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

Primary Purpose

Hepatocellular Carcinoma

Status
Active
Phase
Phase 2
Locations
France
Study Type
Interventional
Intervention
Nivolumab Injection [Opdivo]
Sponsored by
Assistance Publique - Hôpitaux de Paris
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hepatocellular Carcinoma focused on measuring nivolumab; neoadjuvant; electroporation,adjuvant

Eligibility Criteria

18 Years - 99 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Hôpital Jean Verdier

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Nivolumab Injection [Opdivo]

Arm Description

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

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Changes of tumorous and non-tumorous perfusion parameters observed with CUS and MRI after one months of neoadjuvant treatments
Evaluation performed by CUS and MRI
Per nodule rates of early response
Evaluation performed by MRI
Incidences of intra segmental/ extra segmental distant recurrence
Evaluation performed by MRI
Assessment of overall survival
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.
Assessment of tolerance of the immunotherapy treatment:
Adverse events related to Nivolumab infusions will be monitored according to manufacturer guidelines and recommendation.
Compliance to neoadjuvant treatments
Respect of scheduled Nivolumab infusions
Compliance to adjuvant treatments
Respect of scheduled Nivolumab infusions
Frequency of SAEs
adverse events related to Nivolumab infusions will be monitored according to manufacturer guidelines and recommendation.
Frequency of discontinuations treatment due to AEs
adverse events related to Nivolumab infusions will be monitored according to manufacturer guidelines and recommendation.

Full Information

First Posted
July 9, 2018
Last Updated
August 8, 2022
Sponsor
Assistance Publique - Hôpitaux de Paris
Collaborators
Bristol-Myers Squibb
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1. Study Identification

Unique Protocol Identification Number
NCT03630640
Brief Title
Neoadjuvant and Adjuvant Nivolumab in HCC Patients Treated by Electroporation
Acronym
NIVOLEP
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.
Study Type
Interventional

2. Study Status

Record Verification Date
August 2022
Overall Recruitment Status
Active, not recruiting
Study Start Date
October 11, 2018 (Actual)
Primary Completion Date
November 11, 2023 (Anticipated)
Study Completion Date
November 30, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Assistance Publique - Hôpitaux de Paris
Collaborators
Bristol-Myers Squibb

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hepatocellular Carcinoma
Keywords
nivolumab; neoadjuvant; electroporation,adjuvant

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Model Description
Clinical study phase II
Masking
None (Open Label)
Allocation
N/A
Enrollment
43 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Nivolumab Injection [Opdivo]
Arm Type
Experimental
Arm Description
Intravenous Nivolumab 240 Q2W neoadjuvant Intravenous Nivolumab 480 mg Q4W- adjuvant for 12 months
Intervention Type
Drug
Intervention Name(s)
Nivolumab Injection [Opdivo]
Other Intervention Name(s)
Irreversible electroporation
Intervention Description
Intravenous Nivolumab 240 Q2W neoadjuvant Intravenous Nivolumab 480 mg Q4W- adjuvant up to 12 months after EP
Primary Outcome Measure Information:
Title
Local recurrence-free survival during a 1-year follow-up after Nivolumab neoadjuvant/adjuvant therapy and EP procedure
Description
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.
Time Frame
At 1 year
Secondary Outcome Measure Information:
Title
Changes of tumorous and non-tumorous perfusion parameters observed with CUS and MRI after one months of neoadjuvant treatments
Description
Evaluation performed by CUS and MRI
Time Frame
after one month of neoadjuvant treatment
Title
Per nodule rates of early response
Description
Evaluation performed by MRI
Time Frame
At one month after a single procedure of EP
Title
Incidences of intra segmental/ extra segmental distant recurrence
Description
Evaluation performed by MRI
Time Frame
During follow-up (2 yrs)
Title
Assessment of overall survival
Description
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.
Time Frame
At 2-yrs following EP procedure
Title
Assessment of tolerance of the immunotherapy treatment:
Description
Adverse events related to Nivolumab infusions will be monitored according to manufacturer guidelines and recommendation.
Time Frame
During follow-up (2 yrs)
Title
Compliance to neoadjuvant treatments
Description
Respect of scheduled Nivolumab infusions
Time Frame
During follow-up (13 months)
Title
Compliance to adjuvant treatments
Description
Respect of scheduled Nivolumab infusions
Time Frame
During follow-up (13 months)
Title
Frequency of SAEs
Description
adverse events related to Nivolumab infusions will be monitored according to manufacturer guidelines and recommendation.
Time Frame
During follow-up (2 yrs)
Title
Frequency of discontinuations treatment due to AEs
Description
adverse events related to Nivolumab infusions will be monitored according to manufacturer guidelines and recommendation.
Time Frame
During follow-up (2 yrs)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
99 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Pierre NAHON, MD,PhD
Organizational Affiliation
APHP-Hôpital Jean Verdier
Official's Role
Principal Investigator
Facility Information:
Facility Name
Hôpital Jean Verdier
City
Bondy
ZIP/Postal Code
93140
Country
France

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
28453431
Citation
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.
Results Reference
background
PubMed Identifier
26361969
Citation
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.
Results Reference
background
PubMed Identifier
28434648
Citation
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.
Results Reference
background

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Neoadjuvant and Adjuvant Nivolumab in HCC Patients Treated by Electroporation

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