Safety and Efficacy in Pediatric Patients with Relapsed/Refractory Classic Hodgkin Lymphoma Enrolled on an Intergroup Randomized Phase II Study of the Combinations of Ipilimumab, Nivolumab and Brentuximab Vedotin (E4412)

Background: The Phase 1/2 ECOG-ACRIN sponsored intergroup trial E4412 (NCT01896999) investigated brentuximab vedotin (BV) combined with the checkpoint inhibitors nivolumab (N) and ipilimumab (I) in patients with relapsed or refractory classic Hodgkin lymphoma (R/R HL). Here we present the safety and efficacy results for the cohort of pediatric patients aged 12-17 years. Methods: Patients were randomly assigned to treatment with the doublet of BV/N or triplet of BV/N/I, with the following dosing: BV 1.8mg/kg every 21 days for up to 16 cycles; Nivolumab 3mg/mg every 21 days for up to 34 cycles; Ipilimumab 1mg/kg every 9 weeks for up to 9 doses. Response evaluation by PET/CT was performed after 4 cycles. Transplant-eligible patients with CR could discontinue protocol therapy to receive a consolidative autologous stem cell transplant (ASCT). Results: Sixteen pediatric patients with a median age of 16 (range 12-17) were randomized. 75% of patients had received only 1 prior line of treatment with none having previously received BV and only 1 patient with prior ASCT. All patients were treated (8 in each arm) and included in the pediatric safety analysis cohort receiving at least one cycle of therapy. There were four reported grade (gr) 3 or greater toxicities: lymphopenia (gr 3) and neutropenia (gr 3) on the BV/N arm; and neutropenia (gr 4) and rash (gr 3) on the BV/N/I arm. Rash of any grade was more common in patients treated with BV/N/I (n=6) compared to BV/N (n=1). Peripheral sensory neuropathy was reported in 2 patients (BV/N, gr 2, n=2) There were no grade 5 toxicities. Fourteen patients (7 in each arm) were evaluable for response. The CR rate on both the BV/N and BV/N/I arms was 100%. The median survival follow up was 23.7 months (15.7 - 31.7). The 24-month PFS was 57% for BV/N and 100% for BV/N/I. Six patients (2 BV/N; 4 BV/N/I) discontinued protocol therapy to receive a consolidative ASCT. The 24-month PFS for patients consolidated with an ASCT was 100%, with all events occurring in patients randomized to BV/N, but not receiving an ASCT. Conclusion: Pediatric patients receiving both BV/N and BV/N/I had 100% CR rate with limited toxicity. Although this is a small cohort, there have been no progression events observed in patients treated with BV/N/I, including 3 patients treated without a consolidative ASCT.

Forlenza:Bristol Myers Squibb: Consultancy. Ansell:SeaGen: Research Funding; Regeneron Pharmaceuticals, Inc.: Research Funding; Pfizer: Research Funding; AstraZeneca: Research Funding; ADC Therapeutics: Research Funding; Bristol Myers Squibb: Research Funding; Takeda: Research Funding; Affimed: Membership on an entity's Board of Directors or advisory committees, Research Funding. Steidl:Bristol Myers Squibb: Research Funding; AbbVie: Consultancy; EISAI: Consultancy; Seattle Genetics: Consultancy; Bayer: Consultancy; Epizyme: Research Funding; Trillium Therapeutics Inc: Research Funding. Natkunam:Leica Biosystems: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Research Funding; Roche Pharma: Consultancy. Scott:AstraZenenca: Consultancy; Incyte: Consultancy; Janssen: Consultancy; Roche: Research Funding; Abbvie: Consultancy. Mehta-Shah:Verastem Oncology: Research Funding; Innate Pharmaceuticals: Research Funding; Johnson & Johnson/Janssen: Consultancy; Pfizer: Consultancy; Secura Bio: Consultancy, Research Funding; Yingli Pharmaceuticals: Research Funding; Morphosys: Research Funding; Genetech/Roche: Consultancy, Research Funding; Dizal Pharmaceuticals: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Celgene: Research Funding; C4 Therapeutics: Consultancy, Research Funding; Bristol Myers-Squibb: Research Funding; Astra Zeneca: Consultancy, Research Funding; Corvus Pharmaceuticals: Research Funding; Kyowa Hakko Kirin, Karyopharm Therapeutics: Consultancy. Amengual:Incyte: Consultancy; Ipsen: Consultancy; ADCT: Consultancy; Astrazeneca: Consultancy. Kahl:AbbVie: Consultancy; Merck: Consultancy; Roche: Consultancy, Research Funding; Genentech: Consultancy; Lilly: Consultancy; Kite: Consultancy; AstraZeneca: Consultancy, Research Funding; Novartis: Consultancy; Bristol Myers Squibb: Consultancy; BeiGene: Consultancy, Research Funding; ADCT: Consultancy. Diefenbach:FATE Therapeutics: Consultancy, Research Funding; Morphosys: Consultancy, Research Funding; Millenium: Research Funding; Merck: Consultancy, Research Funding; Gilead: Current equity holder in publicly-traded company, Research Funding; Genmab: Consultancy, Research Funding; Genentech/Roche: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Research Funding; MEI Pharma: Consultancy, Research Funding; I MAB: Consultancy, Current equity holder in private company; NYU Grossman School of Medicine/Perlmutter Cancer Center at NYU Langone Health: Current Employment; OverT Therapeutics: Current equity holder in private company; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Consultancy, Research Funding.