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

Lymphoma, Non-Hodgkin Clinical Trial

— NIVEAU  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03366272
• Other study ID #: DSHNHL 2015-1
• Status: Active, not recruiting
• Phase: Phase 2/Phase 3
• Start date: December 5, 2017
• Est. completion date: November 2024

Study information

• Verified date: November 2023
• Source: Universität des Saarlandes
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Description:

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

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 348
• Est. completion date: November 2024
• Est. primary completion date: November 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Lymphoma
• Lymphoma, Non-Hodgkin

Intervention

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
• Rituximab
eight cycles of R-GemOx in 2-wk intervals
• Gemcitabine
eight cycles of (R)-GemOx in 2-wk intervals

Device:
• Oxaliplatin
eight cycles of (R)-GemOx in 2-wk intervals

Locations

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

Sponsors (4)

Lead Sponsor	Collaborator
Universität des Saarlandes	Bristol-Myers Squibb, Lymphoma Study Association, University of Leipzig

Countries where clinical trial is conducted

Austria,  Belgium,  France,  Germany,  Israel,  Netherlands,  Poland,  Portugal, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	PFS	Progression free survival	1 year
Secondary	CR rate	complete response rate	4-6 weeks after cycle 8 (each cycle is 14 days)
Secondary	PR rate	partial response rate	4-6 weeks after cycle 8 (each cycle is 14 days)
Secondary	ORR rate	overall response rate	4-6 weeks after cycle 8 (each cycle is 14 days)
Secondary	Duration of response	Duration of response	up to 2 years after inclusion of last patient
Secondary	Primary Progression rate	Rate of Primary progression	up to 2 years after inclusion of last patient
Secondary	Treatment related deaths rate	Rate of Treatment related deaths	up to 2 years after inclusion of last patient
Secondary	Relapse rate	Rate of relapses	up to 2 years after inclusion of last patient
Secondary	EFS	Event free survival	up to 2 years after inclusion of last patient
Secondary	OS	Overall survival	up to 2 years after inclusion of last patient
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	QoL	Quality of Life (QoL) will be assessed by the EQ-5D-5L questionnaire	up to 1 year after inclusion of last patient
Secondary	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
Secondary	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
Secondary	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
Secondary	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