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Eligible patients will receive an ablative conditioning regimen and be infused with an ECT-001 expanded cord-blood. The ECT-001 expanded CB could be infused fresh, or cryopreserved.

1. Patients will receive a conditioning regimen (such as: cyclophosphamide 120 mg/kg, fludarabine 75mg/m2 and TBI 12 Gy or cyclophosphamide 50 mg/kg, fludarabine 150 mg/m2, thiotepa 10 mg/kg and TBI 4 Gy).
2. The cord to be expanded will undergo CD34+ selection. The CD34- product is cryopreserved and will be thawed and infused on Day +1 post-transplant. The CD34+ product will be placed in a closed culture with UM171 for a 7-day expansion and is infused on Day 0.
3. Patients will receive standard supportive care and GVHD prophylaxis (such as MMF and tacrolimus). Tacrolimus will be discontinued on Day 100 post-transplant unless GVHD arises.

Transplant with an expanded ECT-001 cord blood

Sandra Cohen, MD

Allogeneic hematopoietic stem cell transplantation is a life-saving procedure in patients with blood cancers. Cord blood (CB) represents an alternative source of stem cells, which is associated with a lower risk of relapse, especially in the presence of minimal residual disease in the setting of acute leukemia and myelodysplasia. Furthermore, CB has the added advantage of being associated with a low risk of chronic graft versus host disease (GVHD). Unfortunately, CB transplants are hampered by a higher risk of transplant related mortality (TRM) when compared to bone marrow/peripheral blood transplants because of the limited cell dose of CB.

In the previous UM171 trial (NCT02668315), the CB expansion protocol using the ECT-001-CB technology (UM171 molecule) has proven to be technically feasible and safe. UM171 expanded CB was associated with a median neutrophil recovery at day (D)+18 post transplant. Amongst 22 patients who received a single UM171 CB transplant with a median follow-up of 18 months, risk of TRM (5%) and grade 3-4 acute GVHD (10%) were low. There was no moderate-severe chronic GVHD. Thus, overall and progression free survival at 12 months were impressive at 90% and 74%, respectively. The UM171 expansion protocol allowed access to smaller, better HLA matched CBs as \>80% of patients received a 6-7/8 HLA matched CB. Interestingly there were 5 patients who had already failed an allogeneic transplant and 5 patients with refractory/relapsed acute leukemia/aggressive lymphoma. Despite this high risk population, progression was 20% at 12 months. Hence, in this new trial, investigators are targeting patients with high and very high-risk acute leukemia/myelodysplasia to test the antileukemia effect of this new graft, a UM171 expanded CB.

Methodology:

This is a multi-center open label phase II clinical trial. Patients with high and very high-risk acute leukemia/myelodysplasia will receive a single 5-7/8 HLA matched ECT-001 (UM171) expanded cord blood after an ablative conditioning regimen. This group of patients would be expected to have poor progression free survival (PFS) after a conventional allogeneic transplant (bone marrow-peripheral blood).

Investigators key primary and secondary objectives include:

1. To confirm low Transplant Related Mortality (TRM)
2. To evaluate relapse free survival (RFS)
3. To analyze kinetics of hematologic engraftment;
4. To evaluate the incidence of acute and chronic GVHD
5. To evaluate the safety of the procedure
6. To evaluate incidence of infectious complications
7. To analyze duration of hospitalization
8. To evaluate the incidence of pre-engraftment/engraftment syndrome (PES/ES)
9. To analyze the effect of cryopreservation of the expanded CD34+ fraction on safety and efficacy endpoints

UM171 Expanded Cord Blood In Patients With High-Risk Acute Leukemia/Myelodysplasia

A Phase II Open-label Study of ECT-001-expanded Cord Blood Transplantation in Patients With High-risk Acute Leukemia/Myelodysplasia

If the underlying disease recurs, sequencing will be performed of the leukemias/MDS to identify markers suggesting escape from the immune system: for example down regulation of HLA on cancer cells.

To better understand the effect of ECT-001 expansion a sample of the graft will be transplanted into mice before and after expansion. In addition, the different cell populations of the graft will be analyzed by flow cytometry before and after expansion. UM171 appears to increase significantly the proportion of dendritic cell precursors and mast cell precursors. Confirmation of this observation from the 1st trial will be obtained.

TRM is defined as any death of any cause other than malignant relapse, occurring after the commencement of conditioning regimen that could be related to the transplantation procedure.

RFS will be measured from time of transplant until disease relapse, death or last follow-up.

OS will be measured from time of transplant until disease relapse, death or last follow-up.

Time to neutrophil engraftment is defined as the first day of attainment of an absolute neutrophil count (ANC) ≥0.5 x 109/L for 3 consecutive days. Time to ANC ≥ 0.1 x 109/L will also be documented as it seems to predict TRM.

Absence of neutrophil engraftment by day 42 or secondary graft failure without any obvious cause.

Platelet engraftment is defined as the first day of a sustained platelet count ≥ 20 x 109/L with no platelet transfusion in the preceding 7 days as per CIBMTR standards (www.cibmtr.org).

The time to onset and maximal grade will be recorded. Acute GVHD will be defined as classic acute (time of onset of symptoms ≤ 100 days) or persistent, recurrent, or late onset acute GVHD (time of onset of symptoms \> 100 days) as defined by the NIH. Results will be compared to patients at the same institution transplanted with different stem cell sources.

Defined as per NIH global severity scores for mild, moderate, and severe chronic GVHD.

All adverse events occurring during the clinical trial, including the protocol-defined post-treatment follow-up period, qualifying as a grade ≥ 3 toxicity per the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

Any of the following infections requiring systemic therapy will be captured: invasive candidiasis, aspergillus, other invasive fungi, CMV, adenovirus, EBV, HHV-6, HSV, VZV, PCP, toxoplasmosis and mycobacterium.

Total number of days admitted to the hospital in the first 100 days following transplant. Last day of fever (≥38.0°C) prior to engraftment, and number of days of parenteral feeding during transplant admission.

Stem Cell Network

ExCellThera inc.

Ciusss de L'Est de l'Île de Montréal

Associate Professor University of Montreal

Participants that do not meet criteria for StemEx®, will be registered into the unmanipulated UCB arm and receive the standard conditioning regimen.

StemEx is a stem/progenitor cell-based product of ex-vivo expanded allogeneic UCB, which is administered to the subject in combination with the non-manipulated portion of the same cord blood unit (CBU). The CBU must be cryopreserved in two portions of which the larger (or equal) CBU portion contains at least 1.5 x 107 total nucleated cells (TNC)/Kg. This portion remains unmanipulated and is transplanted on Day 0. StemEx is derived from the smaller (or equal) CBU portion, which is expanded ex vivo for 21 days starting pre-transplant in the presence of cytokines TPO, IL-6, Flt-3L and SCF at a concentration of 50ng/ml and 5μM tetraethylenepentamine (TEPA)

For patients allocated to StemEx® arm:

* Day -20: Start small (or equal) portion expansion at processing site. (II) Conditioning Phase
* Day -6 to -1: Subject receives a RIC regimen containing Fludarabine, Cyclophosphamide and Total Body Irradiation (TBI) (III) Transplantation and Follow-up Phase
* Day 0: CBU unmanipulated portion transplantation (for StemEx® arm) or unmanipulated CBU transplantation.
* Day 1: StemEx® transplantation.
* Day 2 to 3 years: Post transplant follow-up.

StemEx

Patrick Stiff, MD

While cord blood transplants have been performed safely in elderly patients, many still relapse. The investigators propose to intensify the preparative regimen for this patient group in an attempt to decrease relapses, and combine this with an ex vivo expanded Umbilical Cord Blood (UCB) unit.

Allogeneic stem cell transplantation is a life saving procedure in selected high-risk or recurrent hematologic malignancies and marrow failure syndromes. However its wide application is limited by availability of suitably HLA matched adult donors. Umbilical Cord Blood (UCB) has been increasingly used as an alternative hematopoietic stem cell source for these patients. To date, over 10,000 UCB transplants have been performed in both children32-38 and adults.35,39-44 Its advantages include easier procurement, decreased risk to donors, reduced risk of transmitting infections, the immediate availability of cryopreserved units, and acceptable HLA mismatches. The transplantation of UCB allows a greater degree of HLA mismatching without an unacceptably high incidence of graft versus host disease (GVHD). Adult patients receiving myeloablative cord blood transplants have a 90% chance of engraftment, but carry a 50% rate of transplant related mortality.

Umbilical Cord Transplantation for the Elderly Population

The primary endpoint is to demonstrate the efficacy of StemEx® vs. unmanipulated UCB transplantation in the elderly population (\>55years of age) following RIC regimen by demonstrating engraftment with full donor chimerism (\>98%) by Day 100 of more than 60% of the patients who received transplants expanded by the StemEx method.

The day of neutrophil engraftment is defined as the first day of 3 consecutive days of an ANC greater than 500/microliter. The platelet recovery is the first of 3 consecutive measurements tested on different days of a platelet count greater than or equal to 20,000 without requiring platelet transfusions in the previous 7 days. Patients will be monitored for donor cell engraftment as evidenced by neutrophil recovery and donor chimerism in the marrow and/or peripheral blood at serial time points post transplant.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
UM171 Expanded Cord Blood In Patients With High-Risk Acute Leukemia/Myelodysplasia	NCT03913026	High Risk Hemat... Cord Blood Tran...	Transplant with...	18 Years - 70 Years	Ciusss de L'Est de l'Île de Montréal
Umbilical Cord Transplantation for the Elderly Population	NCT01484470	Hematologic Mal...	StemEx	55 Years - 73 Years	Loyola University
UM171 Expanded Cord Blood In Patients With High-Risk Acute Leukemia/Myelodysplasia	NCT03913026	High Risk Hemat... Cord Blood Tran...	Transplant with...	18 Years - 70 Years	Ciusss de L'Est de l'Île de Montréal
Umbilical Cord Transplantation for the Elderly Population	NCT01484470	Hematologic Mal...	StemEx	55 Years - 73 Years	Loyola University

Spots Global Cancer Trial Database for stem cell expansion