ANHL1931: A Randomized Phase 3 trial of Nivolumab (NSC# 748726 IND# 125462) in Combination with Chemo-immunotherapy for the Treatment of Newly Diagnosed Primary Mediastinal B-cell Lymphoma

Abstract ANHL1931, A Randomized Phase 3 trial of Nivolumab (NSC# 748726 IND# 125462) in Combination with Chemo-immunotherapy for the Treatment of Newly Diagnosed Primary Mediastinal B-cell Lymphoma Primary mediastinal B-cell lymphoma (PMBCL) is a rare subtype of aggressive lymphoma typically occurring in adolescent and young adults. The disease shares biologic features with classic Hodgkin lymphoma including the upregulation of PD-1 ligands resulting from alterations in chromosome 9p24.1. Although the majority of patients with PMBCL will experience long term disease control with dose adjusted EPOCH-R, up to 20% will develop primary refractory or relapsed disease. Options in this setting include radiation, stem cell transplantation and CAR-T cell therapy, all of which are associated with significant short and long term toxicities. Recent data demonstrates that PD-1 blockade is an effective strategy in heavily pre-treated patients with PMBCL and may be associated durable responses. We hypothesize the addition of PD-1 blockade to upfront therapy will improve outcomes in PMBCL. In this prospective, randomized study, we will compare chemoimmunotherapy with or without radiotherapy to nivolumab plus chemoimmunotherapy with or without radiotherapy in children and adults with newly diagnosed PMBCL. Prior to randomization, the treating physician will select his or her preferred treatment approach: dose adjusted EPOCH-R, RCHOP without RT unless persistent disease documented at the end of chemotherapy, or RCHOP with planned RT regardless of response at end of chemotherapy. Patients will undergo FDG PET/CT scans at baseline, after cycle 2 (if feasible) and after cycle 6. Patients with end of treatment Deauville 1-3 scans will be followed expectantly, except in the case of planned RT after RCHOP. For Deauville 4 and 5, patients may have serial scans or undergo biopsy. If persistent disease is pathologically confirmed and the disease is localized, the patient will receive involved site radiotherapy. The primary endpoint of the study is progression free survival as determined by independent review committee. Patients will be randomized in a 1:1 fashion to nivolumab plus backbone approach versus backbone approach alone. A key secondary aim is event-free survival as defined as disease relapse or progression, death, biopsy confirmation of residual lymphoma after completion of chemotherapy, or an efficacy finding leading to subsequent anti-lymphoma therapy. Other secondary aims include event-free survival defined as change of subsequent anti-lymphoma therapy for any reason, disease relapse or progression, biopsy confirmation of residual lymphoma after completion of chemotherapy, death or secondary malignancy and overall survival. Assuming an 80% cure rate in the backbone arm, the alternative hypothesis is a 92.8% cure rate with 80.1% power with one-sided α = 0.05. Total planned accrual is 192 patients to get 186 eligible patients and 26 events, with a possible built-in expansion to 244 patients to get 236 eligible patients and 32 events to have 80.1% power with one- sided α = 0.025 if early enrollment rates are sufficiently robust to make that sample size feasible. Toxicity monitoring will be performed after the first 50 randomized patients have completed therapy. Rates of Deauville 5 at end of treatment PET will be assessed after every 30 patients. Exploratory aims will include characterizing the immune profile of patients treated with nivolumab + chemo- immunotherapy and banking radiology images and biospecimens for future correlative studies.