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

Sponsor

Universität des Saarlandes (Other)

Overall Status

Recruiting

CT.gov ID

NCT03366272

Collaborator

Bristol-Myers Squibb (Industry), Lymphoma Study Association (Other), University of Leipzig (Other)

388

Enrollment

Locations

Arms

82.9

Anticipated Duration (Months)

4.9

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Lymphoma, Non-Hodgkin	Drug: Nivolumab Drug: Rituximab Drug: Gemcitabine Device: Oxaliplatin	Phase 2/Phase 3

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 Design

Study Type:

Interventional

Anticipated Enrollment :

388 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Dec 5, 2017

Anticipated Primary Completion Date :

Nov 1, 2022

Anticipated Study Completion Date :

Nov 1, 2024

Arms and Interventions

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: 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 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

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: Nivolumab

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

Outcome Measures

Primary Outcome Measures

PFS [1 year]
Progression free survival

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Landeskrankenhaus Feldkirch	Feldkirch	Austria
2	Innsbruck University Hospital	Innsbruck	Austria
3	Kepler Universitätsklinikum GmbH- Med. Campus III	Linz	Austria
4	Ordensklinikum Linz - Elisabethinen	Linz	Austria
5	Ordensklinikum Linz - Krankenhaus der Barmherzigen Schwestern Linz	Linz	Austria
6	Paracelsus Medical University Salzburg	Salzburg	Austria
7	Klinikum Wels-Grieskirchen GmbH	Wels	Austria
8	Universitätsklinik für Innere Medizin I, AKH Wien	Wien	Austria
9	INSTITUT JULES BORDET -Hematology	Brüssel	Belgium
10	UNIVERSITE CATHOLIQUE DE LOUVAIN SAINT-LUC - Hematology	Brüssel	Belgium
11	UNIVERSITAIR ZIEKENHUIS GENT - Hematology	Gent	Belgium
12	CHU DE LIEGE - Hematology	Liège	Belgium
13	UNIVERSITE CATHOLIQUE DE LOUVAIN MONT GODINNE - Hematology	Yvoir	Belgium
14	CHU Côte de Nacre - Service Hématologie Clinique	Caen	France
15	Hôpital Henri Mondor - Unité "Hémopathies Lymphoïdes" - HDJ 11è	Créteil Cedex	France
16	CHU Dijon - Hôpital d'Enfants - Hématologie Clinique	Dijon	France
17	CHU de Grenoble - Hôpital Albert Michallon - Hématologie Clinique	Grenoble	France
18	CH Départemental Vendée - Onco-Hématologie	La Roche-sur-Yon	France
19	CHRU de Lille - Hôpital Claude Hurriez	Lille	France
20	CHU de Montpellier - Hématologie Clinique	Montpellier	France
21	CHU de Nantes - Hôtel Dieu - Hématologie	Nantes	France
22	Hôpital Saint Louis - Onco-Hématologie	Paris cedex 20	France
23	Hôpital Necker - Hématologie Clinique	Paris	France
24	CHU de Bordeaux - Hôpital Haut Lévêque - Centre François Magendie	Pessac	France
25	CHU Lyon Sud - Hématologie	Pierre-Bénite	France
26	Hôpital Pontchaillou - Hématologie	Rennes	France
27	Centre Henri Becquerel - Hématologie	Rouen	France
28	Institut de Cancèrologie Lucien Neuwirth	Saint-Priest-en-Jarez	France	42271
29	Hôpitaux Universitaires de Strasbourg - Hôpital de Hautepierre	Strasbourg	France
30	IUCT Oncopole - Hématologie	Toulouse	France
31	CHU Nancy - Hôpital de Brabois - Service d'Hématologie et Médecine Interne	Vandoeuvre-les-Nancy	France
32	Sozialstiftung Bamberg	Bamberg	Germany
33	Charité - Universitätsklinikum Berlin, Med. Klinik m. S. Hämatologie	Berlin	Germany
34	Vivantes Klinikum am Urban, Klinik für Innere, Hämatologie und Onkologie	Berlin	Germany
35	Klinikum Chemnitz, Innere Medizin III	Chemnitz	Germany
36	BAG Freiberg-Richter, Jacobasch, Wolf, Illmer	Dresden	Germany
37	Gemeinschaftspraxis Dres. Mohm, Prange-Krex	Dresden	Germany
38	St. Antonius-Hospital Eschweiler, Klinik für Hämatologie	Eschweiler	Germany
39	Universitätsklinikum Essen, Klinik für Hämatologie	Essen	Germany
40	Universitätsmedizin Göttingen, Klinik für Hämatologie	Göttingen	Germany
41	Universitätsklinikum Haale (Saale), Klinik für Innere Medizin IV	Haale	Germany
42	Universitätsklinikum Hamburg-Eppendorf	Hamburg	Germany
43	Medizinische Hochschule Hannover, Klinik für Hämatologie	Hannover	Germany
44	Universitätsklinikum des Saarlandes, Innere Med. I	Homburg	Germany
45	Westpfalz-Klinikum, Klinik für Innere Medizin I	Kaiserslautern	Germany
46	St. Vincentius Kliniken Karlsruhe, Med. Klinik Abt. 2	Karlsruhe	Germany
47	Uni Gießen und Marburg, Klinik für Hämatologie	Marburg	Germany
48	Stauferklinikum Schwäbisch Gmünd, Zentrum für Innere Medizin	Mutlangen	Germany
49	Klinikum der Universität München, Med. Klinik und Poliklinik III	München	Germany
50	Universitätsklinikum Münster	Münster	Germany
51	Brüderkrankenhaus St. Josef Paderborn	Paderborn	Germany
52	Universitätsklinikum Regensburg, Klinik für Innere Medizin III	Regensburg	Germany
53	Universitätsmedizin Rostock, Klinik für Hämatologie	Rostock	Germany
54	Marien Kliniken Siegen, Klinik für Hämatologie, Medizinische Onkologie und Palliativmedizin	Siegen	Germany	57072
55	Klinikum Stuttgart, Klinik für Hämatologie	Stuttgart	Germany
56	Klinikum Mutterhaus der Borromäerinnen, Med. Abteilung I	Trier	Germany
57	Krankenhaus der Barmherzigen Brüder, I. Med. Abteilung	Trier	Germany
58	Universitätsklinikum Tübingen, Innere Medizin II	Tübingen	Germany
59	Uniklinikum Ulm, Klinik für Innere Medizin III	Ulm	Germany
60	Schwarzwald-Baar Klinikum, Innere Medizin II	Villingen-Schwenningen	Germany
61	The Chaim Sheba Medical Center - Division of Hematology and Bone-Marrow Transplantation	Ramat Gan	Israel
62	MC Alkmaar	Alkmaar	Netherlands
63	AMC Academisch Medisch Centrum	Amsterdam	Netherlands
64	VUMC	Amsterdam	Netherlands
65	Reinier de Graaf Gasthuis	Delft	Netherlands
66	Maxima Medisch Centrum	Eindhoven	Netherlands
67	MC Leeuwarden Zuid	Leeuwarden	Netherlands
68	Antonius Ziekenhuis	Nieuwegein	Netherlands
69	Radboudumc Nijmegen	Nijmegen	Netherlands
70	Szpital Specjalistyczny w Brozowie	Brzozów	Poland
71	Oncologic Center	Bydgoszcz	Poland
72	Uniwersyteckie Centrum Kliniczne	Gdańsk	Poland
73	Swietorkrzyskie Centrum Oncologii	Kielce	Poland
74	Samodzielny Publiczny Zakład Opieki Zdrowotnej Szpital Uniwersytecki w Krakowie	Kraków	Poland
75	Samodzielny Publiczny Szpital Kliniczny Nr. 1	Lublin	Poland
76	Oncologic Center	Tomaszów Mazowiecki	Poland
77	Marie Sklodowska-Curie Institute and Oncology	Warsaw	Poland
78	Wojskowy Instytut Medyczny	Warszawa	Poland
79	Instituto Português Oncologia - Hematology	Lisboa	Portugal