A Study Testing an Improved Dose of UM171 to Help Make Cord Blood Transplants More Effective and Safe.

Single-site, Prospective, Open-label Phase I-II Study on Transplantation Using Cord Blood Treated With an Optimized Dose of UM171: Optimized ECT-001-CB.

This clinical study is testing a new way to improve stem cell transplants for adults with high-risk blood cancers, such as leukemia or myelodysplasia, who do not have a suitable donor. The transplant uses stem cells from umbilical cord blood that have been expanded in the lab using a molecule called UM171. Previous studies showed that UM171 helps these cells grow and work better, leading to faster blood count recovery and fewer complications.

In this study, researchers are testing whether increasing the dose of UM171 during the lab expansion process can make the transplant less toxic. The hypothesis is that using a higher dose of UM171 to expand cord blood stem cells will help patients recover blood counts faster after transplant by improving the growth and function of the cells. This may lead to better immune recovery, fewer infections, shorter hospital stays, and improved overall outcomes.

Only seven patients will be enrolled, and they will be followed for one year after their transplant.

This is a single-center, prospective, open-label, dose-escalating Phase I/II clinical trial designed to evaluate the safety, feasibility, and efficacy of ECT-001-CB cord blood transplantation using an optimized dose of UM171, a small molecule that enhances hematopoietic stem cell (HSC) expansion.

Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for patients with high-risk hematologic malignancies. However, some patients lack a suitable donor. Cord blood (CB) is a valuable alternative donor source due to its tolerance for HLA mismatches and lower incidence of chronic graft-versus-host disease (GVHD). Despite these advantages, CB transplantation has declined due to limitations such as low cell dose, delayed engraftment, and increased non-relapse mortality (NRM).

UM171 is a proprietary molecule that has demonstrated the ability to expand CD34⁺ HSCs ex vivo, thereby addressing the cell dose limitation of CB transplants. Previous trials using UM171-expanded CB units (ECT-001-CB) showed promising results, including faster engraftment, improved immune reconstitution, and reduced NRM.

This study builds on prior findings by investigating whether a higher dose of UM171 (125nM vs. the conventional 35nM) can further accelerate neutrophil engraftment and enhance immune recovery. Preclinical data suggest that higher UM171 concentrations may increase the number of long-term repopulating HSCs and promote balanced lymphoid and myeloid differentiation, potentially improving clinical outcomes.

Seven patients with high-risk acute leukemia or myelodysplasia, or other hematologic malignancies requiring HSCT and lacking a suitable donor, will be enrolled over a 12-month period. Patients will receive a single ECT-001-CB transplant following an intermediate or high-intensity conditioning regimen. The CB unit will be expanded ex vivo with escalating doses of UM171 (starting at 70nM, potentially increasing to 125nM based on engraftment outcomes).

Primary endpoints include safety (grade ≥3 adverse events), feasibility of manufacturing and infusion, and time to neutrophil engraftment. Secondary endpoints include NRM, platelet engraftment, graft failure, progression-free survival (PFS), overall survival (OS), incidence of acute and chronic GVHD, immune reconstitution, and time to hospital discharge. Exploratory endpoints include infectious complications, relapse incidence, GVHD-free relapse-free survival (GRFS), advanced immunologic profiling, and comparisons with historical controls.

Safety will be monitored by an independent Data Safety Monitoring Board (DSMB). The study includes predefined stopping rules to ensure patient safety, including thresholds for engraftment delay, graft failure, NRM, and severe GVHD.

This trial aims to optimize CB transplantation by enhancing the efficacy of UM171-expanded grafts, potentially offering a safer and more effective treatment option for patients with limited donor availability.

Inclusion Criteria:

1. Subjects ≥ 18 and ≤ 67 years old,

2. Patient with either i. High risk acute leukemia or myelodysplasia defined as expected 2 year OS or PFS < 40% after a conventional allogeneic HSC transplant or ii. A hematologic malignancy requiring an allogeneic hematopoietic stem cell transplant and lack of a suitable HLA identical, haploidentical or 7/8 HLA matched donor.

3. Availability of an adequate CB for expansion:

   i. ≥ 5/8 HLA match when A, B, C and DRB1 are performed at the allele level.

   ii. Minimal cell dose: TNC ≥ 1.5 x 107/kg, and CD34 ≥ 0.5 x 105/kg. iii. Needs to be erythrodepleted by bank prior to cryopreservation. iv. Must comply with local site regulations AND, come from a cord bank that is FACT, or AABB accredited, or FDA approved or eligible for NMDP IND (unless PI approves another bank).

   v. To meet eligibility criteria, the patient's weight at time of cord selection will be used; however, if this weight has increased by more than 5% at time of admission to hospital and with the new weight the patient no longer meets eligibility criteria for cell dose, LI approval will be required to move forward with the selected cord. Every attempt will be made to always use the most recent weight in cord selection

4. Patients with adequate physical function as measured by:

   i. Karnofsky score ≥ 70% ii. Hematopoietic comorbidity index (HCT-CI): 0-3 for 2nd transplant and age 60-65 years, 0-5 if <60 years old, and 0-2 if 66-67 years.

   iii. Adequate cardiac function: Left ventricular ejection fraction ≥ 40% within 60 days prior to start of conditioning regimen iv. Adequate pulmonary function: Forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1) and diffusing capacity corrected for hemoglobin (DLCOc) ≥ 50% of predicted within 60 days prior to start of conditioning regimen.

   v. Adequate hepatic function: Bilirubin < 2 x ULN unless felt to be related to Gilbert's disease or hemolysis; AST and ALT ≤ 2.5 x ULN (the PI may approve up to 3 times ULN) ; alkaline phosphatase ≤ 5 x ULN.

   vi. Adequate renal function: Estimated or measured creatinine clearance ≥ 60 ml/min/1.73m2.

5. A back up graft must have been identified prior to initiation of conditioning regimen.

6. Signed written informed consent.

7. Female patients of childbearing potential must have a negative serum pregnancy test within 30 days of enrolment and within 30 days of starting of preparative regimen; patient must be willing to use an effective contraceptive method while enrolled in the study.

Exclusion Criteria:

1. Allogeneic or autologous myeloablative transplant within last 6 months.

2. Patients with inadequate physical function as measured by:

   i. Active, uncontrolled bacterial, viral or fungal infection (currently taking medication with evidence of either progression of clinical symptoms or radiologic findings or lack of evidence of response to therapy).

   ii. Presence of a malignancy other than the one for which the HSC transplant is being performed, with an expected survival estimated to be less than 75% at 5 years.

   iii. Seropositivity for HIV. iv. Hepatitis B or C infection with measurable viral load. Patients with hepatitis B or C infection regardless of viral load require clear documentation of absence of cirrhosis by either fibroscan or biopsy.

   v. Liver cirrhosis.

3. Positive anti-donor HLA antibodies with MFI above 1500 against the selected CB (PI may approve an MFI up to 5000; if above 2500, desensitization is strongly recommended)

4. Use of an investigational agent within 30 days (defined as a drug not approved by Health Canada or FDA regardless of indication) of start of chemotherapy unless documented approval obtained from Sponsor.

5. Presence of ≥30% blasts in bone marrow or ≥ 0.5 x109/L blasts in circulating blood

6. Active central nervous system involvement or chloroma > 2 cm.