A Phase I Study with an Expansion Cohort of the Combinations of Ipilimumab, Nivolumab and Brentuximab Vedotin in Patients with Relapsed/Refractory Hodgkin Lymphoma: A Trial of the ECOG-ACRIN Research Group (E4412: Arms G-I)
Authors: Diefenbach Catherine , Hong Fangxin , Ambinder Richard F , Cohen Jonathon B. , Robertson Michael , David Kevin A. , Advani Ranjana H. , Fenske Timothy S. , Barta Stefan Klaus , Palmisano Neil , Svoboda Jakub , Morgan David , Karmali Reem , Kahl Brad S , Ansell Stephen M. 
Published: October 2019

Abstract
Background: Relapsed/refractory (R/R) Hodgkin lymphoma (HL) remains a significant clinical challenge. We hypothesized that using immune checkpoint blockade to activate the immune cells in the tumor microenvironment, and concurrently targeting tumor cells with the CD30 targeting antibody-drug conjugate brentuximab vedotin (BV) could overcome tumor resistance. E4412 is a Phase 1/2 ECOG-ACRIN sponsored study of the combinations of BV, nivolumab (Nivo), and ipilimumab (Ipi) in patients with R/R HL. Here we present the preliminary safety and response data on the full cohort of patients treated in Phase 1 with BV + Ipi + Nivo (Arms G-I). Methods: Patients with confirmed R/R HL were treated with Nivo 3mg/kg, Ipi 1mg/kg and BV 1.2mg/kg (Arm G) or 1.8mg/kg (Arm H) with a 3+3 design, and an expansion cohort (Arm I) of 9 patients with BV at 1.8mg/kg. BV and Nivo are given every 21 days for 16 cycles; Nivo may be continued for an additional 12 months. Ipi is given every 12 weeks except for the first 2 patients in Arm G who received Ipi every 6 weeks for the first 3 cycles. Dose limiting toxicity (DLT) was defined within the first cycle of therapy. Results: As of 6/30/18 22 patients with a median of 2 prior therapies (range 1-5) have been treated; 7 in Arm G, 6 in Arm H, and 9 in Arm I. Median age was 35, range (19-60); 11 patients were male. Nine patients had prior SCT (1 alloSCT, 8 autoSCT); 1 patient had prior BV. Safety: All 22 enrolled patients are evaluable for safety. There were 3 DLTs, one in each arm. In Arm G one patient experienced grade 4 diabetic ketoacidosis and hyperglycemia, and went off treatment after cycle 1. In Arm H, one patient had transient grade 3 AST elevation; this was of no clinical significance and did not require a delay in therapy. In Arm I a post AlloSCT patient had grade 4 Steven-Johnson syndrome with grade 3 pruritis, rash, and GVHD, and came off therapy. Common toxicities considered at least possibly related to drug, are shown in Table 1, and grade 3 or greater toxicity in Table 2. There were no grade 5 AEs or additional grade 4 AEs. Significant grade 3 AEs were: rash, colitis, gastritis, pancreatitis, and arthritis each in one patient, resulting in dose delays but not discontinuation of therapy. One patient experienced grade 2 angioedema in cycle 1 and came off therapy. No significant infusion reactions were noted. Response: Nineteen of 22 patients are evaluable for response. Three patients discontinued treatment after cycle 1 and are not evaluable for response. For the full population the overall response rate (ORR) was 82% (18/22), with a complete response (CR) rate of 68% (15/22). For patients treated with at least 3 cycles of therapy who were evaluable for response, the ORR is 95% (18/19) with a CR rate of 79% (15/19). Six patients went from treatment to SCT. With a median follow-up of 0.52 years median progression free survival (PFS) has not been reached (Figure 1), and with a median follow-up of 0.82 years overall survival (OS) has not been reached (Figure 2). Conclusion: In this study of the triplet combination of BV, Ipi and Nivo for R/R HL, therapy was generally well tolerated, although more grade 3 AEs were seen than in the doublets. In a heavily pretreated patient population, with 9 patients post SCT, the ORR of 95% and CR rate of 79% in evaluable patients is extremely promising. Data will be updated to include longer term PFS and OS by the time of the meeting. Optimization of this strategy is ongoing in E4412, now a randomized phase 2 study comparing the doublet of BV-Nivo to the triplet of BV-Ipi-Nivo.

Disclosures
Diefenbach: Trillium: Research Funding; Incyte: Research Funding; Genentech: Consultancy; Seattle Genetics: Consultancy, Research Funding; Denovo: Research Funding; Acerta: Research Funding; Millenium/Takeda: Research Funding; Merck: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Hong:Merck: Consultancy. Cohen:Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Takeda: Research Funding; BioInvent: Consultancy; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Advani:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Merck: Research Funding; Autolus: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Kura: Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Cell Medica: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Janssen: Research Funding; Millenium: Research Funding; Infinity: Research Funding; Regeneron: Research Funding; Agensys: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Gilead/Kite: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Kyowa: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Forty Seven: Research Funding. Barta:Janssen: Membership on an entity's Board of Directors or advisory committees; Merck, Takeda, Celgene, Seattle Genetics, Bayer: Research Funding. Svoboda:Regeneron: Research Funding; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Merck: Research Funding; Kyowa: Consultancy; TG Therapeutics: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; KITE: Consultancy. Karmali:AstraZeneca: Speakers Bureau; Gilead: Speakers Bureau. Kahl:Genentech: Consultancy; Abbvie: Consultancy; Acerta: Consultancy; Celgene: Consultancy; AstraZeneca: Consultancy; ADC Therapeutics: Consultancy; Seattle Genetics: Consultancy; Juno: Consultancy; CTI: Consultancy; Gilead: Consultancy. Ansell:LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Pfizer: Research Funding; Celldex: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Merck & Co: Research Funding; Takeda: Research Funding.