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Single Dose of the CXCR4 Antagonist BL-8040 Induces Rapid Published OnlineFirst August 23, 2017; DOI: 10.1158/1078-0432.CCR-16-2919 Cancer Therapy: Clinical Clinical Cancer Research Single Dose of the CXCR4 Antagonist BL-8040 Induces Rapid Mobilization for the Collection of Human CD34þ Cells in Healthy Volunteers Michal Abraham1, Yaron Pereg2, Baruch Bulvik1, Shiri Klein3, Inbal Mishalian3, Hana Wald1, Orly Eizenberg1, Katia Beider4, Arnon Nagler4, Rottem Golan2, Abi Vainstein2, Arnon Aharon2, Eithan Galun3, Yoseph Caraco5, Reuven Or6, and Amnon Peled3,4 Abstract Purpose: The potential of the high-affinity CXCR4 antagonist systemic reactions were mitigated by methylprednisolone, BL-8040 as a monotherapy-mobilizing agent and its derived paracetamol, and promethazine pretreatment. In the first part graft composition and quality were evaluated in a phase I clinical of the study, BL-8040 triggered rapid and substantial mobili- þ study in healthy volunteers (NCT02073019). zation of WBCs and CD34 cells in all tested doses. Four hours Experimental Design: The first part of the study was a ran- postdose, the count rose to a mean of 8, 37, 31, and 35 cells/mL domized, double-blind, placebo-controlled dose escalation (placebo, 0.5, 0.75, and 1 mg/kg, respectively). FACS analysis phase. The second part of the study was an open-label phase, in revealed substantial mobilization of immature dendritic, T, B, þ which 8 subjects received a single injection of BL-8040 (1 mg/kg) and NK cells. In the second part, the mean CD34 cells/kg and approximately 4 hours later underwent a standard leukapher- collected were 11.6 Â 106 cells/kg. The graft composition was esis procedure. The engraftment potential of the purified mobi- rich in immune cells. þ lized CD34 cells was further evaluated by transplanting the cells Conclusions: The current data demonstrate that BL-8040 into NSG immunodeficient mice. is a safe and effective monotherapy strategy for the collection þ Results: BL-8040 was found safe and well tolerated at all of large amounts of CD34 cells and immune cells in a one-day doses tested (0.5–1 mg/kg). The main treatment-related adverse procedure for allogeneic HSPC transplantation. Clin Cancer Res; events were mild to moderate. Transient injection site and 23(22); 1–12. Ó2017 AACR. Introduction interindividual variations in circulating progenitor and stem cell numbers (5), requiring 4–6repeateddosingtocollecta Allogenic hematopoietic stem and progenitor cell (HSPC) sufficient number of cells. In addition, although considered transplantation (ALSPCT) has emerged as the preferred strategy generally safe, G-CSF is frequently associated with a variety in the treatment of a variety of hematologic malignancies (1, 2). of side effects. Therefore, improved methods to mobilize and Mobilization of stem cells using granulocyte colony-stimulat- collect HSPCs for transplantation are required. ing factor (G-CSF) from healthy donors is the common clinical It has been proposed that G-CSF induces the mobilization of practice. G-CSF–mobilized peripheral blood mononuclear HSPCs through an indirect mechanism by activating neutrophils cells (PBMC) are routinely used as a source of hematopoietic to secrete a variety of proteolytic enzymes, including elastase, stem cells (HSC) for transplantation (3, 4). Despite the potency cathepsin G, MMP-2, and MMP-9 that can degrade the chemokine of G-CSF in mobilizing stem cells, it ultimately results in broad CXCL12 and its receptor CXCR4. Over recent years, it has become apparent that the interaction between CXCL12 and its receptor, CXCR4, plays a pivotal role in hematopoietic stem cell mobili- 1Biokine Therapeutics Ltd, Ness Ziona, Israel. 2BioLineRx LTD, Modi'in, Israel. zation and engraftment (6–8). Consequently, disruption of 3Goldyne Savad Institute of Gene Therapy, Hebrew University Hospital, Jeru- CXCL12/CXCR4 interactions results in mobilization of hemato- 4 salem, Israel. Hematology Division, Chaim Sheba Medical Center and Tel Aviv poietic stem and progenitor cells from the bone marrow to the University, Tel-Hashomer, Israel. 5Clinical Pharmacology Unit, Hadassah Uni- peripheral blood system. versity Hospital, Jerusalem, Israel. 6Cancer Immunotherapy and Immunobiology Research Center, Hadassah University Hospital, Jerusalem, Israel. Indeed, blockade of the CXCR4 receptor with the reversible CXCR4 antagonist AMD3100 (Plerixafor; Mozobil) results in Note: Supplementary data for this article are available at Clinical Cancer rapid mobilization of HSPCs (9, 10). When AMD3100 as a single Research Online (http://clincancerres.aacrjournals.org/). þ agent was compared with G-CSF as a mobilizer of CD34 cells M. Abraham and Y. Pereg contributed equally to this article. in healthy volunteers, AMD3100 was inferior to G-CSF (5). Corresponding Author: Amnon Peled, Hadassah University Hospital, P.O Box However, AMD3100 increased both G-CSF–stimulated mobili- þ 12000, Jerusalem, Israel. Phone: 972-2677-8780; Fax: 972-26430982; E-mail: zation and the leukapheresis yield of CD34 cells. As such, [email protected] Mozobil was approved in combination with G-CSF for the mobi- þ doi: 10.1158/1078-0432.CCR-16-2919 lization of CD34 cells in patients with lymphoma and multiple Ó2017 American Association for Cancer Research. myeloma that undergo stem cell mobilization (11, 12). www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2017 American Association for Cancer Research. Published OnlineFirst August 23, 2017; DOI: 10.1158/1078-0432.CCR-16-2919 Abraham et al. two consecutive days). Part 1 of the study served to select the Translational Relevance optimal safe and efficacious dose of BL-8040 to be used in part Allogeneic hematopoietic stem and progenitor cell (HSPC) 2. Part 2 (dose expansion) was an open-label study, exploring transplantation (ALSPCT) has emerged as the preferred strat- the safety, tolerability, and pharmacodynamic effect of BL-8040 egy in the treatment of a variety of hematologic malignancies. in a single cohort of healthy subjects who received the selected Improved methods to mobilize and collect leukapheresis (LP) dose regimen of BL-8040 (1 mg/kg) based on the data collected products with shortened time to engraftment, immune recon- from part 1 (numbered 5001–5008). In addition, subjects stitution, and antitumor effects are essential. In the final LP underwent leukapheresis to examine the yield and character- products mobilized and collected after BL-8040, there were istics of the mobilized cells. Each cohort in part 1 consisted of þ þ much higher number of CD34 HPCs compared with CD34 8 subjects; 6 subjects in each cohort randomly allocated to HPCs collected after mobilization with granulocyte colony- receive BL-8040 and 2 subjects to receive placebo. Part 2 stimulating factor (G-CSF). Furthermore, in the LP products involved a single cohort of 8 subjects, who received BL-8040 mobilized and collected after BL-8040, there were much at the selected optimal dose level. þ þ higher number of CD4 CD8 T, NKT, NK, and dendritic cells, compared with LP collected after mobilization with G-CSF. Eligibility criteria This new graft composition may have a different effect on the As this was a dose escalation study in healthy volunteers, engraftment ability, antitumor effect, and immune reconsti- men only selection was for safety reasons to exclude exposure tution potential of the LP product. of childbearing potential subjects. The main criteria for inclu- sion for this study were: healthy male subjects aged between 18 and 45 years, with body mass index (BMI) between 18 and 30 kg/m2 and weight 60 kg. In addition, subjects had to be BL-8040 (BKT140) demonstrates a higher affinity and either surgically sterilized (vasectomy), or if their partner was of longer receptor occupancy for CXCR4 and provides a greater childbearing potential, had to use two methods of contracep- effect on the retention–mobilization balance of bone marrow tion, one of which had to be a barrier method, from the first SCs when compared with AMD3100 in both in vitro and in vivo dose until 3 months after the last dose. All the subjects were mice studies (13–15). Caucasian males. This study investigated the capacity of BL-8040 to mobi- After providing an informed consent, adult male subjects þ lize and retain CD34 cells in healthy volunteers, hypothe- ages 18–45 years old were screened for study eligibility by sizing that a single day procedure of BL-8040 monotherapy assessment of inclusion and exclusion criteria. Inclusion criteria administration (single injection) followed by one apheresis consisted of a BMI measure between 18 and 30 kg/m2 and þ session will provide sufficient amounts of CD34 HSPCs for weight 60 kg. The subjects were healthy as indicated by their transplantation. medical history, physical examination, 12-lead electrocardio- gram (ECG), and laboratory safety tests. Screening procedures Materials and Methods included the collection of demographic data, medical history, physical examination [including height, weight and body mass Clinical study index (BMI)], vital signs (blood pressure, pulse rate, respiration A phase I, two-part study exploring the safety, tolerability, rate and oral temperature), 12-lead electrocardiogram (ECG), pharmacodynamic, and pharmacokinetic effects of ascending and safety laboratory evaluations [hematology, biochemistry, doses of BL-8040 in healthy subjects (study BL-8040.02) after coagulation (PT/INR and aPTT)] and urinalysis. informed consent was obtained. The study was conducted at the Hadassah Clinical Research Center (HCRC), Hadassah
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