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934 Safety and Demonstrated Efficacy of Placenta-Derived Cell Therapy PLX-R18 in Subjects with Incomplete Hematopoietic Recovery Following Hematopoietic Cell Transplantation: A Phase I International Multi-Center Study

Program: Oral and Poster Abstracts
Session: 508. Bone Marrow Failure: Poster I
Hematology Disease Topics & Pathways:
Biological, bone marrow, Therapies, Biological Processes, Clinically relevant, hematopoiesis, transplantation, stem cells
Saturday, December 5, 2020, 7:00 AM-3:30 PM

Hillard Lazarus1*, Carolina Escobar, MD2*, Leland Metheny III, MD1,3, Joseph P. McGuirk, DO4,5, Tsila Zuckerman, MD6,7, Mark Litzow, MD8, Scott D. Rowley, MD9, Racheli Ofir, PhD10*, Liran Shani, MD11* and Jacob M. Rowe, MB, BS12

1Case Western Reserve University, Cleveland, OH
2Texas Oncology-Baylor Charles A. Sammons Cancer Center Blood and Marrow Transplant, Dallas, TX
3Adult Hematologic Malignancies & Stem Cell Transplant Section, University Hospitals Seidman Cancer Center, Cleveland, OH
4The University of Kansas Cancer Center, Westwood, KS
5Division of Hematologic Malignancies & Cellular Therapeutics, University of Kansas Medical Center, Kansas City, KS
6Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Haifa, Israel
7The Ruth and Bruce Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, Haifa, Israel
8Division of Hematology, Mayo Clinic, Rochester, MN
9John Theurer Cancer Center, Myeloma and Lymphoma Divisions, NNJCA, Hackensack, NJ
10Pluristem LTD, HAIFA, Israel
11Pluristem ltd, HAIFA, Israel
12The Ruth and Bruce Rappaport Faculty of Medicine, Shaare Zedek Medical Center, Jerusalem, Israel

Introduction: Failure to engraft donor cells is a devastating complication after allogeneic hematopoietic cell transplantation (HCT) while full engraftment remains a challenge in some recipients. Therapeutic approaches, such as recombinant hematopoietic growth factors, salvage only a minority of patients leaving affected patients at risk for recurrent infections and multiple blood products transfusions. PLX-R18 cells have been shown to mitigate bone marrow failure in rodent and non-human primate models. Further, these human placenta-derived mesenchymal-like adherent stromal cells secrete many cytokines after intramuscular (IM) injection that have been shown to stimulate growth and migration of bone marrow cells in vitro, e.g. MCP-1, IL-6, and IL-8. The initial results of the first cohort of this phase I trial were previously reported (ASH 2018 abstract 3379).

Methods: Enrollment for this multi-center, open label, dose-escalation, phase I trial (ClinicalTrials.gov: NCT03002519) began in October 2017. Eligibility criteria included patients age ≥18 years who underwent either autologous (auto) or allogeneic (allo) HCT but suffered from incomplete hematopoietic recovery at least 3 months post-transplant, defined as failure to maintain either hemoglobin (Hb) >8g/dL and/or neutrophil count (ANC) >1,000/μL and/or platelet (PLT) count >50,000/μL. Other eligibility criteria included no evidence of underlying malignancy at time of enrollment, no active infection and no evidence of grade 3-4 acute or severe chronic GvHD. Subjects were enrolled into 3 dose-escalating cohorts: low-dose at 1M cells/kg (n=3), intermediate-dose at 2M cells/kg (n=6), and high-dose at 4M cells/kg (n=10). The specified dose of PLX-R18 cells was injected IM in multiple locations and given twice, 1 week apart. Cohorts were recruited sequentially, and progression to the next cohort was based on the safety assessment of its predecessor. Adverse event grading used the NCI CTCAE criteria. As of July 2020, all patients in cohorts 1 and 2 (3 & 6 patients, respectively) and 10 patients in cohort 3 were treated. Data were analyzed using the lmerTest package (ver. 3.1.0) in R (ver. 3.6.1) to produce baseline-adjusted least square means. As study is in progress and data collection ongoing, not all subjects have data on all parameters for all time points.

Results: Data on 19 subjects (29-75 yrs) with either allo (n=17) or auto (n=2) HCT are reported herein. Not all patients reached the 9 month time point. Four patients died while on study and 2 withdrew consent within the 1 year follow up period. All deaths and other severe adverse events (SAEs) occurred due to progression of primary disease and were assessed as not related by investigators and sponsor. Most frequent related AEs were injection-site reactions.

The table summarizes number of patients who improved from below the critical level, as defined above, at day 0 to above the critical level for a sustained period. Only those patients that were below the critical blood levels at day 0 are shown. To date, the majority of such patients improved to above the critical level after treatment. For example, 9 patients had ANC <1000/μL at day 0. Of the 4 patients for which data currently exists, all improved to ≥1000/μL at 9 months.

The plots show changes in Hb, ANC and PLT up to 9 months following treatment. The dashed lines represent respective critical levels. Overall, there was improvement in the 3 parameters, with the greatest improvement observed in patients receiving the predicted optimal dose of 4M cells/kg. In this cohort, Hb levels increased from 9.29±0.5 to 13.19±1.2 (p=0.0019), ANC increased from 1.09±0.6 to 5.13±1.7 (p=0.018) and PLT increased from 45.7±10 to 175.9±28 (p=0.000012).

Conclusions: Treatment with PLX-R18 is safe, well-tolerated and clearly effective in some patients. The most frequent AEs were reversible injection site reactions, all without sequelae. An overall improvement was observed in most patients, and among the high-dose cohort clinically impressive improvements in Hb, ANC and PLT were observed. The trial continues to follow up on patients. Upon completion, a large phase II trial, using the optimal dose, is considered for the same indication. Other attractive clinical areas for PLX-R18 therapy include acute radiation syndrome, bone marrow failure, aplastic anemia, myelofibrosis and with HCT as a “pan” cytokine to enhance rapid count recovery in all cells lines.

Disclosures: Lazarus: Pluristem ltd: Consultancy. McGuirk: Pluristem Ltd: Research Funding; Gamida Cell: Research Funding; Bellicum Pharmaceutical: Research Funding; Astellas: Research Funding; Novartis: Research Funding; Fresenius Biotech: Research Funding; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Allo Vir: Consultancy, Honoraria, Research Funding; Kite Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau. Rowley: AbbVie: Current equity holder in publicly-traded company; FATE Therapeutics: Consultancy. Ofir: Pluristem: Current Employment. Shani: Pluristem ltd: Current Employment. Rowe: Pluristem ltd: Consultancy.

*signifies non-member of ASH