E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients in first relapse or progression of aggressive Non-Hodgkin’s Lymphoma who are not eligible neither for autologous nor allogeneic stem cell transplantation. |
Doentes em primeira recidiva ou progressão de Linfoma Não-Hodgkin agressivo que não sejam elegíveis para transplante autólogo, nem alogénico de células estaminais. |
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E.1.1.1 | Medical condition in easily understood language |
Patients in first relapse or progression of aggressive Non-Hodgkin’s Lymphoma who are not eligible neither for autologous nor allogeneic stem cell transplantation. |
Doentes em primeira recidiva ou progressão de Linfoma Não-Hodgkin agressivo que não sejam elegíveis para transplante autólogo, nem alogénico de células estaminais. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 22.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10029547 |
E.1.2 | Term | Non-Hodgkin's lymphoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Improvement of 1-yr PFS by nivolumab plus (R)-GemOx followed by nivolumab consolidation instead of (R)-GemOx alone. |
Melhoria da sobrevivência livre de progressão (PFS) de 1 ano com a adição de Nivolumab ao GemOx-R, seguido de consolidação com Nivolumab em vez de apenas GemOx-R. |
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E.2.2 | Secondary objectives of the trial |
- To determine whether survival can be increased by adding nivolumab to standard (R)-GemOx. - To determine whether outcome can be improved by adding nivolumab to standard (R)-GemOx. - To determine toxicity and protocol adherence of standard (R)-GemOx with or without nivolumab. - To evaluate quality of life of patients with relapsed or refractory aggressive Non-Hodgkin’s Lymphoma treated with (R)-GemOx with or without Nivolumab. - To analyze outcome according to biological parameters. |
- Determinar se é possível aumentar a sobrevivência através da adição de Nivolumab ao GemOx-R padrão. - Determinar se é possível melhorar os resultados em saúde através da adição de Nivolumab ao GemOx-R padrão. - Determinar a toxicidade e a adesão ao protocolo do GemOx-R padrão com ou sem Nivolumab. - Avaliar a qualidade de vida dos doentes com Linfoma Não-Hodgkin agressivo recidivante ou refratário tratados com GemOx-R padrão com ou sem nivolumab. - Analisar os resultados em saúde de acordo com os parâmetros biológicos. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- all patient >65 years of age or older than 18 years f not eligible for neither autologous nor allogeneic stem cell transplantation - Ineligibility for neither autologous nor 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 - Performance status ECOG 0 – 2 - Patients must have only one prior chemotherapy regimen including an anthracycline. The last cytotoxic drug must be given at least four weeks prior randomization. Rituximab must be part of the first-line regimen in case of a 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 use any contraceptive method with a failure rate of less than 1% per year - Written informed consent of the patient - Patient must be covered by social security system. |
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E.4 | Principal exclusion criteria |
- Already initiated lymphoma therapy after first relapse or progression (except for the prephase treatment) - Serious accompanying disorder or impaired organ function (except when due to lymphoma involvement), in particular: heart: angina pectoris CCS >2, cardiac failure e.g. NYHA >2 liver: total bilirubin >1.5 times the upper reference limit (except subjects with Gilbert Syndrome, who can have total bilirubin < 51 μmol/l), aspartate transaminase (AST) or alanine transaminase (ALT) >3 x institutional upper reference limit kidney: creatinine clearance < 30 ml/min - WBC < 2.5 G/l, Neutrophils < 2 G/l, Platelets < 100 G/l (does not apply if cytopenia is caused by lymphoma) - 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 - Patients with an active, known or suspected autoimmune disease - no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration (except for treatment of lymphoma) - Chronic active hepatitis B or C as defined either HBs Ag positive or HBc Ac positive with detectable viral DNA or hepatitis C virus ribonucleic acid positive - 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 (intracerebral, meningeal, intraspinal intradural) or primary CNS lymphoma - Persistent neuropathy grade >2 (unless due to lymphoma involvement) - Pregnancy or breast-feeding women - Women of childbearing potential (WOCBP) - Active serious infections not controlled by oral and/or intravenous antibiotics or antifungal 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
1-year progression free survival (PFS) of patients with B cell lymphoma. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1 year (data collected during the restagings and the follow-up assessments as planned in the protocol (cf. chapter 8.9 in the protocol)) |
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E.5.2 | Secondary end point(s) |
• complete response rate • partial response rate • overall response rate • duration of response • progression rate • rate of treatment-related deaths • relapse rate • Event-free survival • Overall survival • Toxicity • Protocol adherence • quality of life as assessed by the EQ-5D-5L. • outcome according to PD-L1 and PD-1 expression, cell of origin, 9p24.1 alterations |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
• complete response rate , partial response rate, overall response rate : (data collected during the restagings and the follow-up assessments as planned in the protocol (cf. chapter 8.9 in the protocol)) • duration of response : end of study • progression rate : end of study • rate of treatment-related deaths : end of study • relapse rate : end of study • Event-free survival : end of study • Overall survival : end of study • Toxicity : end of study • Protocol adherence : end of study • quality of life as assessed by the EQ-5D-5L : end of study • outcome according to PD-L1 and PD-1 expression, cell of origin, 9p24.1 alterations : end of study
(data collected during the restagings and the follow-up assessments as planned in the protocol (cf. chapter 8.9 in the protocol)) |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Yes |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Standard chemotherapy with Gemcitabine, Oxaliplatin and rituximab in case of B-cell lymphoma |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 76 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Austria |
Belgium |
Czechia |
Germany |
Israel |
Netherlands |
Poland |
Portugal |
France |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 7 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 7 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |