Neoadjuvant and Adjuvant Nivolumab in HCC Patients Treated by Electroporation

NCT03630640 | Completed Phase 2 DMC

• 1 other identifier: P171001J
• Study Type: interventional
• Target: 43
• Locations: 1 country
• Sites: 1

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.

Conditions

Hepatocellular Carcinoma

Keywords

nivolumab; neoadjuvant; electroporation,adjuvant

Outcome Measures

Primary Outcomes (1)

• Local recurrence-free survival during a 1-year follow-up after Nivolumab neoadjuvant/adjuvant therapy and EP procedure

  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.

  At 1 year

Secondary Outcomes (9)

• Changes of tumorous and non-tumorous perfusion parameters observed with CUS and MRI after one months of neoadjuvant treatments

  after one month of neoadjuvant treatment

• Per nodule rates of early response

  At one month after a single procedure of EP

• Incidences of intra segmental/ extra segmental distant recurrence

  During follow-up (2 yrs)

• Assessment of overall survival

  At 2-yrs following EP procedure

• Assessment of tolerance of the immunotherapy treatment:

  During follow-up (2 yrs)

Study Arms (1)

Nivolumab Injection [Opdivo]

EXPERIMENTAL

Intravenous Nivolumab 240 Q2W neoadjuvant Intravenous Nivolumab 480 mg Q4W- adjuvant for 12 months

Drug: Nivolumab Injection [Opdivo]

Interventions

Nivolumab Injection [Opdivo] DRUG

Intravenous Nivolumab 240 Q2W neoadjuvant Intravenous Nivolumab 480 mg Q4W- adjuvant up to 12 months after EP

Also known as: Irreversible electroporation

Nivolumab Injection [Opdivo]

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead
• Bristol-Myers Squibb: collaborator

Study Sites (1)

Hôpital Jean Verdier

Bondy, 93140, France

Location

Related Publications (3)

• 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.

  PMID: 28453431 BACKGROUND

• 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.

  PMID: 26361969 BACKGROUND

• 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.

  PMID: 28434648 BACKGROUND

MeSH Terms

Conditions

Carcinoma, Hepatocellular

Interventions

Nivolumab; Electroporation

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Cytological Techniques; Clinical Laboratory Techniques; Investigative Techniques; Electrochemical Techniques

Study Officials

• Pierre NAHON, MD,PhD

  APHP-Hôpital Jean Verdier

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Clinical study phase II

Study Record Dates

• First Submitted: July 9, 2018
• First Posted: August 15, 2018
• Study Start: October 11, 2018
• Primary Completion: September 30, 2022
• Study Completion: August 19, 2023
• Last Updated: July 31, 2024

Record last verified: 2022-07

Data Sharing

• IPD Sharing: Will not share

Locations

FR (1)