Choo SP, Trojan J, Welling TH Rd, Meyer T, Kang YK, Yeo W, Chopra A, Anderson J, Dela Cruz C, Lang L, Neely J, Tang H, Dastani HB, Melero I. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017 Jun 24;389(10088):2492-2502. doi: 10.1016/S0140-6736(17)31046-2. Epub 2017 Apr 20.

• Responsible Party: Assistance Publique - Hôpitaux de Paris
• ClinicalTrials.gov Identifier: NCT03630640
• Other Study ID Numbers: P171001J
• First Posted: August 15, 2018
• Last Update Posted: August 10, 2022
• Last Verified: August 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Assistance Publique - Hôpitaux de Paris:

nivolumab; neoadjuvant; electroporation,adjuvant

Additional relevant MeSH terms:

Carcinoma, Hepatocellular; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases; Nivolumab; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immune Checkpoint Inhibitors; Molecular Mechanisms of Pharmacological Action