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

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

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

Official Title
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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

Conditions
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Lymphoma, Non-Hodgkin

Intervention / Treatment
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* Drug: Nivolumab
* Drug: Rituximab
* Drug: Gemcitabine
* Device: Oxaliplatin


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: (R)-GemOx<br>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<br>* eight cycles of R-GemOx in 2-wk intervals<br>Drug: Gemcitabine<br>* eight cycles of (R)-GemOx in 2-wk intervals<br>Device: Oxaliplatin<br>* eight cycles of (R)-GemOx in 2-wk intervals<br>|
| Experimental: Nivo-(R)-GemOx<br>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<br>* 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<br>Drug: Rituximab<br>* eight cycles of R-GemOx in 2-wk intervals<br>Drug: Gemcitabine<br>* eight cycles of (R)-GemOx in 2-wk intervals<br>Device: Oxaliplatin<br>* eight cycles of (R)-GemOx in 2-wk intervals<br>|

What is the study measuring?
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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 |