US Study of ECT-001-CB in Pediatric and Young Adult Patients With High-Risk Myeloid Malignancies

Study Overview
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Brief Summary
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Cord blood (CB) transplants are an option for patients lacking an HLA identical donor but are hampered by low cell dose, prolonged aplasia and high transplant related mortality. UM171, a novel and potent agonist of hematopoietic stem cell self renewal could solve this major limitation, allowing for CB's important qualities as lower risk of chronic GVHD and relapse to prevail. In previous trials (NCT02668315, NCT03913026, NCT04103879, and NCT03441958), the CB expansion protocol using the ECT-001-CB technology (UM171 molecule) has proven to be technically feasible and safe in adults. UM171 expanded CB was associated with a prompt (D+17), robust (98%) and durable neutrophil recovery. Amongst patients who received a single UM171 CB transplant with a median follow-up of 18 months, risk of TRM (10%), grade 3-4 acute GVHD (13%) and moderate-severe chronic GVHD (2%) was low at 1 year post-transplant. Incidence of severe viral and bacterial infections was reduced and immunosuppression could be discontinued in 77% of patients at 1 year. Thus, PFS and GRFS were very promising, 72% and 59% at 12 months, 69% and 53% at 24 months, respectively, in particular accounting for a large proportion of very high-risk patients. By a 10-fold increase of CB accessibility, ECT-001-CB allowed access to smaller, better HLA matched CBs. This new study seeks to test a similar strategy in a group of pediatric and young adult patients with high risk myeloid malignancies. 12 patients will be enrolled in the first stage of this 2-stage design protocol. If intervention is considered promising (<= 3 relapses in the first 12 patients), this study will open multicenter and be extended to a second stage (16 additional patients for a total accrual 28).

Official Title
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A Phase I/II Open-Label Study of ECT-001-Expanded Cord Blood Transplantation in Pediatric and Young Adult (<21year) Patients With High-Risk and Very High-Risk Myeloid Malignancies

Conditions
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High Risk Myeloid Malignancies, Cord Blood Transplant

Intervention / Treatment
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* Biological: ECT-001-CB (UM171-Expanded Cord Blood Transplant)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Acute Myeloid Leukemia Chemo-refractory relapse (MRD+) Primary induction failure (no CR or CRi after >= 2 courses of intensive induction therapy): < 30% blasts in evaluable marrow. Relapse after previous allogeneic (or autologous) transplant (>4 months) Secondary or therapy-related MDS/AML Poor response to induction (5-30% blasts) or MDR+ after induction Myelodysplastic syndrome (MDS) Relapse after allogeneic or autologous transplant (>4 months) ≥10 % blasts within 30 days of start of conditioning regimen Poor and very poor cytogenetics abnormalities Chronic myelogenous leukemia: Patients who progressed to blast crisis Mixed Phenotype Acute Leukemia: MRD+ or relapse after previous transplant (>4 months). JMML (Juvenile Myelo-Monocytic Leukemia) Availability of 2 ≥ 4/8 HLA matched CBU (allele level: A, B, C and DRB1) Cord to be expanded: CD34+ cell count ≥ 0.5 x 10^5/kg and TNC ≥ 1.5 x 10^7/kg (pre-cryo) Back up cord: Pre-freeze TNC ≥ 2 x 10^7/kg with CD34+ cells ≥ 1.5 x 10^5/kg. If a single cord does not meet this criterion 2 back up cords will be an acceptable alternative with a minimum for each of 1.5 x 10^7 TNC/kg with 1.0 x 10^5 CD34+/kg. Another acceptable HSC back up source could be a haploidentical with medical clearance prior to starting conditioning regimen. Lansky / Karnofsky >60% Bilirubin < 2 x upper limit of normal (ULN) unless felt to be related to Gilbert's disease or hemolysis; AST and ALT < 3 x ULN; alkaline phosphatase < 5 x ULN Estimated or measured creatinine clearance ≥ 50ml/min/1.73m2 Left ventricular ejection fraction of ≥ 40% FVC, FEV1 and DLCO ≥ 50% of predicted Signed written informed consent Female patients of childbearing potential must have a negative serum pregnancy test within 7 days of enrolment and mush be willing to use an effective contraceptive method while enrolled in the study. Exclusion Criteria: Previous allogeneic transplantation within 4 months. Uncontrolled infection. Presence of other malignancy other than the one for which the CB transplant is being performed, with an expected survival to be less than 75% at 5 years Seropositive for HIV. Hep B and C infection with measurable viral load. Liver cirrhosis. Active CNS disease. Chloroma > 2cm. >30% blasts in marrow in evaluable marrow sample. Pregnancy, breastfeeding, or unwillingness to use appropriate contraception Participation in a trial with an investigational agent within 30days prior to entry in the study. Any abnormal condition or lab result that is considered by the PI capable or altering patient's condition or study outcome.

Ages Eligible for Study
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Minimum Age: 0 Years
Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ECT-001-Expanded CB<br>Patients will receive a myeloablative conditioning regimen (Preferred: Clo/Flu/Bu90, Alternative: MIDI) 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. Patients will receive standard supportive care and GVHD prophylaxis (such as MMF and tacrolimus). | Biological: ECT-001-CB (UM171-Expanded Cord Blood Transplant)<br>* Single UM171-Expanded CB transplant (CD34+: 2.5-50x10^5/kg, CD3+>1x10^6/kg)<br>* Other names: GVHD Prophylaxis: Tacrolimus/MMF;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events of ECT-001-CB | Incidence and severity of AEs according to the modified (for HSCT) CTCAE (v. 5.0) | 100 days | 
| Relapse | Incidence of relapse will be measured from time of transplant | 1 year post-transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Leukemia-free survival | LFS will be measured from time of transplant until disease relapse, death or last follow-up | 1- and 2-year post-transplant | 
| Non-Relapse Mortality | NRM 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 | 1 year post-transplant | 
| GVHD | Incidence of acute and chronic GVHD will be measured by NIH criteria | 1- and 2-year post-transplant | 
| Grade 3 Infections | Incidence and severity of infections requiring systemic therapy, e.g., invasive candidiasis, aspergillus, other invasive fungi, CMV, adenovirus, EBV, HHV-6, HSV, VZV, PCP, toxoplasmosis and mycobacterium | 2-year post-transplant | 
| Hematologic engraftment | Time to neutrophil engraftment (the first day of attainment of an absolute neutrophil count ≥0.5 x 10E9/L for 3 consecutive days. Time to ANC ≥ 0.1 x 10E9/L will also be documented) and time to platelet engraftment (first day of a sustained platelet count ≥ 50 x 10E9/L with no platelet transfusion in the preceding 7 days) | 42 and 100 days | 
| Pre-engraftment/engraftment syndrome | Incidence of pre-engraftment/engraftment syndrome requiring therapy | 2-year post-transplant | 
| Hospitalization events | Duration of transplant admission and number of days in hospital in 1st 100 days, and last day of fever (>38°C) prior to engraftment | 100 days |