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
Blood, vol. 140, pp. 3338–3340
Abstract
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.
Authors 52
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Heidelberg University · University Hospital Heidelberg
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1Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany., Heidelberg, Germany
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2Hematology and Oncology, University Hospital of Halle (Saale), Halle (Saale), Germany
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Martin Luther University Halle-Wittenberg
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3Stem Cell Transplant Unit, Medical Clinic IV, Martin-Luther-University Halle-Wittenberg, Halle, Germany
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Charité - Universitätsmedizin Berlin
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4Klinik für Hämatologie und Onkologie, Charité Universitätsmedizin Berlin - Campus Benjamin Franklin, Berlin, Germany
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Stiftung Charité · Charité - Universitätsmedizin Berlin
Affiliation as printed
5Division of Hematology and Oncology at Campus Benjamin Franklin (CBF), Charité, Berlin, Germany
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6Medizinische Klinik III, Klinikum Chemnitz, Chemnitz, Germany
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7Department of Internal Medicine III, Klinikum Chemnitz, Chemnitz, Germany
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University Hospital Carl Gustav Carus · Technische Universität Dresden
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8Department of Internal Medicine I, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany
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University Hospital Carl Gustav Carus
Affiliation as printed
9Department of Internal Medicine I, University Hospital, Dresden, Germany
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Universitätsklinikum Aachen · RWTH Aachen University
Affiliation as printed
10Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, University Hospital RWTH Aachen, Aachen, Germany
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Heidelberg University · University Hospital Heidelberg · National Center for Tumor Diseases
Affiliation as printed
11Department of Hematology, Oncology and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany
12German Cancer Research Center, NCT-Trial Center, National Center for Tumor Diseases, Heidelberg, Germany
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Affiliation as printed
13Klinik für Hämatologie, Universitätsklinikum Essen, Essen, Germany
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14Goethe University Frankfurt, Frankfurt, Germany
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15Department of Medicine III, Hospital Leverkusen, Leverkusen, Germany
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TUM Klinikum · Technical University of Munich
Affiliation as printed
16Department of Medicine III, Klinikum rechts der Isar, Technical University Munich (TUM), Munich, Germany
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University Hospital Schleswig-Holstein
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17Städtisches Krankenhaus Kiel, Kiel, DEU
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18Hematology, Klinikum Dessau, Dessau, Germany
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Krankenhaus St. Elisabeth und St. Barbara
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2014. Krankenhaus St. Elisabeth und St. Barbara Medizinische Klinik III Pneumologie/Hämatologie-Onkologie/Palliativmedizin, Halle, Germany., Halle-Saale, Germany
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Affiliation as printed
21Johanniter Krankenhaus Genthin-Stendal gGmbH, Stendal, DEU
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22Medizinische Klinik A, Universitätsklinikum Münster, Münster, Germany
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Gemeinschaftsklinikum Mittelrhein
Affiliation as printed
2317. GEMEINSCHAFTSKLINIKUM MITTELRHEIN Ev. Stift St. Martin Klinik für Innere Medizin Schwerpunkt Hämatologie / Onkolgie, Koblenz, Germany., Koblenz, Germany
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LMU Klinikum · Ludwig-Maximilians-Universität München
Affiliation as printed
24Department of Medicine III, University Hospital, LMU Munich, Munich, Germany
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252nd Department of Internal Medicine, Oncology and Hematology, Robert Bosch Hospital, Stuttgart, Germany
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Helios Dr. Horst Schmidt Kliniken Wiesbaden
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26Innere Medizin III, Horst-Schmidt-Kliniken Wiesbaden, Wiesbaden, Germany., Wiesbaden, Germany
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27Department of Hematology and Oncology, Vivantes Klinikum Am Urban, Berlin, Germany
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28Klinikum Nürnberg, Nürnberg, Germany
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29Universitätsklinikum Wuerzburg, Medizinische Klinik Und Poliklinik II, Wuerzburg, DEU
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Medizinische Universität Lausitz - Carl Thiem
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30Department of Hematology and Oncology, Carl-Thiem-Klinikum, Cottbus, Cottbus., Cottbus, Germany
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31Klinik für Innere Medizin II, Universitätsklinikum Jena, Jena, Germany
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32Medical Clinic II, University Hospital of Augsburg, Augsburg, Germany
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Charité - Universitätsmedizin Berlin
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33Department of Hematology, Oncology and Palliative Care, Klinikum Ernst von Bergmann, Academic Teaching Hospital of Charité University Medical School, 10117 Berlin, Germany., Berlin, Germany
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34DRK Krankenhaus Luckenwalde, Luckenwalde, DEU
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Martin Luther University Halle-Wittenberg
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3530. Coordination Centre for Clinical Trials, Faculty of Medicine, Martin-Luther University Halle-Wittenberg, Halle, Germany, Halle, Germany
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Heidelberg University · University Hospital Heidelberg
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36Department of Medicine, Hematology, Oncology and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany
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Martin Luther University Halle-Wittenberg
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37Coordination Centre for Clinical Trials, Faculty of Medicine, Martin-Luther University Halle-Wittenberg, Halle, Germany, Halle-Saale, Germany
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Martin Luther University Halle-Wittenberg
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3830. Coordination Centre for Clinical Trials, Faculty of Medicine, Martin-Luther University Halle-Wittenberg, Halle, Germany, Halle-Saale, Germany
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Martin Luther University Halle-Wittenberg
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39Martin-Luther-Universität Halle-Wittenberg, Town 1, Germany
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40BioLineRx, Ltd., Modi'In, Israel
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41Central Laboratory, University Hospital Halle, Halle/Saale, Germany., Halle-Saale, Germany
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Martin Luther University Halle-Wittenberg
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42Department of Internal Medicine IV, Hematology and Oncology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany., Halle-Saale, Germany
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Affiliation as printed
43BioLineRx Ltd., Modi'in, Israel
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Martin Luther University Halle-Wittenberg
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44Martin-luther-University Halle-Wittenberg, Halle (saale), DEU
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40BioLineRx, Ltd., Modi'In, Israel
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45BioLineRx Ltd., Modiin, Israel
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Martin Luther University Halle-Wittenberg
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37Coordination Centre for Clinical Trials, Faculty of Medicine, Martin-Luther University Halle-Wittenberg, Halle, Germany, Halle-Saale, Germany
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Martin Luther University Halle-Wittenberg
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46Institute of Medical Epidemiology, Biometrics, and Informatics, Martin-Luther-University Halle-Wittenberg, Halle, Germany, Halle-Saale, Germany
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University Hospital Schleswig-Holstein
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47Department of Internal Medicine II, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
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48Department of Hematology, Cell Therapy and Hemostaseology, University Hospital Leipzig, Leipzig, Germany
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Goethe University Frankfurt · University Hospital Frankfurt
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49Dept. of Medicine, Hematology and Oncology, Goethe University Frankfurt, University Hospital, Frankfurt, Germany
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University Hospital Carl Gustav Carus
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50Department of Internal Medicine I, University Hospital Carl Gustav Carus, Dresden, Germany
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51Departement of Medicine III - Hematology, Oncology, and Palliative Care, University of Rostock, Rostock, Germany
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Heidelberg University · University Hospital Heidelberg
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11Department of Hematology, Oncology and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany
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