Lymphoma, Non-Hodgkin
Conditions
Brief summary
This study evaluates the addition of nivolumab to gemcitabine, oxaliplatin plus rituximab in case of B-cell lymphoma
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.
Interventions
DRUGNivolumab
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
DRUGRituximab
eight cycles of R-GemOx in 2-wk intervals
DRUGGemcitabine
eight cycles of (R)-GemOx in 2-wk intervals
DEVICEOxaliplatin
eight cycles of (R)-GemOx in 2-wk intervals
Sponsors
Bristol-Myers Squibb
Lymphoma Study Association
University of Leipzig
Universität des Saarlandes
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| PFS | 1 year | Progression free survival |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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 |
| 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 |
| 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 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 |
| OS | up to 2 years after inclusion of last patient | Overall survival |
Countries
Austria, Belgium, France, Germany, Israel, Netherlands, Poland, Portugal
Outcome results
None listed