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The GVHD prophylaxis regimen on the experimental arm will consist of high dose Cyclophosphamide on Days +3 and +4 followed by abatacept for 6 months. Abatacept at a dose of 10mg/kg will be administered on days +5, +14 and +28, +56, +84, +112, +140, +168

The GVHD prophylaxis regimen on the standard of care arm will consist of methotrexate on Days +1,+3, +6 and +11 and tacrolimus

Day 3 and day 4 following transplant. Dosing will be based on patients' actual weight up to 120% of ideal body weight, above which it will be based on adjusted ideal body weight (ideal weight plus 50% of the difference between ideal and actual weight).

Abatacept at a dose of 10mg/kg will be administered on days +5, +14 and +28, +56, +84, +112, +140, +168

abatacept

standard of care Methotrexate 5 mg/m2 on Days 1, 3, 6 and 11

Dimitrios Tzachanis, MD PhD

Divya Koura, MD

The purpose of this study is to investigate whether the combination of cyclophosphamide and abatacept versus the treatment used in standard of care will reduce the incidence of moderate and severe chronic graft-versus-host disease (GVHD) following hematopoietic stem cell transplantation. GVHD occurs when the cells from your donor (the graft) see your body's cells (the host) as different and attack them.

The experimental GVHD prophylaxis arm consists of cyclophosphamide and abatacept. Cyclophosphamide induces apoptosis of activated T cells and abatacept (CTLA4Ig) blocks activation of T cells by inhibiting the co-stimulatory signal.

Compared to the standard-of-care control arm, the experimental arm is much more convenient and expected to be associated with fewer toxicities.

In addition there is a great theoretical potential for immunological synergy between cyclophosphamide and abatacept for inducing post-transplant immunologic tolerance that clinically might translate into less GVHD without increase in relapse Patients will be randomized 1:1 to the experimental vs the standard of care arm. Randomization will be done prior to the use of any conditional therapy.

The two arms will be stratified by disease (acute leukemia vs others) and donor type (MRD vs MUD/MUD vs Haplo) in an effort to keep them balanced.

The conditioning regimen for both arms will be mainly Busulfan/Fludarabine (A Total Body Irradiation based conditioning regimen will be allowed for diseases such as ALL)

The GVHD prophylaxis regimen on the experimental arm will consist of high dose Cyclophosphamide on Days +3 and +4 followed by abatacept for 6 months.

The GVHD prophylaxis regimen on the standard of care arm will consist of methotrexate on Days +1,+3, +6 and +11 and tacrolimus for patients with a 10/10 matched related or unrelated donor and of high dose cyclophosphamide on Days +3 and +4 followed by tacrolimus and mycophenolate for patients with a haploidentical donor.

Comparing Cyclophosphamide and Abatacept With Standard of Care Treatment Following Stem Cell Transplantation

A Randomized Phase II Trial Comparing a Calcineurin Inhibitor-free Graft-versus-host Disease Prophylaxis Regimen With Post-transplantation Cyclophosphamide and Abatacept to Standard of Care

The occurrence of moderate and severe chronic GVHD at one year post Chronic GVHD will be diagnosed and staged according to the previously published and widely accepted National Institutes of Health consensus criteria

GVHD- and relapse- free survival will be defined as the absence of acute GVHD Grade III or IV or moderate or severe chronic GVHD or relapse or non-relapse mortality by one year post transplant. Acute GVHD will be diagnosed and graded according to Glucksberg criteria

Bristol-Myers Squibb

Assistant Clinical Professor of Medicine

Symptoms and General Pathology

Leukemia

Preleukemia

Myelodysplastic Syndromes

Syndrome

Bone Marrow Diseases

Precancerous Conditions

Acute Graft Versus Host Disease

Fludarabine

Fludarabine phosphate

Thiotepa

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.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Comparing Cyclophosphamide and Abatacept With Standard of Care Treatment Following Stem Cell Transplantation	NCT03680092	GVHD Hematologic Neo...	Cyclophosphamid... abatacept Methotrexate Tacrolimus	18 Years -	University of California, San Diego
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
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
Comparing Cyclophosphamide and Abatacept With Standard of Care Treatment Following Stem Cell Transplantation	NCT03680092	GVHD Hematologic Neo...	Cyclophosphamid... abatacept Methotrexate Tacrolimus	18 Years -	University of California, San Diego

Spots Global Cancer Trial Database for high risk hematologic malignancy