Nivolumab With Gemcitabine, Oxaliplatin + Rituximab in r/r Elderly Lymphoma Patients (NIVEAU)

Improvement of Outcome in Elderly Patients or Patients Not Eligible for High-dose Chemotherapy With Aggressive NHL in First Relapse/Progression by Adding Nivolumab to Gemcitabine, Oxaliplatin Plus Rituximab in Case of B-cell Lymphoma

This study evaluates the addition of nivolumab to gemcitabine, oxaliplatin plus rituximab in case of B-cell lymphoma

Study Overview

• Status: Completed
• Conditions: Lymphoma, Non-Hodgkin
• Intervention / Treatment: Drug: Rituximab; Drug: Gemcitabine; Device: Oxaliplatin; Drug: Nivolumab

Detailed Description

International, multicentre, randomised, open-label, treatment optimisation study, preceded by safety run-in phases conducted for B-cell and T-cell lymphoma separately.

• Study Type: Interventional
• Enrollment (Actual): 348
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Austria
  • Feldkirch, Austria
    • Landeskrankenhaus Feldkirch
  • Innsbruck, Austria
    • Innsbruck University Hospital
  • Linz, Austria
    • Ordensklinikum Linz - Elisabethinen
  • Linz, Austria
    • Kepler Universitätsklinikum GmbH- Med. Campus III
  • Linz, Austria
    • Ordensklinikum Linz - Krankenhaus der Barmherzigen Schwestern Linz
  • Salzburg, Austria
    • Paracelsus Medical University Salzburg
  • Wels, Austria
    • Klinikum Wels-Grieskirchen GmbH
  • Wien, Austria
    • Universitätsklinik für Innere Medizin I, AKH Wien
• Belgium
  • Brüssel, Belgium
    • INSTITUT JULES BORDET -Hematology
  • Brüssel, Belgium
    • UNIVERSITE CATHOLIQUE DE LOUVAIN SAINT-LUC - Hematology
  • Gent, Belgium
    • UNIVERSITAIR ZIEKENHUIS GENT - Hematology
  • Liège, Belgium
    • CHU DE LIEGE - Hematology
  • Yvoir, Belgium
    • UNIVERSITE CATHOLIQUE DE LOUVAIN MONT GODINNE - Hematology
• France
  • Caen, France
    • CHU Côte de Nacre - Service Hématologie Clinique
  • Créteil Cedex, France
    • Hôpital Henri Mondor - Unité "Hémopathies Lymphoïdes" - HDJ 11è
  • Dijon, France
    • CHU Dijon - Hôpital d'Enfants - Hématologie Clinique
  • Grenoble, France
    • CHU de Grenoble - Hôpital Albert Michallon - Hématologie Clinique
  • La Roche-sur-Yon, France
    • CH Départemental Vendée - Onco-Hématologie
  • Lille, France
    • CHRU de Lille - Hôpital Claude Hurriez
  • Montpellier, France
    • CHU de Montpellier - Hématologie Clinique
  • Nantes, France
    • CHU de Nantes - Hôtel Dieu - Hématologie
  • Paris, France
    • Hôpital Necker - Hématologie Clinique
  • Paris cedex 20, France
    • Hôpital Saint Louis - Onco-Hématologie
  • Pessac, France
    • CHU de Bordeaux - Hôpital Haut Lévêque - Centre François Magendie
  • Pierre-Bénite, France
    • CHU Lyon Sud - Hématologie
  • Rennes, France
    • Hôpital Pontchaillou - Hématologie
  • Rouen, France
    • Centre Henri Becquerel - Hématologie
  • Saint-Priest-en-Jarez, France, 42271
    • Institut de Cancérologie Lucien Neuwirth
  • Strasbourg, France
    • Hôpitaux Universitaires de Strasbourg - Hôpital de Hautepierre
  • Toulouse, France
    • IUCT ONCOPOLE - Hématologie
  • Vandoeuvre-les-Nancy, France
    • CHU Nancy - Hôpital de Brabois - Service d'Hématologie et Médecine Interne
• Germany
  • Bamberg, Germany
    • Sozialstiftung Bamberg
  • Berlin, Germany
    • Charité - Universitätsklinikum Berlin, Med. Klinik m. S. Hämatologie
  • Berlin, Germany
    • Vivantes Klinikum am Urban, Klinik für Innere, Hämatologie und Onkologie
  • Chemnitz, Germany
    • Klinikum Chemnitz, Innere Medizin III
  • Dresden, Germany
    • BAG Freiberg-Richter, Jacobasch, Wolf, Illmer
  • Dresden, Germany
    • Gemeinschaftspraxis Dres. Mohm, Prange-Krex
  • Eschweiler, Germany
    • St. Antonius-Hospital Eschweiler, Klinik für Hämatologie
  • Essen, Germany
    • Universitätsklinikum Essen, Klinik für Hämatologie
  • Göttingen, Germany
    • Universitätsmedizin Göttingen, Klinik für Hämatologie
  • Haale, Germany
    • Universitätsklinikum Haale (Saale), Klinik für Innere Medizin IV
  • Hamburg, Germany
    • Universitätsklinikum Hamburg-Eppendorf
  • Homburg, Germany
    • Universitätsklinikum des Saarlandes, Innere Med. I
  • Kaiserslautern, Germany
    • Westpfalz-Klinikum, Klinik für Innere Medizin I
  • Karlsruhe, Germany
    • St. Vincentius Kliniken Karlsruhe, Med. Klinik Abt. 2
  • Marburg, Germany
    • Uni Gießen und Marburg, Klinik für Hämatologie
  • Mutlangen, Germany
    • Stauferklinikum Schwäbisch Gmünd, Zentrum für Innere Medizin
  • München, Germany
    • Klinikum der Universität München, Med. Klinik und Poliklinik III
  • Münster, Germany
    • Universitätsklinikum Münster
  • Paderborn, Germany
    • Brüderkrankenhaus St. Josef Paderborn
  • Regensburg, Germany
    • Universitätsklinikum Regensburg, Klinik für Innere Medizin III
  • Rostock, Germany
    • Universitätsmedizin Rostock, Klinik für Hämatologie
  • Stuttgart, Germany
    • Klinikum Stuttgart, Klinik für Hämatologie
  • Trier, Germany
    • Klinikum Mutterhaus der Borromäerinnen, Med. Abteilung I
  • Trier, Germany
    • Krankenhaus der Barmherzigen Brüder, I. Med. Abteilung
  • Tübingen, Germany
    • Universitätsklinikum Tübingen, Innere Medizin II
  • Ulm, Germany
    • Uniklinikum Ulm, Klinik für Innere Medizin III
  • Villingen-Schwenningen, Germany
    • Schwarzwald-Baar Klinikum, Innere Medizin II
• Israel
  • Ramat Gan, Israel
    • The Chaim Sheba Medical Center - Division of Hematology and Bone-Marrow Transplantation
• Netherlands
  • Alkmaar, Netherlands
    • MC Alkmaar
  • Amsterdam, Netherlands
    • VUMC
  • Amsterdam, Netherlands
    • AMC Academisch Medisch Centrum
  • Delft, Netherlands
    • Reinier de Graaf Gasthuis
  • Eindhoven, Netherlands
    • Maxima Medisch Centrum
  • Leeuwarden, Netherlands
    • MC Leeuwarden Zuid
  • Nieuwegein, Netherlands
    • Antonius Ziekenhuis
  • Nijmegen, Netherlands
    • Radboudumc Nijmegen
• Poland
  • Brzozów, Poland
    • Szpital Specjalistyczny w Brozowie
  • Bydgoszcz, Poland
    • Oncologic Center
  • Gdańsk, Poland
    • Uniwersyteckie Centrum Kliniczne
  • Kielce, Poland
    • Swietorkrzyskie Centrum Oncologii
  • Kraków, Poland
    • Samodzielny Publiczny Zakład Opieki Zdrowotnej Szpital Uniwersytecki w Krakowie
  • Lublin, Poland
    • Samodzielny Publiczny Szpital Kliniczny Nr. 1
  • Tomaszów Mazowiecki, Poland
    • Oncologic Center
  • Warsaw, Poland
    • Marie Sklodowska-Curie Institute and Oncology
  • Warszawa, Poland
    • Wojskowy Instytut Medyczny
• Portugal
  • Lisboa, Portugal
    • Instituto Português Oncologia - Hematology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• patients with first relapse or progression of an aggressive Non-Hodgkin's lymphoma
• all patient >65 years of age or > 18 years if not eligible for neither autologous nor allogeneic stem cell transplantation
• all patient >65 years of age or older than 18 years if HCT-CI score > 2 or patients who underwent prior autologous stem cell transplantation and are not eligible for allogeneic stem cell Transplantation
• All risk groups (IPI 0 to 5)
• Diagnosis of aggressive Non-Hodgkin's lymphoma, based on an excisional biopsy of a lymph node or on an appropriate sample of a lymph node or of an extranodal involvement at initial diagnosis or relapse or Progression. The entities treated in the study will be based on the WHO 2017 classification.
• ECOG 0 - 2
• only one prior chemotherapy regimen including an anthracycline. The last cytotoxic drug must be given at least four weeks before entering the study. Rituximab must be part of the first-line regimen in case of B-cell lymphoma (except for primary CD20- negative lymphoma). Patients may have received prior radiation therapy as part of their first-line therapy
• Men who are sexually active with women of childbearing potential (WOCBP) must not father a child during and up to 6 months after GemOx and up to 12 months after Rituximab and/or Nivolumab. They are advised to do cryoconservation of sperm prior to treatment.
• Written informed consent of the patient
• Patient must be covered by social security system

Exclusion Criteria:

• Already initiated lymphoma therapy after first relapse or progression
• Serious accompanying disorder or impaired organ function
• WBC < 2.5 G/l, Neutrophils < 2 G/l, Platelets < 100 G/l
• Prolongation of QTc interval > 450 ms, demonstrated in one electrocardiogram (done as triplicate). This does not apply for patients with a block of the right and/or left bundle branch.
• Family history for Long QT-Syndrome
• active, known or suspected autoimmune disease
• no requirement for immunosuppressive doses of systemic corticosteroids
• Chronic active hepatitis B or C
• HIV-infection
• Patients with a severe immunodeficiency
• Previous therapy with Nivolumab,Gemcitabine or Oxaliplatin
• Patients with a "currently active" second malignancy other than non-melanoma skin cancer
• CNS involvement of lymphoma
• Persistent neuropathy grade >2
• Pregnancy or breast-feeding women
• Women of childbearing potential
• Active serious infections not controlled by oral and/or intravenous antibiotics or anti-fungal medication
• Any medical condition which in the opinion of the investigator places the subject at an unacceptably high risk for toxicities
• Lymphomas other than those listed in the inclusion criteria notably indolent lymphoma, Mantle cell lymphoma, Burkitt lymphoma, adult T-cell leukemia/lymphoma.
• Persons not able to understand the impact, nature, risks and consequences of the trial (including language barrier)
• Persons not agreeing to the transmission of their pseudonymous data
• Persons depending on sponsor or investigator
• Persons from highly protected Groups
• Allergies and Adverse Drug Reaction History to study drug components
• Participation in another clinical trial with drug intervention within 4 weeks prior to start of the first cycle and during the study. However, participation in a clinical trial of firstline therapy of lymphoma is allowed.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: (R)-GemOx; eight cycles of (R)-GemOx (Gemcitabine 1000 mg/m2, d1, Oxaliplatin 100 mg/m2, d1, Rituximab 375 mg/m2 in case of B-cell lymphoma disease, repeated every 2 wks)	Drug: Rituximab; eight cycles of R-GemOx in 2-wk intervals; Drug: Gemcitabine; eight cycles of (R)-GemOx in 2-wk intervals; Device: Oxaliplatin; eight cycles of (R)-GemOx in 2-wk intervals
Experimental: Nivo-(R)-GemOx; eight cycles of nivolumab (240 mg flatdose) plus (R)-GemOx in 2-wk intervals followed by additional 9 infusions of Nivolumab (480 mg flatdose) in 4-wk intervals as consolidation or up to progression or unacceptable toxicity, whatever occurs first	Drug: Rituximab; eight cycles of R-GemOx in 2-wk intervals; Drug: Gemcitabine; eight cycles of (R)-GemOx in 2-wk intervals; Device: Oxaliplatin; eight cycles of (R)-GemOx in 2-wk intervals; Drug: Nivolumab; eight cycles of nivolumab (240 mg flatdose) plus (R)-GemOx in 2-wk intervals followed by additional 9 infusions of Nivolumab (480 mg flatdose) in 4-wk intervals as consolidation or up to progression or unacceptable toxicity, whatever occurs first

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PFS	Progression free survival	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CR rate	complete response rate	4-6 weeks after cycle 8 (each cycle is 14 days)
PR rate	partial response rate	4-6 weeks after cycle 8 (each cycle is 14 days)
ORR rate	overall response rate	4-6 weeks after cycle 8 (each cycle is 14 days)
Duration of response	Duration of response	up to 2 years after inclusion of last patient
Primary Progression rate	Rate of Primary progression	up to 2 years after inclusion of last patient
Treatment related deaths rate	Rate of Treatment related deaths	up to 2 years after inclusion of last patient
Relapse rate	Rate of relapses	up to 2 years after inclusion of last patient
EFS	Event free survival	up to 2 years after inclusion of last patient
OS	Overall survival	up to 2 years after inclusion of last patient
Toxicities: rates and grades of adverse events	Toxicity: Rates and grades of toxicities will be determined according to CTC-v4.03	up to 2 years after inclusion of last patient
Protocol adherence according to number of given chemotherapy cycles	Protocol adherence will be determined according to number of chemotherapy cycles	up to 2 years after inclusion of last patient
Protocol adherence according to duration of given chemotherapy cycles	Protocol adherence will be determined according to duration of chemotherapy cycles	up to 2 years after inclusion of last patient
Protocol adherence according to cumulative dose of immunochemotherapy given	Protocol adherence will be determined according to cumulative dose of immunochemotherapy given	up to 2 years after inclusion of last patient
Protocol adherence according to relative dose of immunochemotherapy given	Protocol adherence will be determined according to relative dose of immunochemotherapy given	up to 2 years after inclusion of last patient
QoL	Quality of Life (QoL) will be assessed by the EQ-5D-5L questionnaire	up to 1 year after inclusion of last patient
Biological Parameters according to PD-L1 expression alterations	Outcome assessment of response according to PD-L1 expression alterations	up to 2 years after inclusion of last patient
Biological Parameters according to PD-1 expression	Outcome assessment of response according to PD-1 expression	up to 2 years after inclusion of last patient
Biological Parameters according to cell of origin	Outcome assessment of response according to cell of origin	up to 2 years after inclusion of last patient
Biological Parameters according to 9p24.1 alterations	Outcome assessment of response according to 9p24.1 alterations	up to 2 years after inclusion of last patient

Collaborators and Investigators

• Sponsor: Universität des Saarlandes
• Collaborators: Bristol-Myers Squibb; University of Leipzig; Lymphoma Study Association
• Investigators: Principal Investigator: Gerhard Held, Prof, Universität des Saarlandes

Study record dates

Study Major Dates

• Study Start (Actual): December 5, 2017
• Primary Completion (Actual): January 15, 2025
• Study Completion (Actual): January 15, 2025

Study Registration Dates

• First Submitted: September 16, 2017
• First Submitted That Met QC Criteria: December 7, 2017
• First Posted (Actual): December 8, 2017

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 27, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Lymphoma; Lymphoma, Non-Hodgkin; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Antineoplastic Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Oxaliplatin; Nivolumab; Rituximab; Gemcitabine
• Other Study ID Numbers: DSHNHL 2015-1

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No