Analysis of a Safety Run-in Cohort from Niveau, a Phase 3 Study for Patients with 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
Authors: Held Gerhard , Haioun Corinne , Houot Roch , Gaulard Philippe , Molina Thierry , Rosenwald Andreas , André Marc , Hoffmann Joerg , Dreyling Martin , Casasnovas Olivier , Maisonneuve Herve , Tilly Herve , Illmer Thomas , Mayer Stephanie , Kirchen Heinz , La Rosée Paul , Loeffler Markus , Ziepert Marita , Altmann Bettina , Poeschel Viola 
Published: November 2019

Background: Nivolumab, a human anti-PD1 antibody has the potential to increase rituximab-mediated effector mechanism, to target the microenviroment and PD-1 in aggressive Non-Hodgkin lymphoma. Addition of nivolumab might increase efficacy conventional chemotherapy, which is always combined with rituximab in case of B-cell lymphoma. Therefore, a safety run-in was conducted to determine the tolerability of the combination prior to proceeding with a larger randomized phase 3 study aimed to compare of (R)-GemOx vs. Nivolumab plus (R)-GemOx.
Methods: This is an ongoing international, multicenter, randomized, open label study. Key eligibility criteria include: first relapse or progression of an aggressive lymphoma (B-cell as well as peripheral T-cell lymphoma (PTCL)), ineligibility for HDT (defined as >65 years of age or older than 18 years if HCT-CI score > 2), only one prior chemotherapy regimen including an anthracycline and rituximab (R) in case of B-cell lymphoma. A non-randomized safety run-in phase was performed in 16 pts to assess potential toxicities of Nivolumab in combination with (R)-GemOx. Pts were planned to receive 8 bi-weekly cycles of Gemcitabine 1000 mg/m2, Oxaliplatin 100 mg/m2, R 375 mg/m2 all given on day 1. Nivolumab 3 mg/kg was given every two weeks for a total of 26 applications or until progression. Importantly, first application of Nivolumab was prior to first application of R. Response was evaluated after 4 and 8 cycles of (R)-Gemox. Safety analysis was performed after the last patient had gone through interim restaging after 4 cycles of (R)-GemOx.
Progression/relapse of PTCL was scored as severe adverse event (SAE).
Results: Sixteen pts were enrolled in the safety run-in, 10 pts with B cell lymphoma, all DLBCLs and 6 with PTCL. Recruitment was from 12-Jan-2018 until 17-May-2018, snapshot of database on 09-Aug-2018. Median age was 76 years, 9 (56%) pts were male, 8 (50%) had time-to-treatment failure <= 12 months; 14 (88%) had Ann Arbor stage ≥III disease; 10 (63%) had an elevated lactate dehydrogenase level, and 10 (63%) had an International Prognostic Index of 3 to 5. Pts received a median of 6 (1-8) cycles of (R)-GemOx and 7 (1-10) applications of nivolumab. The most common treatment-emergent adverse events (grade ≥3) per documented cycles were thrombocytopenia 24/90 (27%), anemia 11/90 (12%), infection 8/92 (9%), leukocytopenia/neutropenia 6/90 (7%), elevated lipase 3/84 (4%), hyperglycemia 2/79 (3%), pruritus 2/90 (2%), rash 2/90 (2%). Fourteen serious adverse events related to nivolumab occurred in 9 (56%) patients (4 infections, 3 thrombocytopenia, 1 vertigo, 1 hyperkalemia, 1 renal failure, 1 rash, 1 diarrhoea, 1 pyrexia, 1 leptomeningeal vasculitis). Four immune-related AEs occurred (2 grade 3-4 rash, 1 grade 2 pneumonitis, 1 grade 4 leptomeningeal vasculitis leading to treatment discontinuation). Treatment was discontinued due to lymphoma progression in 3 pts with DLBCL and 1 pt with PTCL. One patient with PTCL discontinued treatment due to an immune-related AE (leptomeningeal vasculitis after the 1st cycle).
Because inhibition of PD-1 might conversely induce progression of PTCL, efficacy is part of the safety analysis. So far 3/6 PTCL pts are in ongoing CR for 17, 16 and 14 months, respectively (an update will be presented at the meeting).
Conclusion: The overall safety profile of nivolumab in combination with (R)-GemOx was consistent with those previously reported for (R)-GemOx and nivolumab. The combination does not to result in an increased frequency of immune-related AEs. However, the occurrence of very rare events needs assessment of longer follow-up and recruitment of more pts. Duration of response in PTCL is promising, without evidence for hyperprogression.
The trial proceeded to the randomized phase 3 study and is actively recruiting. An additional safety analysis will be performed after 30 pts have been randomized to the experimental arm.

Disclosures
Held: Acrotech: Research Funding; Amgen: Research Funding; Roche: Consultancy, Other: Travel support, Research Funding; MSD: Consultancy; Bristol-Myers Squibb: Consultancy, Other: Travel support, Research Funding. Haioun:novartis: Honoraria; celgene: Honoraria; roche: Consultancy; celgene: Consultancy; gilead: Consultancy; takeda: Consultancy; janssen cilag: Consultancy; amgen: Honoraria; servier: Honoraria. Houot:Bristol Myers Squibb: Honoraria; Merck Sharp Dohme: Honoraria. Molina:merck: Consultancy; novartis: Consultancy; celgene: Consultancy. Rosenwald:MorphoSys: Consultancy. André:Celgene: Other: Travel grants, Research Funding; Chugai: Research Funding; Takeda Millenium: Research Funding; Johnson & Johnson: Research Funding; Amgen: Other: Travel grants, Research Funding; Roche: Other: Travel grants, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers-Squibb: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Dreyling:Acerta: Other: Scientific advisory board; Bayer: Other: Scientific advisory board, Speakers Bureau; Celgene: Other: Scientific advisory board, Research Funding, Speakers Bureau; Gilead: Other: Scientific advisory board, Speakers Bureau; Janssen: Other: Scientific advisory board, Research Funding, Speakers Bureau; Mundipharma: Other: Scientific advisory board, Research Funding; Novartis: Other: Scientific advisory board; Roche: Other: Scientific advisory board, Research Funding, Speakers Bureau; Sandoz: Other: Scientific advisory board. Tilly:roche: Membership on an entity's Board of Directors or advisory committees; servier: Honoraria; merck: Honoraria; Gilead: Honoraria; Janssen: Honoraria; BMS: Honoraria; Karyopharm: Consultancy; Roche: Consultancy; Celgene: Consultancy, Research Funding; Astra-Zeneca: Consultancy. La Rosée:Novartis: Research Funding; Bristol-Myers-Squibb: Consultancy, Other: Travel support, Speakers Bureau. Poeschel:Astra Zeneca: Other: Travel support; Hexal: Speakers Bureau; Roche: Other: Travel support; Amgen: Other: Travel support; Abbvie: Other: Travel support.

OffLabel Disclosure:
nivolumab, aggressive Non-Hodgkin Lymphoma