Niveau, a Phase 3 Study for Pts with B- or T-Cell Aggressive Non-Hodgkin Lymphoma in First Relapse or Progression Not Eligible for High-Dose Chemotherapy (HDT), Testing Nivolumab in Combination with Gemcitabine, Oxaliplatin (GemOx), Plus Rituximab (R) in Case of B-Cell Lymphoma

Background: Relapse of aggressive B-cell as well as peripheral T-cell lymphoma (PTLC) has a very poor prognosis, especially in pts ineligible for high-dose chemotherapy. Nivolumab, a human anti-PD1 antibody has the potential to increase rituximab-mediated effector mechanisms and to target the microenvironment in Non-Hodgkin lymphoma. Addition of nivolumab might also increase the efficacy of conventional chemotherapy. Therefore, the NIVEAU trial is testing a common conventional chemotherapy regimen (R)-GemOx vs. Nivolumab plus (R)-GemOx

(ClinicalTrials.gov Identifier:NCT03366272).

Design and study population: This is an ongoing joint international, multicenter, randomized, open label study proceeded by a safety run-in phase conducted by several European cooperative study groups (LYSA, HOVON, PLRG, KLS, AGMT, GLA). Key eligibility criteria include: first relapse or progression of an aggressive lymphoma (B-cell as well as PTCL), ineligibility for HDT (defined as >65 years of age or older than 18 years if HCT-CI score > 2 or pts who underwent prior autologous stem cell transplantation and are not eligible for allogeneic stem cell transplantation), only one prior chemotherapy regimen including an anthracycline and rituximab (R) in case of B-cell lymphoma.

Statistical methods: The primary endpoint is 1-year PFS rate. We aim to demonstrate an improvement from 27% to 42% (i.e. a hazard ratio of 0.66), importantly in B-cell lymphoma only. The two-sided question will be answered with an error probability of alpha= 5% (two sided) and a power of 80%. Therefore, it will be necessary to analyze 292 pts. A drop-out rate of 5% of pts results in a sample size of 310 pts with B-cell lymphoma to be randomized. In parallel a maximum of 78 pts with PTCL will be included and randomized without statistical assumption. Based on the results and possible further increasing scientific knowledge an estimation will be done whether an improvement of prognosis of PTCL can be expected. Potentially an adapted statistical hypothesis will be defined and the trial amended to recruit the appropriate sample size of PTCL.

Analysis: A non-randomized safety run-in phase with 16 pts (10 DLBCL/6 PTCL) was performed in 2018. A 2^nd safety analysis will be done after randomization of 30 pts to the experimental arm to allow for comparative description of toxicities between the arms. An interim analysis of efficacy will be performed including the first 180 patients from the B-cell cohort. The final analysis of the primary and secondary endpoint will be performed two years after recruitment of the last pt with B-cell lymphoma.

A comprehensive translational research program will be performed on paired samples of primary diagnosis and relapse (NGS targeted resequencing, gene expression profiling, comparative genomic hybridization), PBMC (flow cytometry), serum, plasma and cell-free DNA.

Study treatment: (R)-GemOx is 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. Standard arm: eight cycles of (R)-GemOx. Experimental arm: eight cycles of nivolumab (3 mg/kg) plus (R)-GemOx in 2-wk intervals followed by additional 18 infusions of Nivolumab (3 mg/kg) in 2-wk intervals as consolidation or up to progression or unacceptable toxicity.

Endpoints: The primary endpoint is 1-year PFS. Secondary endpoints represent efficacy (response rates, duration of response, progression rate, relapse rate, EFS, OS), toxicity (AEs, SAEs, treatment related deaths, secondary malignancies, long-term sequelae), protocol adherence (number of chemotherapy cycles, duration of chemotherapy cycles, cumulative dose and relative dose of gemcitabine, oxaliplatin, rituximab, nivolumab), quality of life (assessed by 5Q-5D-5L) and outcome according to biology.

Conclusion: The NIVEAU-study represents a trial with a clear phase 3 design aiming to improve outcome in pts. with relapsed aggressive B-cell lymphoma ineligible for HDT. Additive recruitment and randomization of PTCL allows to adapt and define a precise statistical assumption in future, depending on interim-results, upcoming knowledge and recruitment. The approach allows to provide phase 3 evidence also in very rare disease entities.