US Study of UM171-Expanded CB in Patients With High Risk Leukemia/Myelodysplasia

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 a previous 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 patients with high-risk hematologic malignancies and multiple comorbidities (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. This new study seeks to test a similar strategy in a group of patients with high risk acute leukemia/myelodysplasia.

Official Title
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A Phase II Open-Label Study of UM171-Expanded Cord Blood Transplantation in Patients With High and Very High Risk Acute Leukemia/Myelodysplasia

Conditions
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High Risk Hematological Malignancy, 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: High and very high-risk hematologic malignancy defined as: Acute Myeloid Leukemia (Primary induction failure, Chemorefractory relapse, Relapse after allogeneic or autologous transplant, High risk AML in CR1, ≥ CR2) Acute Lymphoid leukemia (Primary induction failure, High risk ALL in CR1, ≥ CR2, Chemorefractory relapse, Relapse after allogeneic or autologous transplant) Myelodysplastic syndrome (Relapse after allogeneic or autologous transplant, ≥10% blasts within 30 days of start of conditioning regimen, Poor and very poor cytogenetics abnormalities, CMML with HCT-specific CPSS score high or intermediate-2, Stable disease, Progressive disease while on azacitidine). Chronic myelogenous leukemia (Patients who progressed to blast crisis) Availability of 2 CBs ≥ 4/6 HLA match with pre-freeze CD34+ cell count ≥0.5 x 10E5/kg and TNC≥1.5 x 10E7/kg Karnofsky ≥70. LVE fraction ≥ 40% or fractional shortening >22% FVC, FEV1 and DLCOc ≥ 50% of predicted Bilirubin < 2 x ULN; AST and ALT ≤ 2.5 x ULN; alkaline phosphatase ≤ 5 x ULN. Creatinine < 2.0 mg/dl. HCT-CI ≤3 if patients have ≥5% blasts in the bone marrow and HCT-CI ≤5 if 60-65 years old. Exclusion Criteria: Allogeneic myeloablative transplant within 6 months. Autologous hematopoietic stem cell transplant within 6 months. Active or recent invasive fungal infection. Presence of a malignancy other than the one for which the UCB transplant is being performed and the expected survival related to the malignancy is estimated to be less than 75% at 5 years. HIV positivity. Hepatitis B or C infection with measurable viral load. Liver cirrhosis. Pregnancy, breastfeeding or unwillingness to use appropriate contraception. Any abnormal condition or laboratory result that is considered by the principal investigator capable of altering patient condition or study outcome. Active central nervous system involvement. Chloroma > 2 cm.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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. 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>* Conditioning: High dose TBI (1320 cGy TBI + Fludarabine 75 mg/m2 + Cyclophosphamide 120 mg/kg) or Intermediate Intensity regimen (400 cGy TBI + Fludarabine 150 mg/m2 + Cyclophosphamide 50 mg/kg + Thiotepa 10 mg/kg). Single UM171-Expanded CB transplant (CD34+: 2.5-50x10E5/kg, CD3+>1x10E6/kg) Immunosuppression: Tacrolimus/MMF<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events of ECT-001-CB | All AEs will be graded in severity according to the modified (for HSCT) CTCAE (v. 5.0) | 100 days post-transplant | 
| Adverse events of ECT-001-CB | All AEs will be graded in severity according to the modified (for HSCT) CTCAE (v. 5.0) | 2 years post-transplant | 
| Relapse-free survival | RFS will be measured from time of transplant until disease relapse, death or last follow-up | At 1-year post-transplant | 
| Relapse-free survival | RFS will be measured from time of transplant until disease relapse, death or last follow-up | At 2-year post-transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Neutrophil and Platelet engraftment | 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 platelet engraftment (first day of a sustained platelet count ≥ 20 x 10E9/L with no platelet transfusion in the preceding 7 days) | First 60 days | 
| Incidence of transplant related mortality | 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 | At day 100 post-transplant | 
| Incidence of transplant related mortality | 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 | At 1-year post-transplant | 
| Incidence of GVHD | Acute and chronic GVHD by NIH criteria | At 2 years post-transplant | 
| Incidence of grade 3 or higher infectious complications | Any of infections requiring systemic therapy, e.g., invasive candidiasis, aspergillus, other invasive fungi, CMV, adenovirus, EBV, HHV-6, HSV, VZV, PCP, toxoplasmosis and mycobacterium | At 2 years post-transplant | 
| Incidence of pre-engraftment/engraftment syndrome requiring therapy |  | At 2 years post-transplant | 
| GRFS and CRFS | GRFS and CRFS will be measured from time of transplant until disease relapse, death or last follow-up | At 1-year post-transplant | 
| GRFS and CRFS | GRFS and CRFS will be measured from time of transplant until disease relapse, death or last follow-up | At 2-year post-transplant |