Double-Blind, Placebo Controlled, Randomized, Multicenter, Phase II Study to Assess the Efficacy of the High Affinity CXCR4 Inhibitor BL-8040 As Addition to Consolidation Therapy in AML By the SAL and OSHO Leukemia Study Groups

Background: Leukemia-cell-stroma interactions are an attractive therapy target in AML. The CXC chemokine receptor 4 (CXCR4) and its ligand CXCL12 (SDF-1) are expressed and secreted by myeloid leukemia blasts and play an essential role in the migration, homing, differentiation, proliferation, and retention of myeloid blasts within the protective bone marrow (BM) niche. The high-affinity CXCR4 antagonist BL-8040 is directly toxic for AML blasts and interrupts the interaction between blasts and the protective BM microenvironment.

Objective: The aim of this clinical trial was to evaluate the impact of BL-8040 in combination with standard consolidation therapy on relapse free survival (RFS) in patients with acute myeloid leukemia (AML) in first complete remission (CR, CRp, CRi).

Methods: Adult patients ≥ 18 years with documented 1st CR/CRi/CRp, after induction therapy with cytarabine and an anthracycline, and not scheduled for allogeneic stem cell transplantation were randomized in a 1:1 ratio to receive two cycles (≥ 60 years) or three cycles (<60 years) of high-dose cytarabine plus BL-8040 or placebo as consolidation therapy. The dosage of cytarabine was 1g/m² per dose for subjects older than 60 years and 3 g/m² per dose for subjects younger than 60 years.

Results: Between November 2015 and November 2019, 134 patients of the originally planned number of 202 were recruited at 29 trial sites, 6 patients violated inclusion and/or exclusion criteria and were excluded. Considering the results of the interim analysis, the data monitoring committee recommended to stop recruitment. Thus, no further patients were enrolled. One hundred and twenty-eight patients were randomized (63 placebo; 65 BL-8040). Baseline characteristics were balanced between treatment arms: median age 61 vs 63 years; 2010 ELN favorable or intermediate-risk 95% vs 98%; CXCR4 expression 38% vs 30% in the BL-8040 and standard arm, respectively.

Overall median follow-up time was 25.4 months. Median RFS was similar between arms 10.3 months [95% CI 8.0,12.0] for the BL-8040 arm and 11.5 months [95% CI 8.6,24.1] for the placebo arm (two-sided p=0.98 by log-rank test).The median OS was not reached at the time point of the analysis. Intention to treat (ITT) analyses revealed no difference between placebo and BL-8040, neither for the total cohort, nor for the subset of patients with expression of CXCR4 with respect to RFS (Hazard ratio (HR) 1.0, 95% CI 0.7,1.6, p =0.9, and HR 0.9, 95% CI 0.1,2.9, p =0.9,respectively) or overall survival (OS; HR 1.1, 95% CI 0.6,2.0, p = 0.8, and HR 2.5, 95% CI 0.4,13.8, p = 0.3, respectively). Regarding safety endpoints, overall, 739 and 576 adverse events were documented in the BL-8040 and placebo arm, respectively. Serious adverse events were similar between therapies.

Conclusion: The addition of BL-8040 to intensive consolidation therapy did not improve RFS or OS. Although more side effects were noted, no differences in serious adverse events were observed.

Nogai:Amgen: Other: non-financial support; Celgene: Honoraria; Roche: Honoraria; GSK: Honoraria; BMS: Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Other: non-financial support; Alexion: Honoraria; Janssen: Honoraria, Other: non-financial support. Haenel:Gilead: Consultancy, Honoraria; Pfizer: Honoraria; JAZZ: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Röllig:Servier: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria; Pfizer Inc.: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria; Celgene Corporation: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Amgen Inc.: Honoraria; AbbVie Inc.: Consultancy, Honoraria, Research Funding. Jost:BMS Celgene: Honoraria; Jazz: Honoraria. Schlenk:Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; PharmaMar: Research Funding; AstraZeneca: Research Funding; Pfizer: Honoraria, Research Funding; Abbvie: Research Funding; BergenBio: Honoraria; Novartis: Honoraria. Krug:AbbVie: Honoraria; , Sanofi: Honoraria; BMS: Honoraria; , Leo Pharma,: Honoraria. Goetze:Servier: Honoraria; Abbvie: Honoraria; BMS: Honoraria. Schubert:Alexion: Honoraria; Novartis: Honoraria; Roche: Other; SOBI: Honoraria; Janssen: Honoraria. Subklewe:Pfizer: Consultancy; Roche: Consultancy, Research Funding; Morphosys: Research Funding; Miltenyi Biotech: Research Funding; Gilead: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Seagen: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Takeda: Other: Travel support; Novartis: Consultancy, Speakers Bureau; Celgene/BMS: Consultancy, Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau. Sayer:MSD: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Sorani:BiolineRX: Current Employment. Vainstein:BioLineRx Ltd.: Current Employment, Current equity holder in publicly-traded company. Kadosh:BiolineRX: Current Employment. Platzbecker:Janssen: Honoraria; Takeda: Honoraria; Silence Therapeutics: Honoraria; Novartis: Honoraria; Jazz: Honoraria; Abbvie: Honoraria; BMS/Celgene: Honoraria; Geron: Honoraria. Mueller-Tidow:BiolineRX: Research Funding; Pfizer: Research Funding.